Influenza, biasa disebut sebagai flu, adalah penyakit menular yang disebabkan oleh virus RNA dari keluarga Orthomyxoviridae (virus influenza), yang mempengaruhi burung dan mamalia.

Gejala yang paling umum dari penyakit ini menggigil, demam, sakit tenggorokan, nyeri otot, sakit kepala parah, batuk, kelemahan / kelelahan dan ketidaknyamanan umum. Sakit tenggorokan, demam dan batuk adalah gejala yang paling sering.

Dalam kasus yang lebih serius, influenza menyebabkan pneumonia, yang bisa berakibat fatal, terutama bagi kaum muda dan orang tua. Meskipun sering bingung dengan lain seperti penyakit influenza, terutama pilek, influenza adalah penyakit yang lebih parah daripada flu biasa dan disebabkan oleh berbagai jenis virus.

Influenza dapat menghasilkan mual dan muntah, terutama pada anak,

Biasanya, influenza ditularkan melalui udara dengan batuk atau bersin, membuat aerosol yang mengandung virus. Influenza juga dapat ditularkan melalui kontak langsung dengan kotoran burung atau sekret hidung, atau melalui kontak dengan permukaan yang terkontaminasi.

Aerosol Airborne telah dianggap menyebabkan infeksi yang paling, walaupun yang berarti transmisi yang paling penting adalah tidak benar-benar jelas. Seperti virus dapat dilemahkan oleh sabun, sering mencuci tangan mengurangi risiko infeksi.

Influenza menyebar di seluruh dunia dalam wabah musiman, yang mengakibatkan kematian antara dan orang setiap tahun, sampai jutaan dalam beberapa tahun pandemi.

Rata-rata 41.400 orang meninggal setiap tahun di Amerika Serikat antara 1979 dan 2001 dari influenza.

Tiga Pandemi influenza terjadi pada abad ke-20 dan membunuh puluhan juta orang, dengan masing-masing pandemi disebabkan oleh munculnya strain baru virus pada manusia.

Seringkali, strain baru muncul ketika sebuah virus flu yang ada menyebar ke manusia dari spesies hewan lain, atau ketika suatu strain manusia yang ada mengambil gen baru dari virus yang biasanya menginfeksi burung atau babi.

Strain burung bernama H5N1 mengangkat keprihatinan pandemi influenza baru, setelah itu muncul di Asia pada 1990-an, tetapi tidak berkembang ke bentuk yang menyebar dengan mudah di antara manusia.

Pada bulan April 2009 strain flu baru berkembang bahwa gen gabungan dari manusia, babi, dan flu burung, awalnya dijuluki "flu babi" dan juga dikenal sebagai influenza H1N1, muncul di Meksiko, Amerika Serikat, dan negara-negara lainnya.

Organisasi Kesehatan Dunia menyatakan secara resmi untuk menjadi wabah pandemi pada tanggal 11 Juni 2009. Pernyataan WHO dari tingkat pandemi 6 merupakan indikasi penyebaran, bukan tingkat keparahannya, ketegangan benar-benar memiliki tingkat kematian lebih rendah dari wabah flu biasa.

Vaksinasi terhadap influenza biasanya diberikan kepada orang-orang di negara maju dan unggas ternak.

Vaksin manusia yang paling umum adalah vaksin influenza trivalen (TIV) yang berisi materi dimurnikan dan tidak aktif dari tiga strain virus. Biasanya, vaksin ini meliputi bahan dari dua subtipe virus influenza A dan satu jenis B virus influenza.

Para TIV tidak membawa risiko penularan penyakit, dan memiliki reaktivitas sangat rendah. Sebuah vaksin diformulasikan untuk satu tahun mungkin tidak efektif pada tahun berikutnya, karena virus influenza berkembang cepat, dan strain baru dengan cepat menggantikan yang lebih tua.

Obat antivirus dapat digunakan untuk mengobati influenza, dengan inhibitor neuraminidase yang sangat efektif.

Para''Kata''Influenza berasal dari bahasa Italia yang berarti "pengaruh" dan mengacu pada penyebab penyakit, awalnya, ini dianggap penyakit untuk pengaruh astrologi tidak menguntungkan.

Perubahan dalam berpikir medis menyebabkan modifikasi untuk''influenza del freddo'', yang berarti "pengaruh dingin".

Para''Kata''influenza pertama kali digunakan dalam bahasa Inggris pada 1743 ketika itu diadopsi, dengan pengucapan inggris, selama wabah penyakit di Eropa.

Istilah kuno untuk influenza termasuk''epidemi penyakit selesema'',''penyakit influensa''(dari Perancis),''berkeringat''penyakit, dan''demam''Spanyol (khususnya untuk strain pandemi flu 1918).

Archive for the ‘Tuberculosis’ Category

Symptoms and cure of tuberculosis

Tuberculosis is caused due to infection with the mycobacterium tuberculosis, but everyone, who gets contaminated with the germ, does not get the disease. Most of the time, the immune system can prevent you from becoming sick and only about 10% of people infected with tuberculosis go to on to develop tuberculosis. The symptoms of tuberculosis do not become evident in most cases, unless the disease has advanced.

The common symptoms of tuberculosis include cough for a prolonged duration that is more than three weeks, unexplained or intended weight loss, fatigue, general feeling of tiredness, fever, sweating at night, chills and loss of appetite. Having these signs and symptoms does not mean that you have tuberculosis. There are many other diseases which have the same symptoms. So you need to undergo various tests, so that you are sure that you have tuberculosis. Signs and symptoms of active tuberculosis may also vary depending on the organ that is affected. Most of the times, the lungs of the patients are affected. Symptoms of tuberculosis of the lungs include cough for three or more weeks, blood in cough, chest pain or pain while breathing or coughing. Tuberculosis can also affect organs apart from the lungs. The other organs that are affected by tuberculosis include lymph nodes, genitourinary nodes, bone and joint sites, lining covering the outside of the gastrointestinal tract.

Penyakit Pernapasan

(Bronchitis)

Definisi Bronchitis

Bronchitis adalah penyakit pernapasan dimana selaput lendir pada saluran-saluran bronchial paru meradang. Ketika selaput yang teriritasi membengkak dan tumbuh lebih tebal, ia menyempitkan atau menutup jalan-jalan udara yang kecil dalam paru-paru, berakibat pada serangan-serangan batuk yang disertai oleh dahak yang tebal dan sesak napas. Penyakit mempunyai dua bentuk: akut (berlangsung kurang dari 6 minggu) dan kronis (kambuh seringkali untuk lebih dari dua tahun). Sebagai tambahan, orang-orang dengan asma juga mengalami peradangan lapisan dari tabung-tabung bronchial yang disebut asthmatic bronchitis.

Bronchitis akut bertanggung jawab untuk batuk kering dan produksi dahak yang adakalanya disertai infeksi pernapasan bagian atas. Pada kebanyakan kasus-kasus infeksi berasal dari virus, namun adakalanya ia disebabkan oleh bakteri. Jika sebaliknya anda dalam kesehatan yang baik, selaput lendir akan kembali normal setelah anda telah sembuh dari infeksi awal paru, yang biasanya berlangsung beberapa hari.

Bronchitis kronis adalah kekacauan jangka panjang yang serius yang seringkali memerlukan perawatan medis yang teratur.

Jika anda adalah seorang perokok dan mendapat bronchitis akut, akan lebih sulit untuk anda sembuh. Bahkan satu isapan pada rokok adalah cukup untuk menyebabkan kelumpuhan sementara dari struktur-struktur yang seperti rambut halus dalam paru-paru anda, yang disebut cilia, yang bertanggung jawab untuk menyikat keluar puing-puing, iritan-iritan, dan lendir yang berlebihan.

Jika anda melanjutkan merokok, anda mungkin melakukan kerusakan yang cukup pada cilia ini untuk mencegah mereka dari berfungsi dengan benar, jadi meningkatkan kesempatan-kesempatan anda mengembangkan bronchitis kronis. Pada beberapa perokok-perokok berat, selaputnya terus meradang dan cilia akhirnya berhenti berfungsi semuanya. Tersumbat dengan lendir, paru-paru kemudian menjadi mudah diserang infeksi-infeksi virus dan bakteri, yang melalui waktu mengubah/menyimpangkan dan merusak secara permanen saluran-saluran udara paru. Kondisi permanen ini disebut penyakit rintangan paru kronis atau COPD (chronic obstructive pulmonary disease). Dokter anda dapat melakukan tes pernapasan, yang disebut spirometry, untuk melihat apakah anda telah mengembangkan COPD.

Bronchitis akut adalah sangat umum diantara keduanya anak-anak dan kaum dewasa. Kekacauan sering dapat dirawat secara efektif tanpa bantuan medis dokter. Bagaimanapun, jika anda mempunyai gejala-gejala yang berat/parah atau gigih atau jika anda membatukan darah, anda harus mengunjungi dokter anda. Jika anda menderita dari bronchitis kronis, anda berisiko mengembangkan persoalan-persoalan kardiovaskular serta penyakit-penyakit dan infeksi-infeksi paru yang lebih serius, anda harus dimonitor oleh dokter.

Carbon monoxideFrom Wikipedia, the free encyclopediaJump to: navigation, search

Carbon monoxide

Preferred IUPAC name[hide]

Carbon monoxideOther names[hide]

Carbon monooxideCarbonous oxideCarbon(II) oxide

CarbonylIdentifiers

CAS number 630-08-0

PubChem 281 ChemSpider 275

UNII 7U1EE4V452

EC number 211-128-3UN number 1016KEGG D09706

MeSH Carbon+monoxideChEBI CHEBI:17245

RTECS number FG3500000Beilstein Reference 3587264

Gmelin Reference 421Jmol-3D images Image 1

SMILES[show]

InChI[show]

PropertiesMolecular formula COMolar mass 28.010 g/molAppearance colourless gasOdor odorless

Density789 kg/m3, liquid1.250 kg/m3 at 0 °C, 1 atm1.145 kg/m3 at 25 °C, 1 atm

Melting point −205.02 °C, 68 K, -337 °FBoiling point −191.5 °C, 82 K, -313 °FSolubility in water 27.6 mg/1 L (25 °C)Solubility soluble in chloroform, acetic acid, ethyl

acetate, ethanol, ammonium hydroxide, benzene

Refractive index (nD) 1.0003364

Dipole moment 0.122 DThermochemistry

Std enthalpy offormation ΔfHo

298−110.5 kJ·mol−1

Standard molarentropy So

298198 J·mol−1·K−1

HazardsMSDS External MSDSEU Index 006-001-00-2

EU classificationF T

R-phrases R61 R12 R26 R48/23S-phrases S53 S45

NFPA 704 442

Flash point −191 °C (82 K; −311.8 °F)Autoignitiontemperature 609 °C (882 K; 1,128 °F)

Related compounds

Related carbon oxides

Carbon dioxideCarbon suboxideOxocarbons

Supplementary data pageStructure andproperties n, εr, etc.

Thermodynamicdata

Phase behaviourSolid, liquid, gas

Spectral data UV, IR, NMR, MS (verify) (what is: / ?)

Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Infobox references

Carbon monoxide (C O ) is a colorless, odorless, and tasteless gas that is slightly lighter than air. It is toxic to humans and animals when encountered in higher concentrations, although it is also produced in normal animal metabolism in low quantities, and is thought to have some normal biological functions. In the atmosphere it is spatially variable, short lived, having a role in the formation of ground-level ozone.

Carbon monoxide consists of one carbon atom and one oxygen atom, connected by a triple bond that consists of two covalent bonds as well as one dative covalent bond. It is the simplest oxocarbon, and isoelectronic with the cyanide ion and molecular nitrogen. In coordination complexes the carbon monoxide ligand is called carbonyl.

Carbon monoxide is produced from the partial oxidation of carbon-containing compounds; it forms when there is not enough oxygen to produce carbon dioxide (CO2), such as when operating a stove or an internal combustion engine in an enclosed space. In the presence of oxygen, carbon monoxide burns with a blue flame, producing carbon dioxide.[1] Coal gas, which was widely used before the 1960s for domestic lighting, cooking, and heating, had carbon monoxide as a significant constituent. Some processes in modern technology, such as iron smelting, still produce carbon monoxide as a byproduct.[2]

Worldwide, the largest source of carbon monoxide is natural in origin, due to photochemical reactions in the troposphere that generate about 5 x 1012 kilograms per year.[3] Other natural sources of CO include volcanoes, forest fires, and other forms of combustion.

In biology, carbon monoxide is naturally produced by the action of heme oxygenase 1 and 2 on the heme from hemoglobin breakdown. This process produces a certain amount of carboxyhemoglobin in normal persons, even if they do not breathe any carbon monoxide. Following the first report that carbon monoxide is a normal neurotransmitter in 1993,[4][5] as well as one of three gases that naturally modulate inflammatory responses in the body (the other two being nitric oxide and hydrogen sulfide), carbon monoxide has received a great deal of clinical attention as a biological regulator. In many tissues, all three gases are known to act as anti-inflammatories, vasodilators, and promoters of neovascular growth.[6] Clinical trials of small amounts of carbon monoxide as a drug are ongoing.

Sulfur dioxideFrom Wikipedia, the free encyclopediaJump to: navigation, search

Sulfur dioxide

IUPAC name[hide]

Sulfur dioxideOther names[hide]

Sulfurous anhydrideSulfur(IV) oxide

IdentifiersCAS number 7446-09-5

PubChem 1119ChemSpider 1087

UNII 0UZA3422Q4

EC number 231-195-2UN number 1079, 2037KEGG D05961

MeSH Sulfur+dioxideChEBI CHEBI:18422

ChEMBL CHEMBL1235997

RTECS number WS4550000Beilstein Reference 3535237Gmelin Reference 1443Jmol-3D images Image 1

SMILES[show]

InChI[show]

PropertiesMolecular formula SO2

Molar mass 64.066 g mol−1

Appearance Colorless gasDensity 2.6288 kg m−3

Melting point -72 °C, 201 K, -98 °F

Boiling point −10 °C, 263 K, 14 °FSolubility in water 94 g dm−3[1]

Vapor pressure 237.2 kPaAcidity (pKa) 1.81Basicity (pKb) 12.19Viscosity 0.403 cP (at 0 °C)

StructureSpace group C2v

Coordinationgeometry Digonal

Molecular shape DihedralDipole moment 1.62 D

ThermochemistryStd enthalpy offormation ΔfHo

298-296.81 kJ mol−1

Standard molarentropy So

298248.223 J K−1 mol−1

HazardsEU Index 016-011-00-9

EU classificationT

R-phrases R23, R34, R50S-phrases (S1/2), S9, S26, S36/37/39, S45

NFPA 704 030

LD50 3000 ppm (30 min inhaled, mouse)Related compounds

Related sulfur oxides Sulfur monoxideSulfur trioxide

Related compounds

Ozone

Selenium dioxideSulfurous acidTellurium dioxide

(verify) (what is: / ?)Except where noted otherwise, data are given for materials

in their standard state (at 25 °C, 100 kPa) Infobox references

Sulfur dioxide (also sulphur dioxide) is the chemical compound with the formula S O 2. It is a toxic gas with a pungent, irritating smell, that is released by volcanoes and in various industrial processes. Since coal and petroleum often contain sulfur compounds, their

combustion generates sulfur dioxide unless the sulfur compounds are removed before burning the fuel. Further oxidation of SO2, usually in the presence of a catalyst such as NO2, forms H2SO4, and thus acid rain.[2] Sulfur dioxide emissions are also a precursor to particulates in the atmosphere. Both of these impacts are cause for concern over the environmental impact of these fuels.

Contents

1 Structure and bonding 2 Production

o 2.1 Combustion routes o 2.2 Reduction of higher oxides o 2.3 From sulfite

3 Reactions o 3.1 Industrial reactions o 3.2 Laboratory reactions

4 Uses o 4.1 Precursor to sulfuric acid o 4.2 As a preservative o 4.3 In winemaking o 4.4 As a reducing agent o 4.5 Biochemical and biomedical roles o 4.6 As a refrigerant o 4.7 As a reagent and solvent in the laboratory

5 As an air pollutant 6 Safety

o 6.1 Inhalation o 6.2 Ingestion

7 See also 8 References 9 External links

Structure and bonding

SO2 is a bent molecule with C2v symmetry point group. In terms of electron-counting formalism, the sulfur atom has an oxidation state of +4 and a formal charge of +1.

Two resonance structures of sulfur dioxide

Sulfur and oxygen both have six valence electrons and the molecular bonds in SO2 are shown to be the same as those in ozone. Computational chemistry (using Natural bond orbitals) has found that d-orbitals are not involved in main group chemical bonding (see Hypervalent molecule). Hence, a Lewis structure consisting of an S–O dative sigma bond and an S=O pi

bond is the optimum description, resulting in a bond order of 1.5, like the O–O bonds in ozone.[3]

Production

Combustion routes

Sulfur dioxide is the product of the burning of sulfur or of burning materials that contain sulfur:

S8 + 8 O2 → 8 SO2

The combustion of hydrogen sulfide and organosulfur compounds proceeds similarly.

2 H2S + 3 O2 → 2 H2O + 2 SO2

The roasting of sulfide ores such as pyrite, sphalerite, and cinnabar (mercury sulfide) also releases SO2:[4]

4 FeS2 + 11 O2 → 2 Fe2O3 + 8 SO2

2 ZnS + 3 O2 → 2 ZnO + 2 SO2

HgS + O2 → Hg + SO2

4 FeS + 7O2 → 2 Fe2O3 + 4 SO2

A combination of these reactions is responsible for the largest source of sulfur dioxide, volcanic eruptions. These events can release millions of tonnes of SO2.

Reduction of higher oxides

Sulfur dioxide is a by-product in the manufacture of calcium silicate cement: CaSO4 is heated with coke and sand in this process:

2 CaSO4 + 2 SiO2 + C → 2 CaSiO3 + 2 SO2 + CO2

The action of hot sulfuric acid on copper turnings produces sulfur dioxide.

Cu + 2 H2SO4 → CuSO4 + SO2 + 2 H2O

From sulfite

Sulfite results from the reaction of aqueous base and sulfur dioxide. The reverse reaction involves acidification of sodium metabisulfite:

H2SO4 + Na2S2O5 → 2 SO2 + Na2SO4 + H2O

Reactions

Industrial reactions

Treatment of basic solutions with sulfur dioxide affords sulfite salts:

SO2 + 2 NaOH → Na2SO3 + H2O

Featuring sulfur in the +4 oxidation state, sulfur dioxide is a reducing agent. It is oxidized by halogens to give the sulfuryl halides, such as sulfuryl chloride:

SO2 + Cl2 → SO2Cl2

Sulfur dioxide is the oxidising agent in the Claus process, which is conducted on a large scale in oil refineries. Here sulfur dioxide is reduced by hydrogen sulfide to give elemental sulfur:

SO2 + 2 H2S → 3 S + 2 H2O

The sequential oxidation of sulfur dioxide followed by its hydration is used in the production of sulfuric acid.

2 SO2 + 2 H2O + O2 → 2 H2SO4

Laboratory reactions

Sulfur dioxide can react with certain 1,3-dienes in a cheletropic reaction to give organosulfur compounds.

Sulfur dioxide can bind to metal ions as a ligand to form metal sulfur dioxide complexes, typically where the transition metal is in oxidation state 0 or +1. Many different bonding modes (geometries) are recognized, but in most cases the ligand is monodentate, attached to the metal through sulfur, which can be either planar and pyramidal η1.[3]

Uses

Precursor to sulfuric acid

Sulfur dioxide is an intermediate in the production of sulfuric acid, being converted to sulfur trioxide, and then to oleum, which is made into sulfuric acid. Sulfur dioxide for this purpose is made when sulfur combines with oxygen. The method of converting sulfur dioxide to sulfuric acid is called the contact process. Several billion kilograms are produced annually for this purpose.

As a preservative

Sulfur dioxide is sometimes used as a preservative for dried apricots, dried figs, and other dried fruits owing to its antimicrobial properties, and it is sometimes called E220 when used in this way. As a preservative, it maintains the colorful appearance of the fruit and prevents rotting. It is also added to sulfured molasses.

In winemaking

Sulfur dioxide is an important compound in winemaking, and is designated as parts per million in wine, E number: E220.[5] It is present even in so-called unsulfurated wine at concentrations of up to 10 mg/L.[6] It serves as an antibiotic and antioxidant, protecting wine from spoilage by bacteria and oxidation. Its antimicrobial action also helps to minimize

volatile acidity. Sulfur dioxide is responsible for the words "contains sulfites" found on wine labels.

Sulfur dioxide exists in wine in free and bound forms, and the combinations are referred to as total SO2. Binding, for instance to the carbonyl group of acetaldehyde, varies with the wine in question. The free form exists in equilibrium between molecular SO2 (as a dissolved gas) and bisulfite ion, which is in turn in equilibrium with sulfite ion. These equilibria depend on the pH of the wine. Lower pH shifts the equilibrium towards molecular (gaseous) SO2, which is the active form, while at higher pH more SO2 is found in the inactive sulfite and bisulfite forms. It is the molecular SO2 which is active as an antimicrobial and antioxidant, and this is also the form which may be perceived as a pungent odour at high levels. Wines with total SO2 concentrations below 10 parts per millon (ppm) do not require "contains sulfites" on the label by US and EU laws. The upper limit of total SO2 allowed in wine in the US is 350 ppm; in the EU it is 160 ppm for red wines and 210 ppm for white and rosé wines. In low concentrations, SO2 is mostly undetectable in wine, but at free SO2 concentrations over 50 ppm, SO2 becomes evident in the nose and taste of wine.[citation needed]

SO2 is also a very important compound in winery sanitation. Wineries and equipment must be kept clean, and because bleach cannot be used in a winery due the risk of cork taint,[7] a mixture of SO2, water, and citric acid is commonly used to clean and sanitize equipment. Compounds of ozone (O3) are now used extensively as cleaning products in wineries[citation

needed] due to their efficiency, and because these compounds do not affect the wine or equipment.

As a reducing agent

Sulfur dioxide is also a good reductant. In the presence of water, sulfur dioxide is able to decolorize substances. Specifically it is a useful reducing bleach for papers and delicate materials such as clothes. This bleaching effect normally does not last very long. Oxygen in the atmosphere reoxidizes the reduced dyes, restoring the color. In municipal wastewater treatment, sulfur dioxide is used to treat chlorinated wastewater prior to release. Sulfur dioxide reduces free and combined chlorine to chloride.[8]

Sulfur dioxide is fairly soluble in water, and by both IR and Raman spectroscopy, it is known that the hypothetical sulfurous acid, H2SO3, is not present to any extent. However, such solutions do show spectra of the hydrogen sulfite ion, HSO3

−, by reaction with water, and it is in fact the actual reducing agent present:

SO2 + H2O ⇌ HSO3− + H+

Biochemical and biomedical roles

Sulfur dioxide is toxic in large amounts. It or its conjugate base bisulfite is produced biologically as an intermediate in both sulfate-reducing organisms and in sulfur oxidizing bacteria as well. The role of sulfur dioxide in mammalian biology is not yet well understood.[9] Sulfur dioxide blocks nerve signals from the pulmonary stretch receptors (PSRs) and abolishes the Hering–Breuer inflation reflex.

As a refrigerant

Being easily condensed and possessing a high heat of evaporation, sulfur dioxide is a candidate material for refrigerants. Prior to the development of CFCs, sulfur dioxide was used as a refrigerant in home refrigerators.

As a reagent and solvent in the laboratory

Sulfur dioxide is a versatile inert solvent that has been widely used for dissolving highly oxidizing salts. It is also used occasionally as a source of the sulfonyl group in organic synthesis. Treatment of aryl diazonium salts with sulfur dioxide and cuprous chloride affords the corresponding aryl sulfonyl chloride, for example:[10]

As an air pollutant

A sulfur dioxide plume from the Halemaʻumaʻu vent, glows at night

Sulfur dioxide is a noticeable component in the atmosphere, especially following volcanic eruptions.[11] According to the United States Environmental Protection Agency (as presented by the 2002 World Almanac or in chart form[12]), the following amount of sulfur dioxide was released in the U.S. per year:

Year SO2 (thousands of short tons)1970 31,1611980 25,9051990 23,6781996 18,8591997 19,3631998 19,4911999 18,867

Sulfur dioxide is a major air pollutant and has significant impacts upon human health.[13] In addition the concentration of sulfur dioxide in the atmosphere can influence the habitat suitability for plant communities as well as animal life.[14] Sulfur dioxide emissions are a

precursor to acid rain and atmospheric particulates. Due largely to the US EPA’s Acid Rain Program, the U.S. has witnessed a 33% decrease in emissions between 1983 and 2002. This improvement resulted in part from flue-gas desulfurization, a technology that enables SO2 to be chemically bound in power plants burning sulfur-containing coal or oil. In particular, calcium oxide (lime) reacts with sulfur dioxide to form calcium sulfite:

CaO + SO2 → CaSO3

Aerobic oxidation of the CaSO3 gives CaSO4, anhydrite. Most gypsum sold in Europe comes from flue-gas desulfurization.

Sulfur can be removed from coal during the burning process by using limestone as a bed material in Fluidized bed combustion.[15]

Sulfur can also be removed from fuels prior to burning the fuel, preventing the formation of SO2 because there is no sulfur in the fuel from which SO2 can be formed. The Claus process is used in refineries to produce sulfur as a byproduct. The Stretford process has also been used to remove sulfur from fuel. Redox processes using iron oxides can also be used, for example, Lo-Cat[16] or Sulferox.[17]

Fuel additives, such as calcium additives and magnesium oxide, are being used in gasoline and diesel engines in order to lower the emission of sulfur dioxide gases into the atmosphere.[18]

As of 2006, China was the world's largest sulfur dioxide polluter, with 2005 emissions estimated to be 25.49 million tons. This amount represents a 27% increase since 2000, and is roughly comparable with U.S. emissions in 1980.[19]

Safety

Inhalation

Inhaling sulfur dioxide is associated with increased respiratory symptoms and disease, difficulty in breathing, and premature death.[20] In 2008, the American Conference of Governmental Industrial Hygienists reduced the short-term exposure limit from 5 ppm to 0.25 ppm. The OSHA PEL is currently set at 5 ppm (13 mg/m3) time weighted average. NIOSH has set the IDLH at 100 ppm.[21]

A 2011 systematic review concluded that exposure to sulfur dioxide is associated with preterm birth.[2

HazeFrom Wikipedia, the free encyclopediaJump to: navigation, search For other uses, see Haze (disambiguation).

Haze over Kuala Lumpur.

Los Angeles skyline, showing haze.

Haze over the North China Plain.

A weak cold front, associated with smog, in the Yellow Sea. The cold front, while moving south, picked up the smog from eastern china into a "smog front"

Haze obscuring the Faisal Mosque in Islamabad.

Haze is traditionally an atmospheric phenomenon where dust, smoke and other dry particles obscure the clarity of the sky. The World Meteorological Organization manual of codes includes a classification of horizontal obscuration into categories of fog, ice fog, steam fog, mist, haze, smoke, volcanic ash, dust, sand and snow.[1] Sources for haze particles include farming (ploughing in dry weather), traffic, industry, and wildfires.

Seen from afar (e.g. approaching airplane) and depending upon the direction of view with respect to the sun, haze may appear brownish or bluish, while mist tends to be bluish-grey. Whereas haze often is thought of as a phenomenon of dry air, mist formation is a phenomenon of humid air. However, haze particles may act as condensation nuclei for the subsequent formation of mist droplets; such forms of haze are known as "wet haze."

In the United States and elsewhere, the term "haze" in meteorological literature generally is used to denote visibility-reducing aerosols of the wet type. Such aerosols commonly arise from complex chemical reactions that occur as sulfur dioxide gases emitted during combustion are converted into small droplets of sulfuric acid. The reactions are enhanced in the presence of sunlight, high relative humidity, and stagnant air flow. A small component of wet haze aerosols appear to be derived from compounds released by trees, such as terpenes. For all these reasons, wet haze tends to be primarily a warm-season phenomenon. Large areas of haze covering many thousands of kilometers may be produced under favorable conditions each summer.

Contents

1 Air pollution

2 Obscuration 3 See also 4 Notes 5 External links

Air pollution

Main article: Smog

Haze often occurs when dust and smoke particles accumulate in relatively dry air. When weather conditions block the dispersal of smoke and other pollutants they concentrate and form a usually low-hanging shroud that impairs visibility and may become a respiratory health threat. Industrial pollution can result in dense haze, which is known as smog.

Since 1991, haze has been a particularly acute problem in Southeast Asia, Indonesian forest fires burnt to clear land being the reason. In response the 1997 Southeast Asian haze, the ASEAN countries agreed on a Regional Haze Action Plan (1997) and later signed the Agreement on Transboundary Haze Pollution (2002) however the pollution is still a problem today. Under the agreement the ASEAN secretariat hosts a co-ordination and support unit.[2]

In the United States, the Interagency Monitoring of Protected Visual Environments (IMPROVE) program was developed as a collaborative effort between the US EPA and the National Park Service in order to establish the chemical composition of haze in National Parks and establish air pollution control measures in order to restore the visibility to pre-industrial levels.[3] Additionally, the Clean Air Act requires that any current visibility problems be remedied, and future visibility problems be prevented, in 156 Class I Federal areas located throughout the United States. A full list of these areas is available on EPA's website.[4]

Obscuration

Haze causes issues in the area of terrestrial photography, where the penetration of large amounts of dense atmosphere may be necessary to image distant subjects. This results in the visual effect of a loss of contrast in the subject, due to the effect of light scattering through the haze particles. For these reasons, sunrise and sunset colors appear subdued on hazy days, and stars may be obscured at night. In some cases, attenuation by haze is so great that, toward sunset, the sun disappears altogether before reaching the horizon. (see example).[5] Haze can be defined as an aerial form of the Tyndall effect therefore unlike other atmospheric effects such as cloud and fog, haze is spectrally selective: shorter (blue) wavelengths are scattered more, and longer (red/infrared) wavelengths are scattered less. For this reason many super-telephoto lenses often incorporate yellow filters or coatings to enhance image contrast.

Infrared (IR) imaging may also be used to penetrate haze over long distances, with a combination of IR-pass optical filters (such as the Wratten 89B) and IR-sensitive detector.

NicotineFrom Wikipedia, the free encyclopediaJump to: navigation, search This article is about the chemical compound. For other uses, see Nicotine (disambiguation).

Nicotine

Systematic (IUPAC) name3-[(2S)-1-methylpyrrolidin-2-yl]pyridine

Clinical dataTrade names Nicorette, Nicotrol

AHFS/Drugs.com monographPregnancy cat. D (US)

Legal status Unscheduled (AU) GSL (UK) OTC (US)Dependence liability High

Routes

smoked (as smoking tobacco, mapacho, etc.), insufflated (as tobacco snuff or nicotine nasal spray), chewed (as nicotine gum, tobacco gum or chewing tobacco), transdermal (as nicotine patch, nicogel or topical tobacco paste), intrabuccal (as dipping tobacco, snuffs, dissolvable tobacco or creamy snuff), vaporized (as electronic cigarette, etc.), directly inhaled (as nicotine inhaler), oral (as nicotini), buccal (as snus)

Pharmacokinetic dataBioavailability 20 to 45% (oral)Metabolism hepatic

Half-life 2 hoursIdentifiers

CAS number 54-11-5

ATC code N07 BA01 QP53 AX13 PubChem CID 942

IUPHAR ligand 2585DrugBank DB00184

ChemSpider 80863

UNII 6M3C89ZY6R

KEGG D03365

ChEBI CHEBI:17688

ChEMBL CHEMBL3

Chemical dataFormula C10H14N2

Mol. mass 162.12 g/molSMILES[show]InChI[show]

Physical dataDensity 1.01 g/cm³

Melt. point -79 °C (-110 °F)Boiling point 247 °C (477 °F)

(what is this?) (verify)

Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae) that acts as a nicotinic acetylcholine receptor agonist. The biosynthesis takes place in the roots and accumulation occurs in the leaves of the Solanaceae. It constitutes approximately 0.6–3.0% of the dry weight of tobacco [1] and is present in the range of 2–7 µg/kg of various edible plants.[2] It functions as an antiherbivore chemical; therefore, nicotine was widely used as an insecticide in the past[3][4][5] and nicotine analogs such as imidacloprid are currently widely used.

In low doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (30–60 mg[6]) can be fatal.[7] This stimulant effect is the main factor responsible for the dependence-forming properties of tobacco smoking. According to the American Heart Association, nicotine addiction has historically been one of the hardest addictions to break, while the pharmacological and behavioral characteristics that determine tobacco addiction are similar to those determining addiction to heroin and cocaine. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.6% per year between the years of 1998 and 2005. This was found for all major market categories of cigarettes.[8]

Research in 2011 has found that nicotine inhibits chromatin-modifying enzymes (class I and II histone deacetylases) which increases the ability of cocaine to cause an addiction.[9]

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The tobacco and seeds were brought to

ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo. Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.[10][11] Its chemical empirical formula was described by Melsens in 1843,[12] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[13] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[14]

Historical use of nicotine as an insecticide

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide (waste from the tobacco industry) were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[4]

Currently, nicotine is a permitted pesticide for organic farming because it is derived from a botanical source. Nicotine sulfate sold for use as a pesticide is labeled "DANGER," indicating that it is highly toxic.[5] However, in 2008, the EPA received a request to cancel the registration of the last nicotine pesticide registered in the United States.[15] This request was granted, and after 1 January 2014, this pesticide will not be available for sale.[16]

Chemistry

Nicotine is a hygroscopic, oily liquid that is miscible with water in its base form. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Nicotine easily penetrates the skin. As shown by the physical data, free base nicotine will burn at a temperature below its boiling point, and its vapors will combust at 308 K (35 °C; 95 °F) in air despite a low vapor pressure. Because of this, most of the nicotine is burned when a cigarette is smoked; however, enough is inhaled to cause pharmacological effects.

Optical activity

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[17] The salts of (+)-nicotine are usually dextrorotatory.

Biosynthesis

Nicotine biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[18][19] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.[20]

Pharmacology

Pharmacokinetics

Side effects of nicotine.[21]

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[22] The elimination half-life of nicotine in the body is around two hours.[23]

The amount of nicotine absorbed by the body from smoking depends on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. For chewing tobacco, dipping tobacco, snus and snuff, which are held in the mouth between the lip and gum, or taken in the nose, the amount released into the body tends to be much greater than smoked tobacco.[clarification needed] Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine.

Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[24] Under some conditions, other substances may be formed such as myosmine.[25]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[26]

Detection of use

Medical detection

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[27][28] Nicotine use is not regulated in competitive sports programs, yet the drug has been shown to have a significant beneficial effect on athletic endurance in subjects who have not used nicotine before.[29]

Pharmacodynamics

Nicotine acts on the nicotinic acetylcholine receptors, specifically the ganglion type nicotinic receptor and one CNS nicotinic receptor. The former is present in the adrenal medulla and elsewhere, while the latter is present in the central nervous system (CNS). In small concentrations, nicotine increases the activity of these receptors. Nicotine also has effects on a variety of other neurotransmitters through less direct mechanisms.

In the central nervous system

Effect of nicotine on dopaminergic neurons.

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are responsible for the apparent euphoria and relaxation, and addiction caused by nicotine consumption. Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.[30] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[31]

Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman.[32] These beta-carboline compounds significantly decrease MAO activity in smokers.[32][33] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.[34] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[35]

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[36][37] but not habenulopeduncular structures.[38] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[39]

In the sympathetic nervous system

Nicotine also activates the sympathetic nervous system,[40] acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors,

causing the release of epinephrine (and norepinephrine) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[41]

In adrenal medulla

Effect of nicotine on chromaffin cells.

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.[42]

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[43]

Psychoactive effects

Further information: Psychoactive drug

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[44] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[45] Like any stimulant, it may very rarely cause the often catastrophically uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[46][47]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, vasopressin, histamine, arginine, serotonin, dopamine, autocrine agents, and beta-endorphin.[48] This release of neurotransmitters and hormones is responsible for most of nicotine's effects. Nicotine appears to enhance

concentration [49] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine[50] and increases sensitivity in brain reward systems.[51] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[52]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[53] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use.

Technically, nicotine is not significantly addictive, as nicotine administered alone does not produce significant reinforcing properties.[54] However, after coadministration with an MAOI, such as those found in tobacco, nicotine produces significant behavioral sensitization, a measure of addiction potential. This is similar in effect to amphetamine.[34]

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter's chance of success by 50 to 70%.[55] But in 1990, researchers found that 93% of users returned to smoking within six months.[56]

Nicotine gum, usually in 2-mg or 4-mg doses, and nicotine patches are available, as well as smokeless tobacco, nicotine lozenges and electronic cigarettes.

Side effects

Nicotine increases blood pressure and heart rate in humans.[57] Nicotine can stimulate abnormal proliferation of vascular endothelial cells, similar to that seen in atherosclerosis.[58] Nicotine induces potentially atherogenic genes in human coronary artery endothelial cells.[59] Nicotine could cause microvascular injury through its action on nicotinic acetylcholine receptors (nAChRs),[60] however other mechanisms are also likely at play.

A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,[61] an estrogen-sensitive region of the brain involved in memory formation and retention.

Dependence and withdrawal

See also: Smoking cessation

Modern research shows that nicotine acts on the brain to produce a number of effects. Specifically, research examining its addictive nature has been found to show that nicotine activates the mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of pleasure and euphoria.[62]

Dopamine is one of the key neurotransmitters actively involved in the brain. Research shows that by increasing the levels of dopamine within the reward circuits in the brain, nicotine acts as a chemical with intense addictive qualities. In many studies it has been shown to be more addictive than cocaine and heroin.[63][64][65] Like other physically addictive drugs, nicotine withdrawal causes down-regulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine regulates the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,[66] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.[51] This neuronal brain alteration can persist for months after administration ceases.

A study found that nicotine exposure in adolescent mice retards the growth of the dopamine system, thus increasing the risk of substance abuse during adolescence.[67]

Some have been able to restart their natural dopamine production and bypass months or years of depression caused by nicotine withdrawal by using a combination of 2 over-the-counter supplements: 5-HTP (5-Hydroxytryptophan also known as oxitriptan) and L-Tyrosine (para-hydroxyphenylalanine). Studies of the combination have been conducted only on general depression[68] and no one has yet measured the effects specifically on nicotine withdrawal-related depression. However, anecdotal evidence suggests that the combination can be effective. In addition to being a natural and low-cost alternative to prescription anti-depressants, this protocol also has the benefit of being short-term in that the treatment is only necessary for a few months after nicotine abatement. Certain side effects, especially negative drug interactions, have been found with 5-HTP, so this treatment should not be undertaken in combination with any prescription medication or without specific approval from a doctor.

Immunology prevention

A model of a nicotine molecule

Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule as a hapten to a protein carrier such as Keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over the counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.[69]

Toxicology

See also: Nicotine poisoningNFPA 704

140

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[6][70] Nicotine therefore has a high toxicity in comparison to many other alkaloids such as cocaine, which has an LD50 of 95.1 mg/kg when administered to mice. It is unlikely that a person would overdose on nicotine through smoking alone, although overdose can occur through combined use of nicotine patches or nicotine gum and cigarettes at the same time.[7] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.[71]

Historically, nicotine has not been regarded as a carcinogen and the IARC has not evaluated nicotine in its standalone form and assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.[72][73] Nicotine has been noted to directly cause cancer through a number of different mechanisms such as the activation of MAP Kinases.[74] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[75]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[76]

[77] In one study, nicotine administered to mice with tumors caused increases in tumor size

(twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[78]

The teratogenic properties of nicotine has been investigated. According to a study of ca. 77,000 pregnant women in Denmark, women who used nicotine gum and patches during the early stages of pregnancy were found to face an increased risk of having babies with birth defects. The study showed that women who used nicotine-replacement therapy in the first 12 weeks of pregnancy had a 60% greater risk of having babies with birth defects compared to women who were non-smokers.

Nicotine use among pregnant women has also been correlated to increased frequency of ADHD. Children born to mothers who used tobacco were two and a half times more likely to be diagnosed with ADHD.[79] Froelich estimated that "exposure to higher levels of lead and prenatal tobacco each accounted for 500,000 additional cases of ADHD in U.S. children".[80]

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.[81]

Therapeutic uses

The primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

However, in a few situations, smoking has been observed to apparently be of therapeutic value. These are often referred to as "Smoker’s Paradoxes".[82] Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other ingredients found in tobacco.

For instance, studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention (PCI).[82] Risk of ulcerative colitis has been frequently shown to be reduced by smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.[83][84] Smoking also appears to interfere with development of Kaposi's sarcoma in patients with HIV.[85][86]

Nicotine reduces the chance of preeclampsia,[87] and atopic disorders such as allergic asthma.[88] A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.[89]

Tobacco smoke has been shown to contain compounds capable of inhibiting monoamine oxidase, which is responsible for the degradation of dopamine in the human brain. When dopamine is broken down by MAO-B, neurotoxic by-products are formed, possibly contributing to Parkinson's and Alzheimers disease.[90]

Many such papers regarding Alzheimer's disease[91] and Parkinson's Disease[92] have been published. While tobacco smoking is associated with an increased risk of Alzheimer's disease,[93] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[94] Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.[95][96][97] A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.[98]

Studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processing nicotine in the brain.[99]

Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[100][101] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[102]

Research at Duke University Medical Center found that nicotine may improve the symptoms of depression.[103] Nicotine appears to improve ADHD symptoms. Some studies have focused on benefits of nicotine therapy in adults with ADHD.[104]

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.[105]

Nicotine (in the form of chewing gum or a transdermal patch) has been explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.[106][107][108]

The relationship between smoking and inflammatory bowel disease has been firmly established, but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.[109][110]

Lung cancerFrom Wikipedia, the free encyclopediaJump to: navigation, search

Lung cancerClassification and external resources

Three-dimensional volume rendering of a thorax CT showing a tumor in the lung (marked by arrow)

ICD-10 C 33 -C 34 ICD-9 162DiseasesDB 7616MedlinePlus 007194

eMedicine med/1333 med/1336 emerg/335 radio/807 radio/405 radio/406

MeSH D002283

Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main types of lung cancer are small-cell lung carcinoma (SCLC), also called oat cell cancer, and non-small-cell lung carcinoma (NSCLC). The most common cause of lung cancer is long-term exposure to tobacco smoke,[1] which causes 80–90% of lung cancers.[2] Nonsmokers account for 10–15% of lung cancer cases,[3] and these cases are often attributed to a combination of genetic factors,[4] radon gas,[4] asbestos,[5] and air pollution [4] including secondhand smoke.[6][7]

The most common symptoms are coughing (including coughing up blood), weight loss and shortness of breath.[2] Lung cancer may be seen on chest radiograph and computed tomography (CT scan). The diagnosis is confirmed with a biopsy.[8] This is usually performed by bronchoscopy or CT-guided biopsy. Treatment and prognosis depend on the histological type of cancer, the stage (degree of spread), and the patient's general well-being, measured by performance status. Common treatments include surgery, chemotherapy, and radiotherapy. NSCLC is sometimes treated with surgery, whereas SCLC usually responds better to chemotherapy and radiotherapy.[9]

Survival depends on stage, overall health, and other factors. Overall, 15% of people in the United States diagnosed with lung cancer survive five years after the diagnosis.[10]

Worldwide, lung cancer is the most common cause of cancer-related death in men and women, and is responsible for 1.38 million deaths annually, as of 2008.[11]

Contents

1 Classification o 1.1 Non-small-cell lung carcinoma o 1.2 Small-cell lung carcinoma o 1.3 Others o 1.4 Metastasis

2 Signs and symptoms 3 Causes

o 3.1 Smoking o 3.2 Radon gas o 3.3 Asbestos o 3.4 Air pollution o 3.5 Genetics o 3.6 Other causes

4 Pathogenesis 5 Diagnosis

o 5.1 Staging 6 Prevention

o 6.1 Screening 7 Treatment

o 7.1 Surgery o 7.2 Radiotherapy o 7.3 Chemotherapy o 7.4 Palliative care

8 Prognosis 9 Epidemiology 10 History 11 References 12 External links

Classification

Age-adjusted incidence of lung cancer by histological type[4]

Histological type Incidence (per 100,000 per year)

All types 66.9Adenocarcinoma 22.1

Squamous-cell carcinoma

14.4

Small-cell carcinoma 9.8

Lung cancers are classified according to histological type.[8] This classification has important implications for clinical management and prognosis of the disease. The vast majority of lung

cancers are carcinomas—malignancies that arise from epithelial cells. Lung carcinomas are categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope. The two broad classes are non-small-cell and small-cell lung carcinoma.[12]

Non-small-cell lung carcinoma

Micrograph of squamous carcinoma, a type of non-small-cell carcinoma, FNA specimen, Pap stain

The three main subtypes of NSCLC are adenocarcinoma, squamous-cell lung carcinoma, and large-cell lung carcinoma.[2]

Nearly 40% of lung cancers are adenocarcinoma, which usually originates in peripheral lung tissue.[8] Most cases of adenocarcinoma are associated with smoking; however, among people who have smoked fewer than 100 cigarettes in their lifetimes ("never-smokers"),[2] adenocarcinoma is the most common form of lung cancer.[13] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.[14]

Squamous-cell carcinoma accounts for about 30% of lung cancers. They typically occur close to large airways. A hollow cavity and associated necrosis are commonly found at the center of the tumor.[8]

About 9% of lung cancers are large-cell carcinoma. These are so named because the cancer cells are large, with excess cytoplasm, large nuclei and conspicuous nucleoli.[8]

Small-cell lung carcinoma

Small-cell lung carcinoma (microscopic view of a core needle biopsy)

In small-cell lung carcinoma (SCLC), the cells contain dense neurosecretory granules (vesicles containing neuroendocrine hormones), which give this tumor an endocrine/paraneoplastic syndrome association.[15] Most cases arise in the larger airways (primary and secondary bronchi).[10] These cancers grow quickly and spread early in the

course of the disease. Sixty to seventy percent have metastatic disease at presentation. This type of lung cancer is strongly associated with smoking.[2]

Others

Four main histological subtypes are recognized, although some cancers may contain a combination of different subtypes.[12] Rare subtypes include glandular tumors, carcinoid tumors, and undifferentiated carcinomas.[2]

Metastasis

The lung is a common place for metastasis of tumors from other parts of the body. Secondary cancers are classified by the site of origin; e.g., breast cancer that has spread to the lung is called metastatic breast cancer. Metastases often have a characteristic round appearance on chest radiograph.[16]

Typical immunostaining in lung cancer[2]

Histological type ImmunostainSquamous-cell

carcinomaCK5/6 positiveCK7 negative

Adenocarcinoma CK7 positiveTTF-1 positive

Large-cell carcinoma TTF-1 negative

Small-cell carcinoma

TTF-1 positiveCD56 positiveChromogranin

positiveSynaptophysin

positive

Primary lung cancers themselves most commonly metastasize to the brain, bones, liver, and adrenal glands.[8] Immunostaining of a biopsy is often helpful to determine the original source.[17]

Signs and symptoms

See also: List of cutaneous conditions associated with internal malignancy

Symptoms and signs that may suggest lung cancer include:[2]

coughing weight loss dyspnea (shortness of breath) chest pain hemoptysis (coughing up blood) bone pain clubbing of the fingernails fever fatigue superior vena cava obstruction

dysphagia (difficulty swallowing) wheezing

If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose to pneumonia.[2]

Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease.[18] In lung cancer, these phenomena may include Lambert–Eaton myasthenic syndrome (muscle weakness due to autoantibodies), hypercalcemia, or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to Horner's syndrome, as well as damage to the brachial plexus.[2]

Many of the symptoms of lung cancer (poor appetite, weight loss, fever, fatigue) are not specific.[8] In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the brain, bone, adrenal glands, contralateral (opposite) lung, liver, pericardium, and kidneys.[19] About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest radiograph.[10]

Causes

Cancer develops following genetic damage to DNA. This genetic damage affects the normal functions of the cell, including cell proliferation, programmed cell death (apoptosis) and DNA repair. As more damage accumulates, the risk of cancer increases.[20]

Smoking

NIH graph showing how a general increase in sales of tobacco products in the USA in the first four decades of the 20th century (cigarettes per person per year) led to a corresponding rapid increase in the incidence of lung cancer during the 1930s, '40s and '50s (lung cancer deaths per 100,000 male population per year)

Cross section of a human lung: The white area in the upper lobe is cancer; the black areas are discoloration due to smoking.

Smoking, particularly of cigarettes, is by far the main contributor to lung cancer.[21] Cigarette smoke contains over 60 known carcinogens,[22] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue.[23] Across the developed world, 90% of lung cancer deaths in men during the year 2000 were attributed to smoking (70% for women).[24] Smoking accounts for 80–90% of lung cancer cases.[2]

Passive smoking—the inhalation of smoke from another's smoking—is a cause of lung cancer in nonsmokers. A passive smoker can be classified as someone living or working with a smoker. Studies from the US,[25][26] Europe,[27] the UK,[28] and Australia[29] have consistently shown a significantly increased risk among those exposed to passive smoke.[30] Those who live with someone who smokes have a 20–30% increase in risk while those who work in an environment with second hand smoke have a 16–19% increase in risk.[31] Investigations of sidestream smoke suggest it is more dangerous than direct smoke.[32] Passive smoking causes about 3,400 deaths from lung cancer each year in the USA.[26]

Radon gas

Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the Earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon is the second-most common cause of lung cancer in the USA, after smoking.[26] The risk increases 8–16% for every 100 Bq/m³ increase in the radon concentration.[33] Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates one in

15 homes in the US has radon levels above the recommended guideline of 4 picocuries per liter (pCi/l) (148 Bq/m³).[34]

Asbestos

Asbestos can cause a variety of lung diseases, including lung cancer. Tobacco smoking and asbestos have a synergistic effect on the formation of lung cancer.[5] Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).[35]

Air pollution

Outdoor air pollution has a small effect on increasing the risk of lung cancer.[4] Fine particulates (PM2.5) and sulfate aerosols, which may be released in traffic exhaust fumes, are associated with slightly increased risk.[4][36] For nitrogen dioxide, an incremental increase of 10 parts per billion increases the risk of lung cancer by 14%.[37] Outdoor air pollution is estimated to account for 1–2% of lung cancers.[4]

Genetics

Some people have a genetic predisposition to lung cancer. In relatives of people with lung cancer, the risk is increased 2.4 times. This may be due to genetic polymorphisms.[38]

Other causes

Numerous other substances, occupations, and environmental exposures have been linked to the genesis of cancer in lung tissue of humans. In its List of Classifications by Cancer Sites,[39]the International Agency for Research on Lung Cancer (IARC) states there is "sufficient evidence" to show the following are carcinogenic in lung:

Aluminum production Arsenic and inorganic arsenic compounds Beryllium and beryllium compounds Bis-(chloromethyl) ether Methyl ether (technical grade) Cadmium and cadmium compounds Chromium(VI) compounds Coal (indoor emissions from household coal burning) Combustion (incomplete) Coal gasification Coal-tar pitch Coke production Diesel engine exhaust Gamma radiation Hematite mining (underground) Iron and steel founding MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) Nickel compounds Painting Plutonium Radon-222 and its decay products Rubber production industry

Silica dust (crystalline) Soot Sulfur mustard X-radiation

Pathogenesis

Main article: Carcinogenesis

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.[40] Oncogenes are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.[41] Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas.[42][43] The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.[42] Mutations and amplification of EGFR are common in non-small-cell lung cancer and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently.[42] Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are particularly common in small-cell lung carcinoma. The p53 tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases.[44] Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.[42]

Diagnosis

Chest radiograph showing a cancerous tumor in the left lung

Performing a chest radiograph is one of the first investigative steps if a patient reports symptoms that may suggest lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion.[1] CT imaging is typically used to provide more information about the type and extent of disease. Bronchoscopy or CT-guided biopsy is often used to sample the tumor for histopathology.[10]

CT scan showing a cancerous tumor in the left lung

Lung cancer often appears as a solitary pulmonary nodule on a chest radiograph. However, the differential diagnosis is wide. Many other diseases can also give this appearance, including tuberculosis, fungal infections, metastatic cancer, or organizing pneumonia. Less common causes of a solitary pulmonary nodule include hamartomas, bronchogenic cysts, adenomas, arteriovenous malformation, pulmonary sequestration, rheumatoid nodules, Wegener's granulomatosis, or lymphoma.[45] Lung cancer can also be an incidental finding, as a solitary pulmonary nodule on a chest radiograph or CT scan taken for an unrelated reason.[46] The definitive diagnosis of lung cancer is based on histological examination of the suspicious tissue in the context of the clinical and radiological features.[2]

Emphysema

Print PDF Cite      

Emphysema is a lung disease that, along with chronic bronchitis, represents a type of chronic obstructive pulmonary disease (COPD). Medical scientists have defined emphysema as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by the destruction of their walls, and without obvious fibrosis" (Snider 1985).

COPD is the fourth leading cause of death in the United States, accounting for about 113,000 deaths annually. About 14 million Americans have symptoms of COPD. Among these, 1.65 million have emphysema. Millions more likely have undiagnosed or incipient COPD. The prevalence of COPD peaks in the sixty-five to seventy-four age range, and men are affected more than women.

Pathologists recognize three major types of emphysema: localized (distal acinar, paraseptal), centrilobular (centriacinar), and panlobular (panacinar). Centrilobular emphysema, the most common of the three, is usually caused by cigarette smoking. Cigarette smoke is thought to cause chronic inflammation in the walls of the air sacs (alveoli) of the lung, leading to an imbalance between destructive proteases and protective protease inhibitors. The proteases, such as elastase, gradually destroy the structural proteins (elastin, collagen) in the alveolar walls. Substantial variation in individual susceptibility to cigarette smoke exists, as only about one in seven cigarette smokers develops symptoms of COPD. Other than cigarette smoking, the only condition clearly linked to emphysema is a hereditary disorder called alpha1-antitrypsin deficiency (AAT). This rare condition, which is found in less than one percent of patients with COPD, occurs because the blood level of a glycoprotein (protease inhibitor) is not sufficient to counteract the activity of the proteases. Coal miners and workers chronically exposed to cadmium fumes are at risk to develop emphysema. The effects of other occupational agents, air pollution, and familial factors in the pathogenesis of emphysema are not clear.

Destruction of alveolar walls in emphysema reduces the lung's elasticity, which results in obstruction to airflow in small airways, trapping air in the lung. Other pathophysiologic findings in emphysema include increased lung compliance, elevation of the pressure in the pulmonary arteries (pulmonary hypertension), and abnormal matching of air flow and blood flow (ventilation/perfusion imbalance), which causes hypoxemia (low oxygen level in the blood).

Patients with emphysema suffer from shortness of breath (dyspnea), which typically appears between the ages of fifty and sixty. Initially, the dyspnea is noted only with heavy exertion, but it progresses over time to a persistent, daily symptom that may eventually limit simple activities and even be present at rest. If the patient also has chronic bronchitis, daily cough and sputum production are present. Physical examination in emphysema reveals chest hyperinflation (overdistention) and reduced breath sounds on auscultation (listening to

breathing noises with a stethoscope). In severe cases, there may be signs of respiratory failure and failure of the right side of the heart (cor pulmonale).

The clinical diagnosis of emphysema is suggested by the presence of a risk factor for emphysema (smoking and/or AAT), the clinical findings described above, the absence of alternative diagnoses to explain these findings (e.g., bronchial asthma, bronchiectasis, and central airways obstructive diseases), and evidence of airflow obstruction on spirometry (pulmonary function testing). Airflow obstruction in emphysema is usually irreversible, meaning there is no improvement in the obstruction after inhaling a bronchodilator drug. Specialized pulmonary tests may demonstrate air trapping and reduction in the gas-transfer ability of the lung. The chest radiograph in mild emphysema may be normal, but in severe cases there is hyperinflation. Sometimes large air sacs called bullae are seen. Computed tomographic imaging may confirm lung destruction, bullae, and hyperinflation. Arterial blood-gas analysis and transcutaneous measurement of oxyhemoglobin saturation (oximetry) reveal hypoxemia in advanced emphysema.

Emphysema is treated with a broad-based approach that includes elimination of cigarette smoking, immunization against influenza virus and Streptococcus pneumoniae infection, exercise, maintenance of a healthy lifestyle, and the use of bronchodilator medications (e.g., ipratropium bromide and albuterol). Supplemental oxygen is prescribed if hypoxemia is present. Continuous long-term oxygen therapy improves survival in COPD patients with hypoxemia. Anti-inflammatory drugs such as corticosteroids are helpful in a small percent of emphysema patients. COPD exacerbations, with increasing dyspnea, cough, and sputum production, are usually treated with intensification of the bronchodilator regimen, antibiotics, supplemental oxygen, and in some cases corticosteroids. Hospitalization may be necessary, and in severe cases insertion of a breathing tube into the airway (endotracheal intubation) and mechanical ventilation are necessary. Debilitated COPD patients may benefit from comprehensive outpatient rehabilitation. Rarely, patients with advanced emphysema are treated surgically (removal of large bullae, volume reduction surgery, or lung transplantation).

With the exception of AAT, emphysema is a preventable disease. Smoking abstinence remains the best hope for reducing the morbidity and mortality associated with emphysema. Early detection of airflow limitation in young cigarette smokers may provide a strong stimulus to quit smoking. This is important because smoking cessation is known to slow the rate of decline in lung function in middle-aged smokers with mild COPD.

Survival in patients with COPD is determined by multiple factors, including age, gender, lung function, and levels of oxygen and carbon dioxide in the blood. The prognosis is worse when the airflow obstruction is irreversible. COPD patients with severe obstruction, as defined by spirometry, have a median survival of about four to five years, but there is substantial variability. Death in emphysema patients is usually a result of pneumonia, lung cancer, heart disease, or respiratory failure.

JOHN L. STAUFFER

(SEE ALSO: Asthma; Chronic Respiratory Diseases; Pulmonary Function; Smoking Behavior; Smoking Cessation; Tobacco Control)

BIBLIOGRAPHY

American Thoracic Society (1995). "Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Disease." American Journal Respiratory Critical Care Medicine 152:S77120.

Anthonisen, N. R.; Connett, J. E.; Kiley, J. P.; Altose, M. D.; Bailey, W.C.; Buist, A. S.; Conway, W. A. Jr.; Enright, P. L.; Kanner, R. E.; O'Hara, P.; Owens, G. R.; Scanlon, P. D.; Tashkin, D. P.; and Wise, R. A.(1994). "Effects of Smoking Intervention and the Use of an Inhaled Anticholinergic Bronchodilator on the Rate of Decline of FEV1. The Lung Health Study." Journal of the American Medical Association 272(19): 1497505.

Celli, B., Benditt, J.; and Albert, R. K. (1999) "Chronic Obstructive Pulmonary Disease." In Comprehensive Respiratory Medicine, eds. R. Albert, S. Spiro, and J. Jett, St. Louis, MO: Mosby.

Snider, G. L.; Kleinerman, J.; Thurlbeck, W. M.; and Bengali, Z. H. (1985). "The Definition of Emphysema. Report of a National Heart, Lung, and Blood Institute, Division of Lung Diseases Workshop." American Review of Respiratory Diseases 132:18285.

InfluenzaFrom Wikipedia, the free encyclopediaJump to: navigation, search "Flu" redirects here. For other uses, see Flu (disambiguation).

InfluenzaClassification and external resources

TEM of negatively stained influenza virions, magnified approximately 100,000 times

ICD-10 J 10 , J 11 ICD-9 487DiseasesDB 6791MedlinePlus 000080eMedicine med/1170 ped/3006MeSH D007251

Influenza, commonly known as the 'flu' , is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses. The most common symptoms are chills, fever, sore throat, muscle pains, headache (often severe), coughing, weakness/fatigue and general discomfort.[1] Although it is often confused with other influenza-like illnesses, especially the common cold, influenza is a more severe disease caused by a different type of virus.[2] Influenza may produce nausea and vomiting, particularly in children,[1] but these symptoms are more common in the unrelated gastroenteritis, which is sometimes inaccurately referred to as "stomach flu" or "24-hour flu".[3]

Flu can occasionally lead to pneumonia, either direct viral pneumonia or secondary bacterial pneumonia, even for persons who are usually very healthy.[4][5][6] In particular it is a warning sign if a child (or presumably an adult) seems to be getting better and then relapses with a high fever as this relapse may be bacterial pneumonia.[7] Another warning sign is if the person starts to have trouble breathing.[6]

Typically, influenza is transmitted through the air by coughs or sneezes, creating aerosols containing the virus. Influenza can also be transmitted by direct contact with bird droppings or nasal secretions, or through contact with contaminated surfaces. Airborne aerosols have been thought to cause most infections, although which means of transmission is most important is not absolutely clear.[8] Influenza viruses can be inactivated by sunlight, disinfectants and detergents.[9][10] As the virus can be inactivated by soap, frequent hand washing reduces the risk of infection.[11]

Influenza spreads around the world in seasonal epidemics, resulting in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly deaths,[12] rising to millions in some pandemic years. In the 20th century three influenza pandemics occurred, each caused by the appearance of a new strain of the virus in humans, and killed tens of millions of people. Often, new influenza strains appear when an existing flu virus spreads to humans from another animal species, or when an existing human strain picks up new genes from a virus that usually infects birds or pigs. An avian strain named H5N1 raised the concern of a new influenza pandemic after it emerged in Asia in the 1990s, but it has not evolved to a form that spreads easily between people.[13] In April 2009 a novel flu strain evolved that combined genes from human, pig, and bird flu. Initially dubbed "swine flu" and also known as influenza A/H1N1, it emerged in Mexico, the United States, and several other nations. The World Health Organization officially declared the outbreak to be a pandemic on 11 June 2009 (see 2009 flu pandemic). The WHO's declaration of a pandemic level 6 was an indication of spread, not severity, the strain actually having a lower mortality rate than common flu outbreaks.[14]

Vaccinations against influenza are usually made available to people in developed countries.[15] Farmed poultry is often vaccinated to avoid decimation of the flocks.[16] The most common human vaccine is the trivalent influenza vaccine (TIV) that contains purified and inactivated antigens from three viral strains. Typically, this vaccine includes material from two influenza A virus subtypes and one influenza B virus strain.[17] The TIV carries no risk of transmitting the disease, and it has very low reactivity. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus evolves rapidly, and new strains quickly replace the older ones. Antiviral drugs such as the neuraminidase inhibitor oseltamivir (Tamiflu) have been used to treat influenza;[18] however, their effectiveness is difficult to determine due to much of the data remaining unpublished.[19]

Contents

1 Signs and symptoms 2 Virology

o 2.1 Types of virus o 2.2 Structure, properties, and subtype nomenclature o 2.3 Replication

3 Mechanism o 3.1 Transmission o 3.2 Pathophysiology

4 Prevention o 4.1 Vaccination o 4.2 Infection control

5 Treatment o 5.1 Antivirals

6 Prognosis 7 Epidemiology

o 7.1 Seasonal variations o 7.2 Epidemic and pandemic spread

8 History o 8.1 Etymology o 8.2 Pandemics

9 Society and culture 10 Research 11 In other animals

o 11.1 Bird flu o 11.2 Swine flu

12 References 13 Further reading 14 External links

Signs and symptoms

Most sensitive symptoms for diagnosing influenza[20]

Symptom: sensitivity specificityFever 68–86% 25–73%Cough 84–98% 7–29%Nasal

congestion68–91% 19–41%

All three findings, especially fever, were less sensitive in people over 60 years of age.

Symptoms of influenza,[21] with fever and cough the most common symptoms.[20]

Approximately 33% of people with influenza are asymptomatic.[22]

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38–39 °C (approximately 100–103 °F).[23] Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs.[1] Symptoms of influenza may include:

Fever and extreme coldness (chills shivering, shaking (rigor)) Cough Nasal congestion Body aches , especially joints and throat Fatigue Headache Irritated, watering eyes Reddened eyes, skin (especially face), mouth, throat and nose Petechial Rash [24] In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[25][26] (may be

severe in children with influenza B)[27]

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections,[2] but a flu can be identified by a high fever with a sudden onset and extreme fatigue. Diarrhea is not normally a symptom of influenza in adults,[20] although it has been seen in some human cases of the H5N1 "bird flu"[28] and can be a symptom in children.[25] The symptoms most reliably seen in influenza are shown in the table to the right.[20]

Since antiviral drugs are effective in treating influenza if given early (see treatment section, below), it can be important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore throat and/or nasal congestion can improve diagnostic accuracy.[29] Two decision analysis studies[30][31] suggest that during local outbreaks of influenza, the prevalence will be over 70%,[31] and thus patients with any of these combinations of symptoms may be treated with neuraminidase inhibitors without testing. Even in the absence of a local outbreak, treatment may be justified in the elderly during the influenza season as long as the prevalence is over 15%.[31]

The available laboratory tests for influenza continue to improve. The United States Centers for Disease Control and Prevention (CDC) maintains an up-to-date summary of available laboratory tests.[32] According to the CDC, rapid diagnostic tests have a sensitivity of 70–75% and specificity of 90–95% when compared with viral culture. These tests may be especially useful during the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season (prevalence=10%[31]).

On the more serious side, influenza can occasionally cause either direct viral or secondary bacterial pneumonia.[5][6] The obvious symptom is trouble breathing. In addition, if a child (or presumably an adult) seems to be getting better and then relapses with a high fever, that is a danger sign since this relapse can be bacterial pneumonia.[7]

Virology

Types of virus

Structure of the influenza virion. The hemagglutinin (HA) and neuraminidase(NA) proteins are shown on the surface of the particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to Ribonuclear Proteins (RNPs).

In virus classification influenza viruses are RNA viruses that make up three of the five genera of the family Orthomyxoviridae:[33]

Influenzavirus A Influenzavirus B Influenzavirus C

These viruses are only distantly related to the human parainfluenza viruses, which are RNA viruses belonging to the paramyxovirus family that are a common cause of respiratory infections in children such as croup,[34] but can also cause a disease similar to influenza in adults.[35]

Influenzavirus A

This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics.[36] The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses.[37] The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are:

H1N1 , which caused Spanish Flu in 1918, and Swine Flu in 2009 H2N2 , which caused Asian Flu in 1957 H3N2 , which caused Hong Kong Flu in 1968 H5N1 , which caused Bird Flu in 2004 H7N7 , which has unusual zoonotic potential[38]

H1N2 , endemic in humans, pigs and birds H9N2 H7N2 H7N3 H10N7

Influenzavirus B

Influenza virus nomenclature (for a Fujian flu virus)

This genus has one species, influenza B virus. Influenza B almost exclusively infects humans[37] and is less common than influenza A. The only other animals known to be susceptible to influenza B infection are the seal [39] and the ferret.[40] This type of influenza mutates at a rate 2–3 times slower than type A[41] and consequently is less genetically diverse, with only one influenza B serotype.[37] As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible.[42] This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.[43]

Influenzavirus C

This genus has one species, influenza C virus, which infects humans, dogs and pigs, sometimes causing both severe illness and local epidemics.[44][45] However, influenza C is less common than the other types and usually only causes mild disease in children.[46][47]

Structure, properties, and subtype nomenclature

Influenzaviruses A, B and C are very similar in overall structure.[48] The virus particle is 80–120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur.[49][50] These filamentous forms are more common in influenza C, which can form cordlike structures up to 500 micrometers long on the surfaces of infected cells.[51] However, despite these varied shapes, the viral particles of all influenza viruses are similar in composition.[51] These are made of a viral envelope containing two main types of glycoproteins, wrapped around a central core. The central core contains the viral RNA genome and other viral proteins that package and protect this RNA. RNA tends to be single stranded but in special cases it is double.[50] Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA, each piece of RNA containing either one or two genes, which code for a gene product (protein).[51] For example, the influenza A genome contains 11 genes on eight pieces of RNA, encoding for 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NS1, NS2(NEP: nuclear export protein), PA, PB1 (polymerase basic 1), PB1-F2 and PB2.[52]

Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.[53] Thus, these proteins are targets for antiviral drugs.[54] Furthermore, they are antigens to which antibodies

can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA. These different types of HA and NA form the basis of the H and N distinctions in, for example, H5N1.[55] There are 16 H and 9 N subtypes known, but only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.[56]

Replication

Host cell invasion and replication by the influenza virus. The steps in this process are discussed in the text.

Viruses can replicate only in living cells.[57] Influenza infection and replication is a multi-step process: First, the virus has to bind to and enter the cell, then deliver its genome to a site where it can produce new copies of viral proteins and RNA, assemble these components into new viral particles, and, last, exit the host cell.[51]

Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells, typically in the nose, throat, and lungs of mammals, and intestines of birds (Stage 1 in infection figure).[58] After the hemagglutinin is cleaved by a protease, the cell imports the virus by endocytosis.[59]

The intracellular details are still being elucidated. It is known that virions converge to the microtubule organizing center, interact with acidic endosomes and finally enter the target endosomes for genome release.[60]

Once inside the cell, the acidic conditions in the endosome cause two events to happen: First, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, then the M2 ion channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the core to dissemble and release the viral RNA and core proteins.[51] The viral RNA (vRNA) molecules, accessory proteins and RNA-dependent RNA polymerase are then released into the cytoplasm (Stage 2).[61] The M2 ion channel is blocked by amantadine drugs, preventing infection.[62]

These core proteins and vRNA form a complex that is transported into the cell nucleus, where the RNA-dependent RNA polymerase begins transcribing complementary positive-sense vRNA (Steps 3a and b).[63] The vRNA either is exported into the cytoplasm and translated (step 4) or remains in the nucleus. Newly synthesized viral proteins are either secreted through the Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell,

including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.[64]

Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[65] As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.[58] After the release of new influenza viruses, the host cell dies.

Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the viral genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, the majority of newly manufactured influenza viruses are mutants; this causes antigenic drift, which is a slow change in the antigens on the viral surface over time.[66] The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one type of influenza virus infects a single cell. The resulting rapid change in viral genetics produces antigenic shifts, which are sudden changes from one antigen to another. These sudden large changes allow the virus to infect new host species and quickly overcome protective immunity.[55] This is important in the emergence of pandemics, as discussed below in the section on Epidemiology.

Mechanism

Transmission

Influenza virus shedding (the time during which a person might be infectious to another person) begins the day before symptoms appear and virus is then released for between 5 to 7 days, although some people may shed virus for longer periods. People who contract influenza are most infective between the second and third days after infection.[67] The amount of virus shed appears to correlate with fever, with higher amounts of virus shed when temperatures are highest.[68] Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.[67][69] The transmission of influenza can be modeled mathematically, which helps predict how the virus will spread in a population.[70]

Influenza can be spread in three main ways:[71][72] by direct transmission (when an infected person sneezes mucus directly into the eyes, nose or mouth of another person); the airborne route (when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a hand-shake. The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus.[8][73] In the airborne route, the droplets that are small enough for people to inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an infection.[71] Although a single sneeze releases up to 40,000 droplets,[74] most of these droplets are quite large and will quickly settle out of the air.[71] How long

influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation: with low humidity and a lack of sunlight in winter aiding its survival.[71]

As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes,[75] doorknobs, light switches and other household items.[1] The length of time the virus will persist on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin.[76] However, if the virus is present in mucus, this can protect it for longer periods (up to 17 days on banknotes).[71][75] Avian influenza viruses can survive indefinitely when frozen.[77] They are inactivated by heating to 56 °C (133 °F) for a minimum of 60 minutes, as well as by acids (at pH <2).[77]

Pathophysiology

The different sites of infection (shown in red) of seasonal H1N1 versus avian H5N1. This influences their lethality and ability to spread.

The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone (ACTH) resulting in lowered cortisol levels.[78] Knowing which genes are carried by a particular strain can help predict how well it will infect humans and how severe this infection will be (that is, predict the strain's pathophysiology).[45][79]

For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several human proteases.[59] In mild and avirulent viruses, the structure of the hemagglutinin means that it can only be cleaved by proteases found in the throat and lungs, so these viruses cannot infect other tissues. However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.[79]

The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind.[80] Strains that are easily transmitted between people have hemagglutinin proteins that bind to receptors in the upper part of the respiratory tract, such as in the nose, throat and mouth. In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs.[81] This difference in the site of infection may be part of the reason why the H5N1 strain causes severe viral pneumonia in the lungs, but is not easily transmitted by people coughing and sneezing.[82][83]

Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells.[2][84] In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.[85] This massive immune response might produce a life-threatening cytokine storm. This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza,[86] and the 1918 pandemic strain.[87][88] However, another possibility is that these large amounts of cytokines are just a result of the massive levels of viral replication produced by these strains, and the immune response does not itself contribute to the disease.[89]

Prevention

VaccinationMain article: Influenza vaccine

Giving an influenza vaccination

The influenza vaccine is recommended by the World Health Organization and United States Center for Disease Control and Prevention for high-risk groups, such as children, the elderly, health care workers, and people who have chronic illnesses such as asthma, diabetes, heart disease, or are immuno-compromised among others.[90][91] In healthy adults it is modestly effective in decreasing the amount of influenza-like symptoms in a population.[92] Evidence is supportive of a decreased rate of influenza in children over the age of two.[93] In those with chronic obstructive pulmonary disease vaccination reduces exacerbations,[94] it is not clear if it reduces asthma exacerbations.[95] There is insufficient evidence to support a change in patient outcomes via immunizing health care workers.[96] This includes health care workers who care for the elderly.[97] Evidence supports a lower rate of influenza-like illness in many groups who are immunocompromised such as those with: HIV/AIDS, cancer, and post organ transplant.[98]

Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Every year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year (see Historical annual reformulations of the influenza vaccine), allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains.[99] The vaccine is reformulated each season for a few specific flu strains but dose not include all the strains active in the world during that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time.[100] It is also possible to get infected just before vaccination and get sick with the strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.[101]

Vaccines can cause the immune system to react as if the body were actually being infected, and general infection symptoms (many cold and flu symptoms are just general infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.[102]

The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings. It has generally been found to be a cost-effective intervention, especially in children[103] and the elderly,[104] however the results of economic evaluations of influenza vaccination have often been found to be dependent on key assumptions.[105]

Infection controlFurther information: Influenza prevention

Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching your eyes, nose or mouth;[106] frequent hand washing (with soap and water, or with alcohol-based hand rubs);[107] covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended.[108] Although face masks might help prevent transmission when caring for the sick,[109][110] there is mixed evidence on beneficial effects in the community.[108][111] Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms.[112][113]

Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections.[114] Alcohol is an effective sanitizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer.[115] In hospitals, quaternary ammonium compounds and bleach are used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms.[115] At home, this can be done effectively with a diluted chlorine bleach.[116]

During past pandemics, closing schools, churches and theaters slowed the spread of the virus but did not have a large effect on the overall death rate.[117][118] It is uncertain if reducing public gatherings, by for example closing schools and workplaces, will reduce transmission since people with influenza may just be moved from one area to another; such measures would also be difficult to enforce and might be unpopular.[108] When small numbers of people are infected, isolating the sick might reduce the risk of transmission.[108]

Treatment

Main article: Influenza treatment

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen (paracetamol) to relieve the fever and muscle aches associated with the flu.[119] Children and teenagers with flu symptoms (particularly fever) should avoid taking aspirin during an influenza infection (especially influenza type B), because doing so can lead to Reye's syndrome, a rare but potentially fatal disease of the liver.[120] Since influenza is caused by a virus, antibiotics have

no effect on the infection; unless prescribed for secondary infections such as bacterial pneumonia. Antiviral medication may be effective, but some strains of influenza can show resistance to the standard antiviral drugs and there is concern about the quality of the research.[121]

Antivirals

The two classes of antiviral drugs used against influenza are neuraminidase inhibitors (oseltamivir and zanamivir) and M2 protein inhibitors (adamantane derivatives). Neuraminidase inhibitors are currently preferred for flu virus infections since they are less toxic and possibly more effective.[89] However, their effectiveness is disputed.[19] In 2009, the World Health Organization recommended that persons in high risk groups, including pregnant women, children under two, and persons with respiratory problems, begin taking antivirals as soon as they start experiencing flu symptoms.[122][123]

Neuraminidase inhibitors

Neuraminidase inhibitors include the antiviral medications oseltamivir (Tamiflu) and zanamivir (Relenza). These medications may be effective against both influenza A and B, however the confidence of the research community in this conclusion is low as much of the trial data remains unpublished.[19][124] Different strains of influenza viruses have differing degrees of resistance against these antivirals, and it is impossible to predict what degree of resistance a future pandemic strain might have.[125] The FDA deems their effect to be modest.[19]

M2 inhibitors

The antiviral drugs amantadine and rimantadine block a viral ion channel (M2 protein) and prevent the virus from infecting cells.[62] These drugs are sometimes effective against influenza A if given early in the infection but are always ineffective against influenza B because B viruses do not possess M2 molecules.[126] Measured resistance to amantadine and rimantadine in American isolates of H3N2 has increased to 91% in 2005.[127] This high level of resistance may be due to the easy availability of amantadines as part of over-the-counter cold remedies in countries such as China and Russia,[128] and their use to prevent outbreaks of influenza in farmed poultry.[129][130] The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of drug resistance.[131]

Prognosis

Influenza's effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop life-threatening complications (such as pneumonia). Influenza, thus, can be deadly, especially for the weak, young and old, or chronically ill.[55] People with a weak immune system, such as people with advanced HIV infection or transplant patients (whose immune systems are medically suppressed to prevent transplant organ rejection), suffer from particularly severe disease.[132] Other high-risk groups include pregnant women and young children.[133]

The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause

worsening of coronary heart disease or congestive heart failure.[134] Smoking is another risk factor associated with more serious disease and increased mortality from influenza.[135]

According to the World Health Organization: "Every winter, tens of millions of people get the flu. Most are only ill and out of work for a week, yet the elderly are at a higher risk of death from the illness. We know the worldwide death toll exceeds a few hundred thousand people a year, but even in developed countries the numbers are uncertain, because medical authorities don't usually verify who actually died of influenza and who died of a flu-like illness."[136] Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 50 years old, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis, sinus, and ear infections.[101]

In some cases, an autoimmune response to an influenza infection may contribute to the development of Guillain-Barré syndrome.[137] However, as many other infections can increase the risk of this disease, influenza may only be an important cause during epidemics.[137][138] This syndrome has been believed to also be a rare side effect of influenza vaccines. One review gives an incidence of about one case per million vaccinations.[139] Getting infected by influenza itself increases both the risk of death (up to 1 in 10,000) and increases the risk of developing GBS to a much higher level than the highest level of suspected vaccine involvement (approx. 10 times higher by recent estimates).[140][141]

Epidemiology

Seasonal variationsFurther information: Flu season

Seasonal risk areas for influenza: November–April (blue), April–November (red), and year-round (yellow).

Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.[99]

A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the year. Many scholars have pondered where influenza could possibly reside during Summer in both hemispheres. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person. Increased travel due to the Northern

Hemisphere winter holiday season may also play a role.[142] Another factor is that cold temperatures lead to drier air, which may dehydrate mucus, preventing the body from effectively expelling virus particles. The virus also survives longer on surfaces at colder temperatures and aerosol transmission of the virus is highest in cold environments (less than 5 °C) with low relative humidity.[143] Indeed, the lower air humidity in winter seems to be the main cause of seasonal influenza transmission in temperate regions.[144][145]

However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks of infection are seen mainly during the rainy season.[146] Seasonal changes in contact rates from school terms, which are a major factor in other childhood diseases such as measles and pertussis, may also play a role in the flu. A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles.[147] H5N1 exhibits seasonality in both humans and birds.[148]

An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus.[149] This idea was first proposed by Robert Edgar Hope-Simpson in 1965.[150] He proposed that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or artificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.

Epidemic and pandemic spreadFurther information: Flu pandemic

Antigenic drift creates influenza viruses with slightly modified antigens, while antigenic shift generates viruses with entirely novel antigens.

As influenza is caused by a variety of species and strains of viruses, in any given year some strains can die out while others create epidemics, while yet another strain can cause a pandemic. Typically, in a year's normal two flu seasons (one per hemisphere), there are between three and five million cases of severe illness and up to 500,000 deaths worldwide, which by some definitions is a yearly influenza epidemic.[151] Although the incidence of influenza can vary widely between years, approximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every year in the United States.[152][153] On average 41,400 people died each year in the United States between 1979 and 2001 from influenza.[154] In 2010 the Centers for Disease Control and Prevention (CDC) in the United States changed the way it reports the 30 year estimates for deaths. Now they are reported as a range from a low of about 3,300 deaths to a high of 49,000 per year.[155]

Roughly three times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill tens of millions of people (see pandemics section). One study

estimated that if a strain with similar virulence to the 1918 influenza emerged today, it could kill between 50 and 80 million people.[156]

Antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

New influenza viruses are constantly evolving by mutation or by reassortment.[37] Mutations can cause small changes in the hemagglutinin and neuraminidase antigens on the surface of the virus. This is called antigenic drift, which slowly creates an increasing variety of strains until one evolves that can infect people who are immune to the pre-existing strains. This new variant then replaces the older strains as it rapidly sweeps through the human population, often causing an epidemic.[157] However, since the strains produced by drift will still be reasonably similar to the older strains, some people will still be immune to them. In contrast, when influenza viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains and human strains; this is called antigenic shift. If a human influenza virus is produced that has entirely new antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a pandemic.[158] In contrast to this model of pandemics based on antigenic drift and shift, an alternative approach has been proposed where the periodic pandemics are produced by interactions of a fixed set of viral strains with a human population with a constantly changing set of immunities to different viral strains.[159]

The generation time for influenza (the time from one infection to the next) is very short (only 2 days). This explains why influenza epidemics start and finish in a short time scale of only a few months.[160]

From a public health point of view, flu epidemics spread rapidly and are very difficult to control. Most influenza virus strains are not very infectious and each infected individual will only go on to infect one or two other individuals (the basic reproduction number for influenza is generally around 1.4). However, the generation time for influenza is extremely short: the time from a person becoming infected to when he infects the next person is only two days. The short generation time means that influenza epidemics generally peak at around 2 months and burn out after 3 months[clarification needed] : the decision to intervene in an influenza epidemic therefore has to be taken early, and the decision is therefore often made on the back of incomplete data. Another problem is that individuals become infectious before they become symptomatic, which means that putting people in quarantine after they become ill is not an effective public health intervention.[160] For the average person, viral shedding tends to peak on day two whereas symptoms peak on day three.[22]

History

Etymology

The word Influenza comes from the Italian language meaning "influence" and refers to the cause of the disease; initially, this ascribed illness to unfavorable astrological influences.[161] Changes in medical thought led to its modification to influenza del freddo, meaning "influence of the cold". The word influenza was first used in English to refer to the disease we know today in 1703 by J. Hugger of the University of Edinburgh in his thesis De Catarrho epidemio, vel Influenza, prout in India occidentali sese ostendit.[162] Archaic terms for influenza include epidemic catarrh, grippe (from the French, first used by Molyneaux in 1694 [163]), sweating sickness, and Spanish fever (particularly for the 1918 flu pandemic strain).[164]

PandemicsFurther information: Influenza pandemic, Spanish flu, Hong Kong flu

The difference between the influenza mortality age distributions of the 1918 epidemic and normal epidemics. Deaths per 100,000 persons in each age group, United States, for the interpandemic years 1911–1917 (dashed line) and the pandemic year 1918 (solid line).[165]

The symptoms of human influenza were clearly described by Hippocrates roughly 2,400 years ago.[166][167] Although the virus seems to have caused epidemics throughout human history, historical data on influenza are difficult to interpret, because the symptoms can be similar to those of other respiratory diseases.[168][169] The disease may have spread from Europe to the Americas as early as the European colonization of the Americas; since almost the entire indigenous population of the Antilles was killed by an epidemic resembling influenza that broke out in 1493, after the arrival of Christopher Columbus.[170][171]

The first convincing record of an influenza pandemic was of an outbreak in 1580, which began in Russia and spread to Europe via Africa. In Rome, over 8,000 people were killed, and several Spanish cities were almost wiped out. Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of 1830–1833 being particularly widespread; it infected approximately a quarter of the people exposed.[169]

The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates range from 50 to 100 million people.[172][173][174] This pandemic has been described as "the greatest medical holocaust in history" and may have killed as many people as the Black Death.[169] This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.[174] Indeed, symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred."[173] The majority of deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.[175]

The 1918 flu pandemic (Spanish flu pandemic) was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.[165][173] Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.[176] This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world's population was killed. As many as 25 million may have been killed in the first 25 weeks; in contrast, HIV/AIDS has killed 25 million in its first 25 years.[173]

Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and the 1968 Hong Kong Flu (type A, H3N2 strain), but even these smaller outbreaks killed millions of people. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish Flu of 1918.[165]

Known flu pandemics [55] [169] [177]

Name of pandemic Date Deaths Case fatality rate

Subtype involved

Pandemic Severity Index

Asiatic (Russian) Flu [178]

1889–1890

1 million 0.15% possibly H3N8 NA

1918 flu pandemic(Spanish flu)[179]

1918–1920

20 to 100 million

2% H1N1 5

Asian Flu 1957–1958

1 to 1.5 million

0.13% H2N2 2

Hong Kong Flu 1968–1969

0.75 to 1 million

<0.1% H3N2 2

2009 flu pandemic [180]

2009–2010

18,000 0.03% H1N1 NA

The first influenza virus to be isolated was from poultry, when in 1901 the agent causing a disease called "fowl plague" was passed through Chamberland filters, which have pores that are too small for bacteria to pass through.[181] The etiological cause of influenza, the Orthomyxoviridae family of viruses, was first discovered in pigs by Richard Shope in 1931.[182] This discovery was shortly followed by the isolation of the virus from humans by a group headed by Patrick Laidlaw at the Medical Research Council of the United Kingdom in 1933.[183] However, it was not until Wendell Stanley first crystallized tobacco mosaic virus in 1935 that the non-cellular nature of viruses was appreciated.

The main types of influenza viruses in humans. Solid squares show the appearance of a new strain, causing recurring influenza pandemics. Broken lines indicate uncertain strain identifications.[184]

The first significant step towards preventing influenza was the development in 1944 of a killed-virus vaccine for influenza by Thomas Francis, Jr.. This built on work by Australian Frank Macfarlane Burnet, who showed that the virus lost virulence when it was cultured in fertilized hen's eggs.[185] Application of this observation by Francis allowed his group of researchers at the University of Michigan to develop the first influenza vaccine, with support from the U.S. Army.[186] The Army was deeply involved in this research due to its experience of influenza in World War I, when thousands of troops were killed by the virus in a matter of months.[173] In comparison to vaccines, the development of anti-influenza drugs has been slower, with amantadine being licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being developed.[56]

Society and culture

Further information: Social impact of H5N1

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.[187] However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[188] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.[189]

Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.[190] On 1 November 2005, United States President George W. Bush unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza[191] backed by a request to Congress for $7.1 billion to begin implementing the plan.[192] Internationally, on 18 January 2006, donor nations pledged US$2 billion to combat bird flu at the two-day International Pledging Conference on Avian and Human Influenza held in China.[193]

In an assessment of the 2009 H1N1 pandemic on selected countries in the Southern Hemisphere, data suggest that all countries experienced some time-limited and/or geographically isolated socio/economic effects and a temporary decrease in tourism most likely due to fear of 2009 H1N1 disease. It is still too early to determine whether the H1N1 pandemic has caused any long-term economic impacts.[194]

Research

Further information: Influenza research

Dr. Terrence Tumpey examining a reconstructed 1918 Spanish flu virus in a biosafety level 3 environment.

Research on influenza includes studies on molecular virology, how the virus produces disease (pathogenesis), host immune responses, viral genomics, and how the virus spreads (epidemiology). These studies help in developing influenza countermeasures; for example, a better understanding of the body's immune system response helps vaccine development, and a detailed picture of how influenza invades cells aids the development of antiviral drugs. One important basic research program is the Influenza Genome Sequencing Project, which is creating a library of influenza sequences; this library should help clarify which factors make one strain more lethal than another, which genes most affect immunogenicity, and how the virus evolves over time.[195]

Research into new vaccines is particularly important, as current vaccines are very slow and expensive to produce and must be reformulated every year. The sequencing of the influenza genome and recombinant DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new antigens into a previously developed vaccine

strain.[196] New technologies are also being developed to grow viruses in cell culture, which promises higher yields, less cost, better quality and surge capacity.[197] Research on a universal influenza A vaccine, targeted against the external domain of the transmembrane viral M2 protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier Saelens and their team[198][199][200] and has now successfully concluded Phase I clinical trials. There has been some research success towards a "universal flu vaccine" that produces antibodies against proteins on the viral coat which mutate less rapidly, and thus a single shot could potentially provide longer-lasting protection.[201][202][203]

A number of biologics, therapeutic vaccines and immunobiologics are also being investigated for treatment of infection caused by viruses. Therapeutic biologics are designed to activate the immune response to virus or antigens. Typically, biologics do not target metabolic pathways like anti-viral drugs, but stimulate immune cells such as lymphocytes, macrophages, and/or antigen presenting cells, in an effort to drive an immune response towards a cytotoxic effect against the virus. Influenza models, such as murine influenza, are convenient models to test the effects of prophylactic and therapeutic biologics. For example, Lymphocyte T-Cell Immune Modulator inhibits viral growth in the murine model of influenza.[204]

In other animals

H5N1

Influenza A virus

o subtype H5N1

Genetic structure

Infection

Human mortality

Global spread

o in 2004

o in 2005

o in 2006

o in 2007

Social impact

Pandemic

Vaccine

v

t

e

Further information: Influenzavirus A, H5N1 and Transmission and infection of H5N1

Influenza infects many animal species, and transfer of viral strains between species can occur. Birds are thought to be the main animal reservoirs of influenza viruses.[205] Sixteen forms of hemagglutinin and nine forms of neuraminidase have been identified. All known subtypes (HxNy) are found in birds, but many subtypes are endemic in humans, dogs, horses, and pigs; populations of camels, ferrets, cats, seals, mink, and whales also show evidence of prior infection or exposure to influenza.[42] Variants of flu virus are sometimes named according to the species the strain is endemic in or adapted to. The main variants named using this convention are: Bird Flu, Human Flu, Swine Flu, Horse Flu and Dog Flu. (Cat flu generally refers to Feline viral rhinotracheitis or Feline calicivirus and not infection from an influenza virus.) In pigs, horses and dogs, influenza symptoms are similar to humans, with cough, fever and loss of appetite.[42] The frequency of animal diseases are not as well-studied as human infection, but an outbreak of influenza in harbor seals caused approximately 500 seal deaths off the New England coast in 1979–1980.[206] On the other hand, outbreaks in pigs are common and do not cause severe mortality.[42] Vaccines have also been developed to protect poultry from avian influenza. These vaccines can be effective against multiple strains and are used either as part of a preventative strategy, or combined with culling in attempts to eradicate outbreaks.[207]

Bird flu

Flu symptoms in birds are variable and can be unspecific.[208] The symptoms following infection with low-pathogenicity avian influenza may be as mild as ruffled feathers, a small reduction in egg production, or weight loss combined with minor respiratory disease.[209] Since these mild symptoms can make diagnosis in the field difficult, tracking the spread of avian influenza requires laboratory testing of samples from infected birds. Some strains such as Asian H9N2 are highly virulent to poultry and may cause more extreme symptoms and significant mortality.[210] In its most highly pathogenic form, influenza in chickens and turkeys produces a sudden appearance of severe symptoms and almost 100% mortality within two days.[211] As the virus spreads rapidly in the crowded conditions seen in the intensive farming of chickens and turkeys, these outbreaks can cause large economic losses to poultry farmers.

An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for "highly pathogenic avian influenza virus of type A of subtype H5N1") causes H5N1 flu, commonly known as "avian influenza" or simply "bird flu", and is endemic in many bird populations, especially in Southeast Asia. This Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of other birds in an attempt to control its spread. Most references in the media to "bird flu" and most references to H5N1 are about this specific strain.[212][213]

At present, HPAI A(H5N1) is an avian disease, and there is no evidence suggesting efficient human-to-human transmission of HPAI A(H5N1). In almost all cases, those infected have

had extensive physical contact with infected birds.[214] In the future, H5N1 may mutate or reassort into a strain capable of efficient human-to-human transmission. The exact changes that are required for this to happen are not well understood.[215] However, due to the high lethality and virulence of H5N1, its endemic presence, and its large and increasing biological host reservoir, the H5N1 virus was the world's pandemic threat in the 2006–07 flu season, and billions of dollars are being raised and spent researching H5N1 and preparing for a potential influenza pandemic.[190]

Swine flu

Chinese inspectors on an airplane, checking passengers for fevers, a common symptom of swine flu

In pigs swine influenza produces fever, lethargy, sneezing, coughing, difficulty breathing and decreased appetite.[216] In some cases the infection can cause abortion. Although mortality is usually low, the virus can produce weight loss and poor growth, causing economic loss to farmers.[216] Infected pigs can lose up to 12 pounds of body weight over a 3 to 4 week period.[216] Direct transmission of an influenza virus from pigs to humans is occasionally possible (this is called zoonotic swine flu). In all, 50 human cases are known to have occurred since the virus was identified in the mid-20th century, which have resulted in six deaths.[217]

In 2009, a swine-origin H1N1 virus strain commonly referred to as "swine flu" caused the 2009 flu pandemic, but there is no evidence that it is endemic to pigs (i.e. actually a swine flu) or of transmission from pigs to people, instead the virus is spreading from person to person.[218][219] This strain is a reassortment of several strains of H1N1 that are usually found separately, in humans, birds, and pigs.[220]

References

1. ^ a b c d "Influenza: Viral Infections: Merck Manual Home Edition". Merck. Retrieved 15 March 2008.

2. ^ a b c Eccles, R (2005). "Understanding the symptoms of the common cold and influenza". Lancet Infect Dis 5 (11): 718–25. doi:10.1016/S1473-3099(05)70270-X. PMID 16253889.

3. ̂ Seasonal Flu vs. Stomach Flu by Kristina Duda, R.N.; Retrieved 12 March 2007 (Website: "About, Inc., A part of The New York Times Company")

4. ̂ Ballinger, MN; Standiford, TJ (Sep 2010). "Postinfluenza bacterial pneumonia: host defenses gone awry". J Interferon Cytokine Res 30 (9): 643–52. doi:10.1089/jir.2010.0049. PMID 20726789.

5. ^ a b Hospitalized Patients with 2009 H1N1 Influenza in the United States, April–June 2009, New England Journal of Medicine, Jain, Kamimoto, et al., 12 November 2009.

6. ^ a b c Transcript of virtual press conference with Gregory Hartl, Spokesperson for H1N1, and Dr Nikki Shindo, Medical Officer, Global Influenza Programme, World Health Organization, 12 November 2009.

7. ^ a b Report Finds Swine Flu Has Killed 36 Children, New York Times, DENISE GRADY, 3 September 2009.

8. ^ a b Brankston G, Gitterman L, Hirji Z, Lemieux C, Gardam M (April 2007). "Transmission of influenza A in human beings". Lancet Infect Dis 7 (4): 257–65. doi:10.1016/S1473-3099(07)70029-4. PMID 17376383.

9. ̂ Suarez, D; Spackman E, Senne D, Bulaga L, Welsch A, Froberg K (2003). "The effect of various disinfectants on detection of avian influenza virus by real time RT-PCR". Avian Dis 47 (3 Suppl): 1091–5. doi:10.1637/0005-2086-47.s3.1091. PMID 14575118.

10. ̂ Avian Influenza (Bird Flu): Implications for Human Disease. Physical characteristics of influenza A viruses. UMN CIDRAP.

11. ̂ Jefferson T, Del Mar CB, Dooley L, et al. (2011). "Physical interventions to interrupt or reduce the spread of respiratory viruses". Cochrane Database Syst Rev (7): CD006207. doi:10.1002/14651858.CD006207.pub4. PMID 21735402.

12. ̂ Influenza (Seasonal), World Health Organization, April 2009. Retrieved 13 February 2010.13. ̂ "Avian influenza ("bird flu") fact sheet". WHO. February 2006. Retrieved 20 October 2006.14. ̂ World Health Organization. World now at the start of 2009 influenza pandemic.

http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/index.html

15. ̂ WHO position paper: influenza vaccines WHO weekly Epidemiological Record 19 August 2005, vol. 80, 33, pp. 277–288.

16. ̂ Villegas, P (1998). "Viral diseases of the respiratory system". Poult Sci 77 (8): 1143–5. PMID 9706079.

17. ̂ Horwood F, Macfarlane J (October 2002). "Pneumococcal and influenza vaccination: current situation and future prospects". Thorax 57 (Suppl 2): II24–II30. PMC 1766003. PMID 12364707.

18. ̂ World Health Organization, Global Alert and Response (GAR), Antiviral drugs for pandemic (H1N1) 2009: definitions and use, 22 December 2009.

19. ^ a b c d Jefferson T, Jones MA, Doshi P, et al. (2012). "Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children". Cochrane Database Syst Rev 1: CD008965. doi:10.1002/14651858.CD008965.pub3. PMID 22258996.

20. ^ a b c d Call S, Vollenweider M, Hornung C, Simel D, McKinney W (2005). "Does this patient have influenza?". JAMA 293 (8): 987–97. doi:10.1001/jama.293.8.987. PMID 15728170.

21. ̂ Centers for Disease Control and Prevention > Influenza Symptoms Page last updated 16 November 2007. Retrieved 28 April 2009.

22. ^ a b Time Lines of Infection and Disease in Human Influenza: A Review of Volunteer Challenge Studies, American Journal of Epidemiology, Carrat, Vergu, Ferguson, et al., 167 (7): 775–785, 2008. " . . . In almost all studies, participants were individually confined for 1 week. . . " See especially Figure 5 which shows that virus shedding tends to peak on day 2 whereas symptoms tend to peak on day 3.

23. ̂ Suzuki E, Ichihara K, Johnson AM (January 2007). "Natural course of fever during influenza virus infection in children". Clin Pediatr (Phila) 46 (1): 76–9. doi:10.1177/0009922806289588. PMID 17164515.

24. ̂ Silva ME, Cherry JD, Wilton RJ, Ghafouri NM, Bruckner DA, Miller MJ (August 1999). "Acute fever and petechial rash associated with influenza A virus infection". Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America 29 (2): 453–4. doi:10.1086/520240. PMID 10476766.

25. ^ a b Richards S (2005). "Flu blues". Nurs Stand 20 (8): 26–7. PMID 16295596.

26. ̂ Heikkinen T (July 2006). "Influenza in children". Acta Paediatr. 95 (7): 778–84. doi:10.1080/08035250600612272. PMID 16801171.

27. ̂ Kerr AA, McQuillin J, Downham MA, Gardner PS (1975). "Gastric 'flu influenza B causing abdominal symptoms in children". Lancet 1 (7902): 291–5. doi:10.1016/S0140-6736(75)91205-2. PMID 46444.

28. ̂ Hui DS (March 2008). "Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection". Respirology 13 Suppl 1: S10–3. doi:10.1111/j.1440-1843.2008.01247.x. PMID 18366521.

29. ̂ Monto A, Gravenstein S, Elliott M, Colopy M, Schweinle J (2000). "Clinical signs and symptoms predicting influenza infection". Arch Intern Med 160 (21): 3243–7. doi:10.1001/archinte.160.21.3243. PMID 11088084.

30. ̂ Smith K, Roberts M (2002). "Cost-effectiveness of newer treatment strategies for influenza". Am J Med 113 (4): 300–7. doi:10.1016/S0002-9343(02)01222-6. PMID 12361816.

31. ^ a b c d Rothberg M, Bellantonio S, Rose D (2 September 2003). "Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy". Ann Intern Med 139 (5 Pt 1): 321–9. PMID 12965940.

32. ̂ Centers for Disease Control and Prevention. Lab Diagnosis of Influenza. Retrieved 1 May 2009

33. ̂ Kawaoka Y (editor) (2006). Influenza Virology: Current Topics. Caister Academic Press. ISBN 978-1-904455-06-6.

34. ̂ Vainionpää R, Hyypiä T (April 1994). "Biology of parainfluenza viruses". Clin. Microbiol. Rev. 7 (2): 265–75. doi:10.1128/CMR.7.2.265. PMC 358320. PMID 8055470.

35. ̂ Hall CB (June 2001). "Respiratory syncytial virus and parainfluenza virus". N. Engl. J. Med. 344 (25): 1917–28. doi:10.1056/NEJM200106213442507. PMID 11419430.

36. ̂ Klenk (2008). "Avian Influenza: Molecular Mechanisms of Pathogenesis and Host Range". Animal Viruses: Molecular Biology. Caister Academic Press. ISBN 978-1-904455-22-6.

37. ^ a b c d Hay, A; Gregory V, Douglas A, Lin Y (29 December 2001). "The evolution of human influenza viruses". Philos Trans R Soc Lond B Biol Sci 356 (1416): 1861–70. doi:10.1098/rstb.2001.0999. PMC 1088562. PMID 11779385.

38. ̂ Fouchier, RAM; Schneeberger, PM; Rozendaal, FW; Broekman, JM; Kemink, SA; Munster, V; Kuiken, T; Rimmelzwaan, GF et al. (2004). "Avian influenza A virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome". Proceedings of the National Academy of Sciences 101 (5): 1356–61. Bibcode 2004PNAS..101.1356F. doi:10.1073/pnas.0308352100. PMC 337057. PMID 14745020.

39. ̂ Osterhaus, A; Rimmelzwaan G, Martina B, Bestebroer T, Fouchier R (2000). "Influenza B virus in seals". Science 288 (5468): 1051–3. Bibcode 2000Sci...288.1051O. doi:10.1126/science.288.5468.1051. PMID 10807575.

40. ̂ Jakeman KJ, Tisdale M, Russell S, Leone A, Sweet C (August 1994). "Efficacy of 2'-deoxy-2'-fluororibosides against influenza A and B viruses in ferrets". Antimicrob. Agents Chemother. 38 (8): 1864–7. PMC 284652. PMID 7986023.

41. ̂ Nobusawa, E; Sato K (April 2006). "Comparison of the mutation rates of human influenza A and B viruses". J Virol 80 (7): 3675–8. doi:10.1128/JVI.80.7.3675-3678.2006. PMC 1440390. PMID 16537638.

42. ^ a b c d R, Webster; Bean W, Gorman O, Chambers T, Kawaoka Y (1992). "Evolution and ecology of influenza A viruses". Microbiol Rev 56 (1): 152–79. PMC 372859. PMID 1579108.

43. ̂ Zambon, M (November 1999). "Epidemiology and pathogenesis of influenza". J Antimicrob Chemother 44 Suppl B (90002): 3–9. doi:10.1093/jac/44.suppl_2.3. PMID 10877456.

44. ̂ Matsuzaki, Y; Sugawara K, Mizuta K, Tsuchiya E, Muraki Y, Hongo S, Suzuki H, Nakamura K (2002). "Antigenic and genetic characterization of influenza C viruses which caused two outbreaks in Yamagata City, Japan, in 1996 and 1998". J Clin Microbiol 40 (2): 422–9. doi:10.1128/JCM.40.2.422-429.2002. PMC 153379. PMID 11825952.

45. ^ a b Taubenberger, JK; Morens, DM (2008). "The pathology of influenza virus infections". Annu Rev Pathol 3: 499–522. doi:10.1146/annurev.pathmechdis.3.121806.154316. PMC 2504709. PMID 18039138.

46. ̂ Matsuzaki, Y; Katsushima N, Nagai Y, Shoji M, Itagaki T, Sakamoto M, Kitaoka S, Mizuta K, Nishimura H (1 May 2006). "Clinical features of influenza C virus infection in children". J Infect Dis 193 (9): 1229–35. doi:10.1086/502973. PMID 16586359.

47. ̂ Katagiri, S; Ohizumi A, Homma M (July 1983). "An outbreak of type C influenza in a children's home". J Infect Dis 148 (1): 51–6. doi:10.1093/infdis/148.1.51. PMID 6309999.

48. ̂ International Committee on Taxonomy of Viruses descriptions of:Orthomyxoviridae[dead

link],Influenzavirus B[dead link] and Influenzavirus C[dead link]

49. ̂ International Committee on Taxonomy of Viruses. "The Universal Virus Database, version 4: Influenza A".[dead link]

50. ^ a b Lamb RA, Choppin PW (1983). "The gene structure and replication of influenza virus". Annu. Rev. Biochem. 52: 467–506. doi:10.1146/annurev.bi.52.070183.002343. PMID 6351727.

51. ^ a b c d e Bouvier NM, Palese P (September 2008). "The biology of influenza viruses". Vaccine 26 Suppl 4: D49–53. doi:10.1016/j.vaccine.2008.07.039. PMC 3074182. PMID 19230160.

52. ̂ Ghedin, E; Sengamalay, NA; Shumway, M; Zaborsky, J; Feldblyum, T; Subbu, V; Spiro, DJ; Sitz, J et al. (October 2005). "Large-scale sequencing of human influenza reveals the dynamic nature of viral genome evolution". Nature 437 (7062): 1162–6. Bibcode 2005Natur.437.1162G. doi:10.1038/nature04239. PMID 16208317.

53. ̂ Suzuki, Y (2005). "Sialobiology of influenza: molecular mechanism of host range variation of influenza viruses". Biol Pharm Bull 28 (3): 399–408. doi:10.1248/bpb.28.399. PMID 15744059.

54. ̂ Wilson, J; von Itzstein M (July 2003). "Recent strategies in the search for new anti-influenza therapies". Curr Drug Targets 4 (5): 389–408. doi:10.2174/1389450033491019. PMID 12816348.

55. ^ a b c d Hilleman, M (19 August 2002). "Realities and enigmas of human viral influenza: pathogenesis, epidemiology and control". Vaccine 20 (25–26): 3068–87. doi:10.1016/S0264-410X(02)00254-2. PMID 12163258.

56. ^ a b Lynch JP, Walsh EE (April 2007). "Influenza: evolving strategies in treatment and prevention". Semin Respir Crit Care Med 28 (2): 144–58. doi:10.1055/s-2007-976487. PMID 17458769.

57. ̂ Smith AE, Helenius A (April 2004). "How viruses enter animal cells". Science 304 (5668): 237–42. Bibcode 2004Sci...304..237S. doi:10.1126/science.1094823. PMID 15073366.

58. ^ a b Wagner, R; Matrosovich M, Klenk H (May–June 2002). "Functional balance between haemagglutinin and neuraminidase in influenza virus infections". Rev Med Virol 12 (3): 159–66. doi:10.1002/rmv.352. PMID 11987141.

59. ^ a b Steinhauer DA (May 1999). "Role of hemagglutinin cleavage for the pathogenicity of influenza virus". Virology 258 (1): 1–20. doi:10.1006/viro.1999.9716. PMID 10329563.

60. ̂ Liu SL, Zhang ZL, Tian ZQ, Zhao HS, Liu H, Sun EZ, Xiao GF, Zhang W, Wang HZ, Pang DW (2011) Effectively and efficiently dissecting the infection of influenza virus by quantum dot-based single-particle tracking. ACS Nano

61. ̂ Lakadamyali, M; Rust M, Babcock H, Zhuang X (5 August 2003). "Visualizing infection of individual influenza viruses". Proc Natl Acad Sci USA 100 (16): 9280–5. Bibcode 2003PNAS..100.9280L. doi:10.1073/pnas.0832269100. PMC 170909. PMID 12883000.

62. ^ a b Pinto LH, Lamb RA (April 2006). "The M2 proton channels of influenza A and B viruses". J. Biol. Chem. 281 (14): 8997–9000. doi:10.1074/jbc.R500020200. PMID 16407184.

63. ̂ Cros, J; Palese P (September 2003). "Trafficking of viral genomic RNA into and out of the nucleus: influenza, Thogoto and Borna disease viruses". Virus Res 95 (1–2): 3–12. doi:10.1016/S0168-1702(03)00159-X. PMID 12921991.

64. ̂ Kash, J; Goodman A, Korth M, Katze M (July 2006). "Hijacking of the host-cell response and translational control during influenza virus infection". Virus Res 119 (1): 111–20. doi:10.1016/j.virusres.2005.10.013. PMID 16630668.

65. ̂ Nayak, D; Hui E, Barman S (December 2004). "Assembly and budding of influenza virus". Virus Res 106 (2): 147–65. doi:10.1016/j.virusres.2004.08.012. PMID 15567494.

66. ̂ Drake, J (1 May 1993). "Rates of spontaneous mutation among RNA viruses". Proc Natl Acad Sci USA 90 (9): 4171–5. Bibcode 1993PNAS...90.4171D. doi:10.1073/pnas.90.9.4171. PMC 46468. PMID 8387212.

67. ^ a b Carrat F, Luong J, Lao H, Sallé A, Lajaunie C, Wackernagel H (2006). "A 'small-world-like' model for comparing interventions aimed at preventing and controlling influenza pandemics". BMC Med 4: 26. doi:10.1186/1741-7015-4-26. PMC 1626479. PMID 17059593.

68. ̂ "CDC H1N1 Flu : Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009–2010 Season". Centers for Disease Control and Prevention.

69. ̂ Mitamura K, Sugaya N (2006). "[Diagnosis and Treatment of influenza—clinical investigation on viral shedding in children with influenza]". Uirusu 56 (1): 109–16. doi:10.2222/jsv.56.109. PMID 17038819.

70. ̂ Grassly NC, Fraser C (June 2008). "Mathematical models of infectious disease transmission". Nat. Rev. Microbiol. 6 (6): 477–87. doi:10.1038/nrmicro1845. PMID 18533288.

71. ^ a b c d e Weber TP, Stilianakis NI (November 2008). "Inactivation of influenza A viruses in the environment and modes of transmission: a critical review". J. Infect. 57 (5): 361–73. doi:10.1016/j.jinf.2008.08.013. PMID 18848358.

72. ̂ Hall CB (August 2007). "The spread of influenza and other respiratory viruses: complexities and conjectures". Clin. Infect. Dis. 45 (3): 353–9. doi:10.1086/519433. PMID 17599315.

73. ̂ Tellier R (November 2006). "Review of aerosol transmission of influenza A virus". Emerging Infect. Dis. 12 (11): 1657–62. doi:10.3201/eid1211.060426. PMID 17283614.

74. ̂ Cole E, Cook C (1998). "Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies". Am J Infect Control 26 (4): 453–64. doi:10.1016/S0196-6553(98)70046-X. PMID 9721404.

75. ^ a b Thomas Y, Vogel G, Wunderli W et al. (May 2008). "Survival of influenza virus on banknotes". Appl. Environ. Microbiol. 74 (10): 3002–7. doi:10.1128/AEM.00076-08. PMC 2394922. PMID 18359825.

76. ̂ Bean B, Moore BM, Sterner B, Peterson LR, Gerding DN, Balfour HH (July 1982). "Survival of influenza viruses on environmental surfaces". J. Infect. Dis. 146 (1): 47–51. doi:10.1093/infdis/146.1.47. PMID 6282993.

77. ^ a b "Influenza Factsheet". Center for Food Security and Public Health, Iowa State University. p. 7

78. ̂ Jefferies WM, Turner JC, Lobo M, Gwaltney JM Jr (1998). "Low plasma levels of adrenocorticotropic hormone in patients with acute influenza". Clin Infect Dis. 26 (3): 708–10. doi:10.1086/514594. PMID 9524849.

79. ^ a b Korteweg C, Gu J (May 2008). "Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans". Am. J. Pathol. 172 (5): 1155–70. doi:10.2353/ajpath.2008.070791. PMC 2329826. PMID 18403604.

80. ̂ Nicholls JM, Chan RW, Russell RJ, Air GM, Peiris JS (April 2008). "Evolving complexities of influenza virus and its receptors". Trends Microbiol. 16 (4): 149–57. doi:10.1016/j.tim.2008.01.008. PMID 18375125.

81. ̂ van Riel D, Munster VJ, de Wit E et al. (April 2006). "H5N1 Virus Attachment to Lower Respiratory Tract". Science 312 (5772): 399. doi:10.1126/science.1125548. PMID 16556800.

82. ̂ Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka Y (March 2006). "Avian flu: influenza virus receptors in the human airway". Nature 440 (7083): 435–6. Bibcode 2006Natur.440..435S. doi:10.1038/440435a. PMID 16554799.

83. ̂ van Riel D, Munster VJ, de Wit E et al. (October 2007). "Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals". Am. J. Pathol. 171 (4): 1215–23. doi:10.2353/ajpath.2007.070248. PMC 1988871. PMID 17717141.

84. ̂ Schmitz N, Kurrer M, Bachmann M, Kopf M (2005). "Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection". J Virol 79 (10): 6441–8. doi:10.1128/JVI.79.10.6441-6448.2005. PMC 1091664. PMID 15858027.

85. ̂ Winther B, Gwaltney J, Mygind N, Hendley J (1998). "Viral-induced rhinitis". Am J Rhinol 12 (1): 17–20. doi:10.2500/105065898782102954. PMID 9513654.

86. ̂ Cheung CY, Poon LL, Lau AS et al. (December 2002). "Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease?". Lancet 360 (9348): 1831–7. doi:10.1016/S0140-6736(02)11772-7. PMID 12480361.

87. ̂ Kobasa D, Jones SM, Shinya K et al. (January 2007). "Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus". Nature 445 (7125): 319–23. Bibcode 2007Natur.445..319K. doi:10.1038/nature05495. PMID 17230189.

88. ̂ Kash JC, Tumpey TM, Proll SC et al. (October 2006). "Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus". Nature 443 (7111): 578–81. Bibcode 2006Natur.443..578K. doi:10.1038/nature05181. PMC 2615558. PMID 17006449.

89. ^ a b Beigel J, Bray M (April 2008). "Current and future antiviral therapy of severe seasonal and avian influenza". Antiviral Res. 78 (1): 91–102. doi:10.1016/j.antiviral.2008.01.003. PMC 2346583. PMID 18328578.

90. ̂ "Vaccine use". World Health Organization. Retrieved 6 December 2012.91. ̂ Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, Strikas RA (July 2006). "Prevention and

Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)". MMWR Recomm Rep 55 (RR–10): 1–42. PMID 16874296.

92. ̂ Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E (2010). "Vaccines for preventing influenza in healthy adults". Cochrane Database Syst Rev (7): CD001269. doi:10.1002/14651858.CD001269.pub4. PMID 20614424.

93. ̂ Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Ferroni E (2012). "Vaccines for preventing influenza in healthy children". Cochrane Database Syst Rev 8: CD004879. doi:10.1002/14651858.CD004879.pub4. PMID 22895945.

94. ̂ Poole PJ, Chacko E, Wood-Baker RW, Cates CJ (2006). "Influenza vaccine for patients with chronic obstructive pulmonary disease". Cochrane Database Syst Rev (1): CD002733. doi:10.1002/14651858.CD002733.pub2. PMID 16437444.

95. ̂ Cates CJ, Jefferson TO, Rowe BH (2008). "Vaccines for preventing influenza in people with asthma". Cochrane Database Syst Rev (2): CD000364. doi:10.1002/14651858.CD000364.pub3. PMID 18425863.

96. ̂ Abramson ZH (2012). "What, in Fact, Is the Evidence That Vaccinating Healthcare Workers against Seasonal Influenza Protects Their Patients? A Critical Review". Int J Family Med 2012: 205464. doi:10.1155/2012/205464. PMID 23209901.

97. ̂ Thomas RE, Jefferson T, Lasserson TJ (2010). "Influenza vaccination for healthcare workers who work with the elderly". Cochrane Database Syst Rev (2): CD005187. doi:10.1002/14651858.CD005187.pub3. PMID 20166073.

98. ̂ Beck, CR; McKenzie, BC; Hashim, AB; Harris, RC; University of Nottingham Influenza and the ImmunoCompromised (UNIIC) Study, Group,; Nguyen-Van-Tam, JS (2012 Oct). "Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by

etiology.". The Journal of infectious diseases 206 (8): 1250–9. doi:10.1093/infdis/jis487. PMID 22904335.

99. ^ a b Recommended composition of influenza virus vaccines for use in the 2006–2007 influenza season WHO report 14 February 2006. Retrieved 19 October 2006.

100. ̂ Holmes, E; Ghedin E, Miller N, Taylor J, Bao Y, St George K, Grenfell B, Salzberg S, Fraser C, Lipman D, Taubenberger J (September 2005). "Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses". PLoS Biol 3 (9): e300. doi:10.1371/journal.pbio.0030300. PMC 1180517. PMID 16026181.

101. ^ a b Key Facts about Influenza (Flu) Vaccine CDC publication. Published 17 October 2006. Retrieved 18 October 2006.

102. ̂ Questions & Answers: Flu Shot CDC publication updated 24 July 2006. Retrieved 19 October 2006.

103. ̂ Newall, Anthony T.; Jit, Mark; Beutels, Philippe (1 August 2012). "Economic Evaluations of Childhood Influenza Vaccination". PharmacoEconomics 30 (8): 647–660. doi:10.2165/11599130-000000000-00000.

104. ̂ Postma, Maarten J; Baltussen, Rob PM; Palache, Abraham M; Wilschut, Jan C (1 April 2006). "Further evidence for favorable cost-effectiveness of elderly influenza vaccination". Expert Review of Pharmacoeconomics & Outcomes Research 6 (2): 215–227. doi:10.1586/14737167.6.2.215. PMID 20528557.

105. ̂ Newall, Anthony T.; Kelly, Heath; Harsley, Stuart; Scuffham, Paul A. (1 June 2009). "Cost Effectiveness of Influenza Vaccination in Older Adults". PharmacoEconomics 27 (6): 439–450. doi:10.2165/00019053-200927060-00001. PMID 19640008.

106. ̂ Center for Disease Control and Prevention: "QUESTIONS & ANSWERS: Novel H1N1 Flu (Swine Flu) and You". Retrieved 15 December 2009.

107. ̂ Grayson ML, Melvani S, Druce J et al. (February 2009). "Efficacy of soap and water and alcohol-based hand-rub preparations against live H1N1 influenza virus on the hands of human volunteers". Clin. Infect. Dis. 48 (3): 285–91. doi:10.1086/595845. PMID 19115974.

108. ^ a b c d Aledort JE, Lurie N, Wasserman J, Bozzette SA (2007). "Non-pharmaceutical public health interventions for pandemic influenza: an evaluation of the evidence base". BMC Public Health 7: 208. doi:10.1186/1471-2458-7-208. PMC 2040158. PMID 17697389.

109. ̂ MacIntyre CR, Cauchemez S, Dwyer DE et al. (February 2009). "Face mask use and control of respiratory virus transmission in households". Emerging Infect. Dis. 15 (2): 233–41. doi:10.3201/eid1502.081167. PMC 2662657. PMID 19193267.

110. ̂ Bridges CB, Kuehnert MJ, Hall CB (October 2003). "Transmission of influenza: implications for control in health care settings". Clin. Infect. Dis. 37 (8): 1094–101. doi:10.1086/378292. PMID 14523774.

111. ̂ Interim Guidance for the Use of Masks to Control Influenza Transmission Coordinating Center for Infectious Diseases (CCID) 8 August 2005

112. ̂ Murin, Susan; Kathryn Smith Bilello (2005). "Respiratory tract infections: another reason not to smoke". Cleveland Clinic Journal of Medicine 72 (10): 916–920. doi:10.3949/ccjm.72.10.916. PMID 16231688. Retrieved 1 October 2009.

113. ̂ Kark, J D; M Lebiush, L Rannon (1982). "Cigarette smoking as a risk factor for epidemic a(h1n1) influenza in young men". The New England Journal of Medicine 307 (17): 1042–1046. doi:10.1056/NEJM198210213071702. ISSN 0028-4793. PMID 7121513.

114. ̂ Hota B; Hota, B. (2004). "Contamination, disinfection, and cross-colonization: are hospital surfaces reservoirs for nosocomial infection?". Clin Infect Dis 39 (8): 1182–9. doi:10.1086/424667. PMID 15486843.

115. ^ a b McDonnell G, Russell A (1 January 1999). "Antiseptics and disinfectants: activity, action, and resistance". Clin Microbiol Rev 12 (1): 147–79. PMC 88911. PMID 9880479.

116. ̂ "Chlorine Bleach: Helping to Manage the Flu Risk". Water Quality & Health Council. April 2009. Retrieved 12 May 2009.

117. ̂ Hatchett RJ, Mecher CE, Lipsitch M (2007). "Public health interventions and epidemic intensity during the 1918 influenza pandemic". Proc Natl Acad Sci U S A. 104 (18): 7582–7587. Bibcode 2007PNAS..104.7582H. doi:10.1073/pnas.0610941104. PMC 1849867. PMID 17416679.

118. ̂ Bootsma MC, Ferguson NM (2007). "The effect of public health measures on the 1918 influenza pandemic in U.S. cities". Proc Natl Acad Sci U S A. 104 (18): 7588–7593. Bibcode 2007PNAS..104.7588B. doi:10.1073/pnas.0611071104. PMC 1849868. PMID 17416677.

119. ̂ "Flu: MedlinePlus Medical Encyclopedia". U.S. National Library of Medicine. Retrieved 7 February 2010.

120. ̂ Glasgow, J; Middleton B (2001). "Reye syndrome — insights on causation and prognosis". Arch Dis Child 85 (5): 351–3. doi:10.1136/adc.85.5.351. PMC 1718987. PMID 11668090.

121. ̂ Hurt AC, Ho HT, Barr I (October 2006). "Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors". Expert Rev Anti Infect Ther 4 (5): 795–805. doi:10.1586/14787210.4.5.795. PMID 17140356.

122. ̂ Transcript of virtual press conference with Gregory Hartl, Spokesperson for H1N1, and Dr Nikki Shindo, Medical Officer, Global Influenza Programme, World Health Organization, 12 November 2009. " . . . persistent or rapidly worsening symptoms should also be treated with antivirals. These symptoms include difficulty breathing and a high fever that lasts beyond 3 days. . . [page 1]" " . . . The pandemic virus can cause severe pneumonia even in healthy young people . . . [page 2]"

123. ̂ Jamieson, D. J.; Honein, M. A.; Rasmussen, S. A.; Williams, J. L.; Swerdlow, D. L.; Biggerstaff, M. S.; Lindstrom, S.; Louie, J. K. et al. (2009). "H1N1 2009 influenza virus infection during pregnancy in the USA". The Lancet 374 (9688): 451–458. doi:10.1016/S0140-6736(09)61304-0. edit

124. ̂ Hsu J, Santesso N, Mustafa R, et al. (April 2012). "Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies". Ann. Intern. Med. 156 (7): 512–24. doi:10.1059/0003-4819-156-7-201204030-00411. PMID 22371849.

125. ̂ Webster, Robert G; Govorkova, EA (2006). "H5N1 Influenza — Continuing Evolution and Spread" (PDF). N Engl J Med 355 (21): 2174–77. doi:10.1056/NEJMp068205. PMID 17124014.

126. ̂ Stephenson, I; Nicholson K (1999). "Chemotherapeutic control of influenza". J Antimicrob Chemother 44 (1): 6–10. doi:10.1093/jac/44.1.6. PMID 10459804.

127. ̂ "High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents — United States, 2005–06 influenza season". MMWR Morb Mortal Wkly Rep 55 (2): 44–6. 2006. PMID 16424859.

128. ̂ Bright, Rick A; Medina, Marie-jo; Xu, Xiyan; Perez-Oronoz, Gilda; Wallis, Teresa R; Davis, Xiaohong M; Povinelli, Laura; Cox, Nancy J et al. (2005). "Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern". The Lancet 366 (9492): 1175–81. doi:10.1016/S0140-6736(05)67338-2. PMID 16198766.

129. ̂ Ilyushina NA, Govorkova EA, Webster RG (October 2005). "Detection of amantadine-resistant variants among avian influenza viruses isolated in North America and Asia". Virology 341 (1): 102–6. doi:10.1016/j.virol.2005.07.003. PMID 16081121.

130. ̂ Parry J (July 2005). "Use of antiviral drug in poultry is blamed for drug resistant strains of avian flu". BMJ 331 (7507): 10. doi:10.1136/bmj.331.7507.10. PMC 558527. PMID 15994677.

131. ̂ Centers for Disease Control and Prevention. CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season. 14 January 2006. Retrieved 2007-01-01

132. ̂ Hayden FG (March 1997). "Prevention and treatment of influenza in immunocompromised patients". Am. J. Med. 102 (3A): 55–60; discussion 75–6. doi:10.1016/S0002-9343(97)80013-7. PMID 10868144.

133. ̂ Whitley RJ, Monto AS (2006). "Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents". J Infect Dis. 194 S2: S133–8. doi:10.1086/507548. PMID 17163386.

134. ̂ Angelo SJ, Marshall PS, Chrissoheris MP, Chaves AM (April 2004). "Clinical characteristics associated with poor outcome in patients acutely infected with Influenza A". Conn Med 68 (4): 199–205. PMID 15095826.

135. ̂ Murin S, Bilello K (2005). "Respiratory tract infections: another reason not to smoke". Cleve Clin J Med 72 (10): 916–20. doi:10.3949/ccjm.72.10.916. PMID 16231688.

136. ̂ Sandman, Peter M; Lanard, Jody (2005). "Bird Flu: Communicating the Risk". Perspectives in Health Magazine 10 (2): 1–6.

137. ^ a b Sivadon-Tardy V, Orlikowski D, Porcher R et al. (January 2009). "Guillain-Barré syndrome and influenza virus infection". Clin. Infect. Dis. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.

138. ̂ Jacobs BC, Rothbarth PH, van der Meché FG et al. (October 1998). "The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study". Neurology 51 (4): 1110–5. PMID 9781538.

139. ̂ Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P (March 2009). "Safety of trivalent inactivated influenza vaccines in adults: Background for pandemic influenza vaccine safety monitoring". Vaccine 27 (15): 2114–2120. doi:10.1016/j.vaccine.2009.01.125. PMID 19356614.

140. ̂ Stowe J, Andrews N, Wise L, Miller E (February 2009). "Investigation of the temporal association of Guillain-Barre syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Research Database". Am. J. Epidemiol. 169 (3): 382–8. doi:10.1093/aje/kwn310. PMID 19033158.

141. ̂ Sivadon-Tardy V, Orlikowski D, Porcher R et al. (January 2009). "Guillain-Barré syndrome and influenza virus infection". Clin. Infect. Dis. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491.

142. ̂ Weather and the Flu Season NPR Day to Day, 17 December 2003. Retrieved, 19 October 2006

143. ̂ Lowen, AC; Mubareka, S; Steel, J; Palese, P (October 2007). "Influenza virus transmission is dependent on relative humidity and temperature" (PDF). PLoS Pathogens 3 (10): 1470–6. doi:10.1371/journal.ppat.0030151. PMC 2034399. PMID 17953482.

144. ̂ Shaman J, Kohn M (March 2009). "Absolute humidity modulates influenza survival, transmission, and seasonality". Proc. Natl. Acad. Sci. U.S.A. 106 (9): 3243–8. Bibcode 2009PNAS..106.3243S. doi:10.1073/pnas.0806852106. PMC 2651255. PMID 19204283.

145. ̂ Shaman J, Pitzer VE, Viboud C, Grenfell BT, Lipsitch M (February 2010). Ferguson, Neil M. ed. "Absolute humidity and the seasonal onset of influenza in the continental United States". PLoS Biol. 8 (2): e1000316. doi:10.1371/journal.pbio.1000316. PMC 2826374. PMID 20186267.

146. ̂ Shek, LP; Lee, BW (2003). "Epidemiology and seasonality of respiratory tract virus infections in the tropics". Paediatric respiratory reviews 4 (2): 105–11. doi:10.1016/S1526-0542(03)00024-1. PMID 12758047.

147. ̂ Dushoff, J; Plotkin, JB; Levin, SA; Earn, DJ (2004). "Dynamical resonance can account for seasonality of influenza epidemics". Proceedings of the National Academy of

Sciences of the United States of America 101 (48): 16915–6. Bibcode 2004PNAS..10116915D. doi:10.1073/pnas.0407293101. PMC 534740. PMID 15557003.

148. ̂ WHO Confirmed Human Cases of H5N1 Data published by WHO Epidemic and Pandemic Alert and Response (EPR). Retrieved 24 October 2006

149. ̂ Cannell, J; Vieth R, Umhau J, Holick M, Grant W, Madronich S, Garland C, Giovannucci E (2006). "Epidemic influenza and vitamin D". Epidemiol Infect 134 (6): 1129–40. doi:10.1017/S0950268806007175. PMC 2870528. PMID 16959053.

150. ̂ HOPE-SIMPSON, R (1965). "The nature of herpes zoster: a long-term study and a new hypothesis". Proc R Soc Med 58: 9–20. PMC 1898279. PMID 14267505.

151. ̂ Influenza WHO Fact sheet No. 211 revised March 2003. Retrieved 22 October 2006.

152. ̂ Thompson, W; Shay D, Weintraub E, Brammer L, Cox N, Anderson L, Fukuda K (2003). "Mortality associated with influenza and respiratory syncytial virus in the United States". JAMA 289 (2): 179–86. doi:10.1001/jama.289.2.179. PMID 12517228.

153. ̂ Thompson, W; Shay D, Weintraub E, Brammer L, Bridges C, Cox N, Fukuda K (2004). "Influenza-associated hospitalizations in the United States". JAMA 292 (11): 1333–40. doi:10.1001/jama.292.11.1333. PMID 15367555.

154. ̂ Jonathan Dushoff; Plotkin, JB; Viboud, C; Earn, DJ; Simonsen, L (2006). Mortality due to Influenza in the United States — An Annualized Regression Approach Using Multiple-Cause Mortality Data. 163. 181–7. doi:10.1093/aje/kwj024. PMID 16319291. Retrieved 29 October 2009. "The regression model attributes an annual average of 41,400 (95% confidence interval: 27,100, 55,700) deaths to influenza over the period 1979–2001"

155. ̂ Julie Steenhuysen (26 August 2010). "CDC backs away from decades-old flu death estimate". Reuters. Retrieved 13 September 2010. "Instead of the estimated 36,000 annual flu deaths in the United States ... the actual number in the past 30 years has ranged from a low of about 3,300 deaths to a high of nearly 49,000, the CDC said on Thursday"

156. ̂ Murray CJ, Lopez AD, Chin B, Feehan D, Hill KH (December 2006). "Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918–20 pandemic: a quantitative analysis". Lancet 368 (9554): 2211–8. doi:10.1016/S0140-6736(06)69895-4. PMID 17189032.

157. ̂ Wolf, Yuri I; Viboud, C; Holmes, EC; Koonin, EV; Lipman, DJ (2006). "Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza A virus". Biol Direct 1 (1): 34. doi:10.1186/1745-6150-1-34. PMC 1647279. PMID 17067369.

158. ̂ Parrish, C; Kawaoka Y (2005). "The origins of new pandemic viruses: the acquisition of new host ranges by canine parvovirus and influenza A viruses". Annual Rev Microbiol 59: 553–86. doi:10.1146/annurev.micro.59.030804.121059. PMID 16153179.

159. ̂ Recker M, Pybus OG, Nee S, Gupta S (2007). "The generation of influenza outbreaks by a network of host immune responses against a limited set of antigenic types". Proc Natl Acad Sci U S A. 104 (18): 7711–16. Bibcode 2007PNAS..104.7711R. doi:10.1073/pnas.0702154104. PMC 1855915. PMID 17460037.

160. ^ a b Ferguson, NM; Cummings DA, Cauchemez S, Fraser C, Riley S, Meeyai A, Iamsirithaworn S, Burke DS (2005). "Strategies for containing an emerging influenza pandemic in Southeast Asia". Nature 437 (7056): 209–14. Bibcode 2005Natur.437..209F. doi:10.1038/nature04017. PMID 16079797.

161. ̂ Influenza, The Oxford English Dictionary, second edition.162. ̂ Creighton, Charles (1965): A History Of Epidemics In Britain, With Additional

Material By D.E.C. Eversley163. ̂ Potter, CW (2001). "A history of influenza". Journal of applied microbiology 91 (4):

572–579. doi:10.1046/j.1365-2672.2001.01492.x. PMID 11576290.164. ̂ Smith, P (2009). "Swine Flu". Croatian Medical Journal 50 (4): 412–5.

doi:10.3325/cmj.2009.50.412. PMC 2728380. PMID 19673043.

165. ^ a b c Taubenberger, J; Morens D (2006). "1918 Influenza: the mother of all pandemics". Emerg Infect Dis 12 (1): 15–22. PMID 16494711.

166. ̂ Martin, P; Martin-Granel E (June 2006). "2,500-year evolution of the term epidemic". Emerg Infect Dis 12 (6): 976–80. doi:10.3201/eid1206.051263. PMID 16707055.

167. ̂ Hippocrates; Adams, Francis (transl.) (400 BCE). "Of the Epidemics". Retrieved 18 October 2006.

168. ̂ Beveridge, W I (1991). "The chronicle of influenza epidemics". History and Philosophy of the Life Sciences 13 (2): 223–234. PMID 1724803.

169. ^ a b c d Potter CW (October 2001). "A History of Influenza". Journal of Applied Microbiology 91 (4): 572–579. doi:10.1046/j.1365-2672.2001.01492.x. PMID 11576290.

170. ̂ Guerra, Francisco (1988). "The Earliest American Epidemic: The Influenza of 1493". Social Science History 12 (3): 305–325. doi:10.2307/1171451. JSTOR 1171451. PMID 11618144. (only the first page can be read for free, but that has enough information about influenza being the main disease brought by Columbus killing 90 % of the indiginous population)

171. ̂ Guerra, F (1993). "The European-American exchange". History and Philosophy of the Life Sciences 15 (3): 313–327. PMID 7529930.

172. ̂ Taubenberger, Jeffery; David Morens (2006). "1918 Influenza: the Mother of All Pandemics". Emerging Infectious Diseases 12 (1). Retrieved 5 September 2012.

173. ^ a b c d e Knobler S, Mack A, Mahmoud A, Lemon S, ed. "1: The Story of Influenza". The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005). Washington, D.C.: The National Academies Press. pp. 60–61.

174. ^ a b Patterson, KD; Pyle GF (Spring 1991). "The geography and mortality of the 1918 influenza pandemic". Bull Hist Med. 65 (1): 4–21. PMID 2021692.

175. ̂ Taubenberger JK, Reid AH, Janczewski TA, Fanning TG (December 2001). "Integrating historical, clinical and molecular genetic data in order to explain the origin and virulence of the 1918 Spanish influenza virus". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356 (1416): 1829–39. doi:10.1098/rstb.2001.1020. PMC 1088558. PMID 11779381.

176. ̂ Simonsen, L; Clarke M, Schonberger L, Arden N, Cox N, Fukuda K (July 1998). "Pandemic versus epidemic influenza mortality: a pattern of changing age distribution". J Infect Dis 178 (1): 53–60. PMID 9652423.

177. ̂ "Ten things you need to know about pandemic influenza". World Health Organization. 14 October 2005. Archived from the original on 23 September 2009. Retrieved 26 September 2009.

178. ̂ Valleron AJ, Cori A, Valtat S, Meurisse S, Carrat F, Boëlle PY (May 2010). "Transmissibility and geographic spread of the 1889 influenza pandemic". Proc. Natl. Acad. Sci. U.S.A. 107 (19): 8778–81. Bibcode 2010PNAS..107.8778V. doi:10.1073/pnas.1000886107. PMC 2889325. PMID 20421481.

179. ̂ Mills CE, Robins JM, Lipsitch M (December 2004). "Transmissibility of 1918 pandemic influenza". Nature 432 (7019): 904–6. Bibcode 2004Natur.432..904M. doi:10.1038/nature03063. PMID 15602562.

180. ̂ Donaldson LJ, Rutter PD, Ellis BM et al. (2009). "Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study". BMJ 339: b5213. doi:10.1136/bmj.b5213. PMC 2791802. PMID 20007665.

181. ̂ Heinen PP (15 September 2003). "Swine influenza: a zoonosis". Veterinary Sciences Tomorrow. ISSN 1569-0830.

182. ̂ Shimizu, K (October 1997). "History of influenza epidemics and discovery of influenza virus". Nippon Rinsho 55 (10): 2505–201. PMID 9360364.

183. ̂ Smith, W; Andrewes CH, Laidlaw PP (1933). "A virus obtained from influenza patients". Lancet 2 (5732): 66–68. doi:10.1016/S0140-6736(00)78541-2.

184. ̂ Palese P (December 2004). "Influenza: old and new threats". Nat. Med. 10 (12 Suppl): S82–7. doi:10.1038/nm1141. PMID 15577936.

185. ̂ Sir Frank Macfarlane Burnet: Biography The Nobel Foundation. Retrieved 22 October 2006

186. ̂ Kendall, H (2006). "Vaccine Innovation: Lessons from World War II". Journal of Public Health Policy 27 (1): 38–57. doi:10.1057/palgrave.jphp.3200064. PMID 16681187.

187. ̂ Statement from President George W. Bush on Influenza Retrieved 26 October 2006

188. ̂ Brainerd, E. and M. Siegler (2003), "The Economic Effects of the 1918 Influenza Epidemic", CEPR Discussion Paper, no. 3791.

189. ̂ Poland G (2006). "Vaccines against avian influenza—a race against time" (PDF). N Engl J Med 354 (13): 1411–3. doi:10.1056/NEJMe068047. PMID 16571885.

190. ^ a b Rosenthal, E; Bradsher, K (16 March 2006). "Is Business Ready for a Flu Pandemic?". The New York Times. Retrieved 17 April 2006.

191. ̂ National Strategy for Pandemic Influenza Whitehouse.gov Retrieved 26 October 2006.

192. ̂ Bush Outlines $7 Billion Pandemic Flu Preparedness Plan US Mission to the EU. Retrieved 12 December 2009.

193. ̂ Donor Nations Pledge $1.85 Billion to Combat Bird Flu Newswire Retrieved 26 October 2006.

194. ̂ Assessment of the 2009 Influenza A (H1N1) Outbreak on Selected Countries in the Southern Hemisphere. 2009. http://flu.gov/professional/global/southhemisphere.html

195. ̂ Influenza A Virus Genome Project at The Institute of Genomic Research. Retrieved 19 October 2006

196. ̂ Subbarao K, Katz J (2004). "Influenza vaccines generated by reverse genetics". Curr Top Microbiol Immunol 283: 313–42. PMID 15298174.

197. ̂ Bardiya N, Bae J (2005). "Influenza vaccines: recent advances in production technologies". Appl Microbiol Biotechnol 67 (3): 299–305. doi:10.1007/s00253-004-1874-1. PMID 15660212.

198. ̂ Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W (October 1999). "A universal influenza A vaccine based on the extracellular domain of the M2 protein". Nat. Med. 5 (10): 1157–63. doi:10.1038/13484. PMID 10502819.

199. ̂ Fiers W, Neirynck S, Deroo T, Saelens X, Jou WM (December 2001). "Soluble recombinant influenza vaccines". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356 (1416): 1961–3. doi:10.1098/rstb.2001.0980. PMC 1088575. PMID 11779398.

200. ̂ Fiers W, De Filette M, Birkett A, Neirynck S, Min Jou W (July 2004). "A "universal" human influenza A vaccine". Virus Res. 103 (1–2): 173–6. doi:10.1016/j.virusres.2004.02.030. PMID 15163506.

201. ̂ Petsch B, Schnee M, Vogel AB, et al. (November 2012). "Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection". Nat. Biotechnol.. doi:10.1038/nbt.2436. PMID 23159882.

202. ̂ Stephen Adams (8 July 2011). "Universal flu vaccine a step closer". The Telegraph.203. ̂ Ekiert, DC; Friesen, RHE; Bhabha, G; Kwaks, T; Jongeneelen, M; Yu, W; Ophorst, C;

Cox, F et al. (2011). "A Highly Conserved Neutralizing Epitope on Group 2 Influenza a Viruses". Science 333 (6044): 843–50. Bibcode 2011Sci...333..843E. doi:10.1126/science.1204839. PMC 3210727. PMID 21737702.

204. ̂ Gingerich, DA (2008). "Lymphocyte T-Cell Immunomodulator: Review of the ImmunoPharmacology of a new Veterinary Biologic" (PDF). Journal of Applied Research in Veterinary Medicine 6 (2): 61–68. Retrieved 5 December 2010.

205. ̂ Gorman O, Bean W, Kawaoka Y, Webster R (1990). "Evolution of the nucleoprotein gene of influenza A virus". J Virol 64 (4): 1487–97. PMC 249282. PMID 2319644.

206. ̂ Hinshaw V, Bean W, Webster R, Rehg J, Fiorelli P, Early G, Geraci J, St Aubin D (1984). "Are seals frequently infected with avian influenza viruses?". J Virol 51 (3): 863–5. PMC 255856. PMID 6471169.

207. ̂ Capua, I; Alexander D (2006). "The challenge of avian influenza to the veterinary community" (PDF). Avian Pathol 35 (3): 189–205. doi:10.1080/03079450600717174. PMID 16753610.

208. ̂ Elbers A, Koch G, Bouma A (2005). "Performance of clinical signs in poultry for the detection of outbreaks during the avian influenza A (H7N7) epidemic in The Netherlands in 2003". Avian Pathol 34 (3): 181–7. doi:10.1080/03079450500096497. PMID 16191700.

209. ̂ Capua, I; Mutinelli, F (2001). "Low pathogenicity (LPAI) and highly pathogenic (HPAI) avian influenza in turkeys and chicken". A Colour Atlas and Text on Avian Influenza. Bologna: Papi Editore. pp. 13–20. ISBN 88-88369-00-7.

210. ̂ Bano S, Naeem K, Malik S (2003). "Evaluation of pathogenic potential of avian influenza virus serotype H9N2 in chickens". Avian Dis 47 (3 Suppl): 817–22. doi:10.1637/0005-2086-47.s3.817. PMID 14575070.

211. ̂ Swayne D, Suarez D (2000). "Highly pathogenic avian influenza". Rev Sci Tech 19 (2): 463–82. PMID 10935274.

212. ̂ Li K, Guan Y, Wang J, Smith G, Xu K, Duan L, Rahardjo A, Puthavathana P, Buranathai C, Nguyen T, Estoepangestie A, Chaisingh A, Auewarakul P, Long H, Hanh N, Webby R, Poon L, Chen H, Shortridge K, Yuen K, Webster R, Peiris J (2004). "Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia". Nature 430 (6996): 209–13. Bibcode 2004Natur.430..209L. doi:10.1038/nature02746. PMID 15241415.

213. ̂ Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Rahardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge KF, Yuen KY, Webster RG, Peiris JS. "The Threat of Pandemic Influenza: Are We Ready?" Workshop Summary The National Academies Press (2005) "Today's Pandemic Threat: Genesis of a Highly Pathogenic and Potentially Pandemic H5N1 Influenza Virus in Eastern Asia", pages 116–130

214. ̂ Liu J (2006). "Avian influenza—a pandemic waiting to happen?" (PDF). J Microbiol Immunol Infect 39 (1): 4–10. PMID 16440117.

215. ̂ Salomon R, Webster RG (February 2009). "The influenza virus enigma". Cell 136 (3): 402–10. doi:10.1016/j.cell.2009.01.029. PMC 2971533. PMID 19203576.

216. ^ a b c Kothalawala H, Toussaint MJ, Gruys E (June 2006). "An overview of swine influenza". Vet Q 28 (2): 46–53. PMID 16841566.

217. ̂ Myers KP, Olsen CW, Gray GC (April 2007). "Cases of swine influenza in humans: a review of the literature". Clin. Infect. Dis. 44 (8): 1084–8. doi:10.1086/512813. PMC 1973337. PMID 17366454.

218. ̂ Maria Zampaglione (29 April 2009). "Press Release: A/H1N1 influenza like human illness in Mexico and the USA: OIE statement". World Organisation for Animal Health. Archived from the original on 30 April 2009. Retrieved 29 April 2009.

219. ̂ Grady, Denise (1 May 2009). "W.H.O. Gives Swine Flu a Less Loaded, More Scientific Name". The New York Times. Retrieved 31 March 2010.

PneumoniaFrom Wikipedia, the free encyclopediaJump to: navigation, search For other uses, see Pneumonia (disambiguation).

PneumoniaClassification and external resources

A chest X-ray showing a very prominent wedge-shaped bacterial pneumonia in the right lung.

ICD-10 J 12 , J 13 , J 14 , J 15 , J 16 , J 17 , J 18 , P 23 ICD-9 480-486, 770.0DiseasesDB 10166MedlinePlus 000145eMedicine topic listMeSH D011014

Pneumonia is an inflammatory condition of the lung—affecting primarily the microscopic air sacs known as alveoli.[1][2] It is usually caused by infection with viruses or bacteria and less commonly other microorganisms, certain drugs and other conditions such as autoimmune diseases.[1][3]

Typical symptoms include a cough, chest pain, fever, and difficulty breathing.[4] Diagnostic tools include x-rays and culture of the sputum. Vaccines to prevent certain types of pneumonia are available. Treatment depends on the underlying cause. Presumed bacterial pneumonia is treated with antibiotics. If the pneumonia is severe, the affected person is generally admitted to hospital.

Annually, pneumonia affects approximately 450 million people, seven percent of the world's total, and results in about 4 million deaths. Although pneumonia was regarded by William Osler in the 19th century as "the captain of the men of death",[5] the advent of antibiotic therapy and vaccines in the 20th century has seen improvements in survival.[6] Nevertheless, in developing countries, and among the very old, the very young and the chronically ill, pneumonia remains a leading cause of death.[6][7]

Contents

1 Signs and symptoms 2 Cause

o 2.1 Bacteria o 2.2 Viruses o 2.3 Fungi o 2.4 Parasites o 2.5 Idiopathic

3 Pathophysiology o 3.1 Viral o 3.2 Bacterial

4 Diagnosis

o 4.1 Physical exam o 4.2 Imaging o 4.3 Microbiology o 4.4 Classification o 4.5 Differential diagnosis

5 Prevention o 5.1 Vaccination o 5.2 Other

6 Management o 6.1 Bacterial o 6.2 Viral o 6.3 Aspiration

7 Prognosis o 7.1 Clinical prediction rules o 7.2 Pleural effusion, empyema, and abscess o 7.3 Respiratory and circulatory failure

8 Epidemiology o 8.1 Children

9 History 10 Society and culture 11 References 12 External links

Signs and symptoms

Main symptoms of infectious pneumonia

People with infectious pneumonia often have a productive cough, fever accompanied by shaking chills, shortness of breath, sharp or stabbing chest pain during deep breaths, and an increased respiratory rate.[9] In the elderly, confusion may be the most prominent sign.[9] The typical signs and symptoms in children under five are fever, cough, and fast or difficult breathing.[10]

Symptoms frequency[8]

Symptom FrequencyCough 79–91%Fatigue 90%Fever 71–75%Shortness of breath 67–75%Sputum 60–65%Chest pain 39–49%

Fever is not very specific, as it occurs in many other common illnesses, and may be absent in those with severe disease or malnutrition. In addition, a cough is frequently absent in children less than 2 months old.[10] More severe signs and symptoms may include: blue-tinged skin, decreased thirst, convulsions, persistent vomiting, extremes of temperature, or a decreased level of consciousness.[10][11]

Bacterial and viral cases of pneumonia usually present with similar symptoms.[12] Some causes are associated with classic, but non-specific, clinical characteristics. Pneumonia caused by Legionella may occur with abdominal pain, diarrhea, or confusion,[13] while pneumonia caused by Streptococcus pneumoniae is associated with rusty colored sputum,[14] and pneumonia caused by Klebsiella may have bloody sputum often described as "currant jelly".[8] Bloody sputum (known as hemoptysis) may also occur with tuberculosis, Gram-negative pneumonia, and lung abscesses as well as more commonly with acute bronchitis.[11] Mycoplasma pneumonia may occur in association with swelling of the lymph nodes in the neck, joint pain, or a middle ear infection.[11] Viral pneumonia presents more commonly with wheezing than does bacterial pneumonia.[12]

Cause

The bacterium Streptococcus pneumoniae, a common cause of pneumonia, imaged by an electron microscope

Pneumonia is primarily due to infections caused by bacteria or viruses and less commonly by fungi and parasites. Although there are more than 100 strains of infectious agents identified, only a few are responsible for the majority of the cases. Mixed infections with both viruses and bacteria may occur in up to 45% of infections in children and 15% of infections in adults.[6] A causative agent may not be isolated in approximately half of cases despite careful testing.[15]

The term pneumonia is sometimes more broadly applied to any condition resulting in inflammation of the lungs (caused for example by autoimmune diseases, chemical burns or drug reactions); however, this inflammation is more accurately referred to as pneumonitis.[16]

[17] Infective agents were historically divided into "typical" and "atypical" based on their presumed presentations, but the evidence has not supported this distinction, thus it is no longer emphasized.[18]

Conditions and risk factors that predispose to pneumonia include: smoking, immunodeficiency, alcoholism, chronic obstructive pulmonary disease, chronic kidney disease, and liver disease.[11] The use of acid-suppressing medications -such as proton-pump

inhibitors or H2 blockers- is associated with an increased risk[19] of pneumonia. Old age also predisposes pneumonia.[11]

BacteriaMain article: Bacterial pneumonia

Bacteria are the most common cause of community-acquired pneumonia (CAP), with Streptococcus pneumoniae isolated in nearly 50% of cases.[20][21] Other commonly isolated bacteria include: Haemophilus influenzae in 20%, Chlamydophila pneumoniae in 13%, and Mycoplasma pneumoniae in 3% of cases;[20] Staphylococcus aureus; Moraxella catarrhalis; Legionella pneumophila and Gram-negative bacilli.[15] A number of drug-resistant versions of the above infections are becoming more common, including drug-resistant Streptococcus pneumoniae (DRSP) and methicillin-resistant Staphylococcus aureus (MRSA).[11]

The spreading of organisms is facilitated when risk factors are present.[15] Alcoholism is associated with Streptococcus pneumoniae, anaerobic organisms and Mycobacterium tuberculosis; smoking facilitates the effects of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Legionella pneumophila. Exposure to birds is associated with Chlamydia psittaci; farm animals with Coxiella burnetti; aspiration of stomach contents with anaerobic organisms; and cystic fibrosis with Pseudomonas aeruginosa and Staphylococcus aureus.[15]Streptococcus pneumoniae is more common in the winter,[15] and should be suspected in persons who aspirate a large amount anaerobic organisms.[11]

VirusesMain article: Viral pneumonia

In adults, viruses account for approximately a third[6] and in children for about 15% of pneumonia cases.[22] Commonly implicated agents include: rhinoviruses, coronaviruses, influenza virus, respiratory syncytial virus (RSV), adenovirus, and parainfluenza.[6][23] Herpes simplex virus rarely causes pneumonia, except in groups such as: newborns, persons with cancer, transplant recipients, and people who have significant burns.[24] People following organ transplantation or those who are otherwise immunocompromised present high rates of cytomegalovirus pneumonia.[22][24] Those with viral infections may be secondarily infected with the bacteria Streptococcus pneumoniae, Staphylococcus aureus, or Haemophilus influenzae, particularly when other health problems are present.[11][22] Different viruses predominate at different periods of the year, for example during influenza season influenza may account for over half of all viral cases.[22] Outbreaks of other viruses also occasionally occur, including hantaviruses and coronavirus.[22]

FungiMain article: Fungal pneumonia

Fungal pneumonia is uncommon, but occur more commonly in individuals with weakened immune systems due to AIDS, immunosuppressive drugs, or other medical problems.[15][25] It is most often caused by Histoplasma capsulatum, blastomyces, Cryptococcus neoformans, Pneumocystis jiroveci, and Coccidioides immitis. Histoplasmosis is most common in the Mississippi River basin, and coccidioidomycosis is most common in the Southwestern United States.[15] The number of cases have been increasing in the later half of the 20th century due to increasing travel and rates of immunosuppression in the population.[25]

ParasitesMain article: Parasitic pneumonia

A variety of parasites can affect the lungs, including: Toxoplasma gondii, Strongyloides stercoralis, Ascaris lumbricoides, and Plasmodium malariae.[26] These organisms typically enter the body through direct contact with the skin, ingestion, or via an insect vector.[26] Except for Paragonimus westermani, most parasites do not specifically affect the lungs but involve the lungs secondarily to other sites.[26] Some parasites, particularly those belonging to the Ascaris and Strongyloides genera, stimulate a strong eosinophilic reaction, which may result in eosinophilic pneumonia.[26] In other infections, such as malaria, lung involvement is primarily due to cytokine-induced systemic inflammation.[26] In the developed world these infections are most common in people returning from travel or in immigrants.[26] Globally these infections are most common in those who are immunodeficient.[27]

IdiopathicMain article: Idiopathic interstitial pneumonia

Idiopathic interstitial pneumonia or noninfectious pneumonia[28] are a class of diffuse lung diseases. They include: diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, lymphocytic interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, and usual interstitial pneumonia.[29]

Pathophysiology

Pneumonia fills the lung's alveoli with fluid, hindering oxygenation. The alveolus on the left is normal, whereas the one on the right is full of fluid from pneumonia.

Pneumonia frequently starts as an upper respiratory tract infection that moves into the lower respiratory tract.[30]

Viral

Viruses may reach the lung by a number of different routes. Respiratory syncytial virus is typically contracted when people touch contaminated objects and than they touch their eyes or nose.[22] Other viral infections occur when contaminated airborne droplets are inhaled through the mouth or nose.[11] Once in the upper airway the viruses may make their way in the lungs, where they invade the cells lining the airways, alveoli, or lung parenchyma.[22] Some viruses such as measles and herpes simplex may reach the lungs via the blood.[31] The invasion of the lungs may lead to varying degrees of cell death.[22] When the immune system responds to the infection, even more lung damage may occur.[22] White blood cells, mainly mononuclear cells, primarily generate the inflammation.[31] As well as damaging the lungs, many viruses simultaneously affect other organs and thus disrupt other body functions. Viruses also make the body more susceptible to bacterial infections; in this way bacterial pneumonia can arise as a co-morbid condition.[23]

Bacterial

Most bacteria enter the lungs via small aspirations of organisms residing in the throat or nose.[11] Half of normal people have these small aspirations during sleep.[18] While the throat always contains bacteria, potentially infectious ones reside there only at certain times and under certain conditions.[18] A minority of types of bacteria such as Mycobacterium tuberculosis and Legionella pneumophila reach the lungs via contaminated airborne droplets.[11] Bacteria can spread also via the blood.[12] Once in the lungs, bacteria may invade the spaces between cells and between alveoli, where the macrophages and neutrophils (defensive white blood cells) attempt to inactivate the bacteria.[32] The neutrophils also release cytokines, causing a general activation of the immune system.[33] This leads to the fever, chills, and fatigue common in bacterial pneumonia.[33] The neutrophils, bacteria, and fluid from surrounding blood vessels fill the alveoli resulting in the consolidation seen on chest X-ray.[34]

Diagnosis

Crackles

Menu0:00Crackles heard in the lungs of a person with pneumonia using a stethoscope.

Problems listening to this file? See media help.

Pneumonia is typically diagnosed based on a combination of physical signs and a chest X-ray.[35] However, the underlying cause can be difficult to confirm, as there is no definitive test able to distinguish between bacterial and non-bacterial origin.[6][35] The World Health Organization has defined pneumonia in children clinically based on either a cough or difficulty breathing and a rapid respiratory rate, chest indrawing, or a decreased level of

consciousness.[36] A rapid respiratory rate is defined as greater than 60 breaths per minute in children under 2 months old, 50 breaths per minute in children 2 months to 1 year old, or greater than 40 breaths per minute in children 1 to 5 years old.[36] In children, increased respiratory rate and lower chest indrawing are more sensitive than hearing chest crackles with a stethoscope.[10]

In adults, investigations are generally not needed in mild cases[37]: there is a very low risk of pneumonia if all vital signs and auscultation are normal.[38] In persons requiring hospitalization, pulse oximetry, chest radiography and blood tests—including a complete blood count, serum electrolytes, C-reactive protein level and possibly liver function tests—are recommended.[37] The diagnosis of influenza-like illness can be made based on the signs and symptoms; however, confirmation of an influenza infection requires testing.[39] Thus, treatment is frequently based on the presence of influenza in the community or a rapid influenza test.[39]

Physical exam

Physical examination may sometimes reveal low blood pressure, high heart rate or low oxygen saturation.[11] The respiratory rate may be faster than normal and this may occur a day or two before other signs.[11][18] Examination of the chest may be normal, but may show decreased chest expansion on the affected side. Harsh breath sounds from the larger airways that are transmitted through the inflamed lung are termed bronchial breathing, and are heard on auscultation with a stethoscope.[11] Crackles (rales) may be heard over the affected area during inspiration.[11] Percussion may be dulled over the affected lung, and increased, rather than decreased, vocal resonance distinguishes pneumonia from a pleural effusion.[9]

Imaging

CT of the chest demonstrating right sided pneumonia (left side of the image).

A chest radiograph is frequently used in diagnosis.[10] In people with mild disease, imaging is needed only in those with potential complications, those who have not improved with treatment, or those in which the cause in uncertain.[10][37] If a person is sufficiently sick to require hospitalization, a chest radiograph is recommended.[37] Findings do not always correlate with the severity of a disease and do not reliably distinguish between bacterial infection and viral infection.[10]

X-ray presentations of pneumonia may be classified as lobar pneumonia, bronchopneumonia (also known as lobular pneumonia), and interstitial pneumonia.[40] Bacterial, community-acquired pneumonia, classically show lung consolidation of one lung segmental lobe which is known as lobar pneumonia.[20] However, findings may vary, and other patterns are common in other types of pneumonia.[20] Aspiration pneumonia may present with bilateral opacities

primarily in the bases of the lungs and on the right side.[20] Radiographs of viral pneumonia may appear normal, hyper-inflated, have bilateral patchy areas, or present similar to bacterial pneumonia with lobar consolidation.[20] Radiologic findings may not be present in the early stages of the disease, especially in the presence of dehydration; or may be difficult to be interpreted in those who are obese or have a history of lung disease.[11] A CT scan can give additional information in indeterminate cases.[20]

Microbiology

In patients managed in the community, determining the causative agent is not cost effective and typically does not alter management.[10] For people who do not respond to treatment, sputum culture should be considered, and culture for Mycobacterium tuberculosis should be carried out in persons with a chronic productive cough.[37] Testing for other specific organisms may be recommended during outbreaks, for public health reasons.[37] In those who are hospitalized for severe disease, both sputum and blood cultures are recommended,[37] as well as testing the urine for antigens to Legionella and Streptococcus.[41] Viral infections can be confirmed via detection of either the virus or its antigens with culture or polymerase chain reaction (PCR), among other techniques.[6] The causative agent is determined in only 15% of cases with routine microbiological tests.[9]

ClassificationMain article: Classification of pneumonia

Pneumonitis refers to lung inflammation; pneumonia refers to pneumonitis, usually due to infection but sometimes non-infectious, that has the additional feature of pulmonary consolidation.[42] Pneumonia is most commonly classified by where or how it was acquired: community-acquired, aspiration, healthcare-associated, hospital-acquired, and ventilator-associated pneumonia.[20] It may also be classified by the area of lung affected: lobar pneumonia, bronchial pneumonia and acute interstitial pneumonia;[20] or by the causative organism.[43] Pneumonia in children may additionally be classified based on signs and symptoms as non-severe, severe, or very severe.[44]

Differential diagnosis

Several diseases can present with similar signs and symptoms to pneumonia, such as: chronic obstructive pulmonary disease (COPD), asthma, pulmonary edema, bronchiectasis, lung cancer, and pulmonary emboli.[9] Unlike pneumonia, asthma and COPD typically present with wheezing, pulmonary edema presents with an abnormal electrocardiogram, cancer and bronchiectasis present with a cough of longer duration, and pulmonary emboli presents with acute onset sharp chest pain and shortness of breath.[9]

Prevention

Prevention includes vaccination, environmental measures and appropriate treatment of other health problems.[10] It is believed that if appropriate preventive measures were instituted globally, mortality among children could be reduced by 400,000 and if proper treatment were universally available, childhood deaths could be decreased by another 600,000.[12]

Vaccination

Vaccination prevents against certain bacterial and viral pneumonias both in children and adults. Influenza vaccines are modestly effective against influenza A and B.[6][45] The Center for Disease Control and Prevention (CDC) recommends yearly vaccination for every person 6 months and older.[46] Immunizing health care workers decreases the risk of viral pneumonia among their patients.[41] When influenza outbreaks occur, medications such as amantadine or rimantadine may help prevent the condition.[47] It is unknown if zanamivir or oseltamivir are effective due to the fact that the company that manufactures oseltamivir has refused to release the trial data for independent analysis.[48]

Vaccinations against Haemophilus influenzae and Streptococcus pneumoniae have good evidence to support their use.[30] Vaccinating children against Streptococcus pneumoniae has led to a decreased incidence of these infections in adults, because many adults acquire infections from children. A Streptococcus pneumoniae vaccine is available for adults, and has been found to decrease the risk of invasive pneumococcal disease.[49] Other vaccines for which there to support for a protective effect against pneumonia include: pertussis, varicella, and measles.[50]

Other

Smoking cessation [37] and reducing indoor air pollution, such as that from cooking indoors with wood or dung, are both recommended.[10][12] Smoking appears to be the single biggest risk factor for pneumococcal pneumonia in otherwise healthy adults.[41] Hand hygiene and coughing into ones sleeve may also be effective preventative measures.[50] Wearing surgical masks by those who are sick may also prevent illness.[41]

Appropriately treating underlying illnesses (such as HIV/AIDS, diabetes mellitus, and malnutrition) can decrease the risk of pneumonia.[12][50][51] In children less than 6 months of age exclusive breast feeding reduces both the risk and severity of disease.[12] In those with HIV/AIDS and a CD4 count of less than 200 cells/uL the antibiotic trimethoprim/sulfamethoxazole decreases the risk of Pneumocystis pneumonia [52] and may also be useful for prevention in those who are immunocomprised but do not have HIV.[53]

Testing pregnant women for Group B Streptococcus and Chlamydia trachomatis, and administering antibiotic treatment, if needed, reduces rates of pneumonia in infants;[54][55] preventive measures for HIV transmission from mother to child may also be efficient.[56] Suctioning the mouth and throat of infants with meconium-stained amniotic fluid has not been found to reduce the rate of aspiration pneumonia and may cause potential harm,[57] thus this practice is not recommended in the majority of situations.[57] In the frail elderly good oral health care may lower the risk of aspiration pneumonia.[58]

Management

Typically, oral antibiotics, rest, simple analgesics, and fluids suffice for complete resolution.[37] However, those with other medical conditions, the elderly, or those with significant trouble breathing may require more advanced care. If the symptoms worsen, the pneumonia does not improve with home treatment, or complications occur,

CURB-65Symptom Points

Confusion 1Urea>7 mmol/l 1Respiratory rate>30 1S B P <90mmHg, DBP<60mmHg 1Age>=65 1

hospitalization may be required.[37] Worldwide, approximately 7–13% of cases in children result in hospitalization[10] while in the developed world between 22 and 42% of adults with community-acquired pneumonia are admitted.[37] The CURB-65 score is useful for determining the need for admission in adults.[37] If the score is 0 or 1 people can typically be managed at home, if it is 2 a short hospital stay or close follow-up is needed, if it is 3–5 hospitalization is recommended.[37] In children those with respiratory distress or oxygen saturations of less than 90% should be hospitalized.[59] The utility of chest physiotherapy in pneumonia has not yet been determined.[60] Non-invasive ventilation may be beneficial in those admitted to the intensive care unit.[61] Over-the-counter cough medicine has not been found to be effective[62] nor has the use of zinc in children.[63] There is insufficient evidence for mucolytics.[62]

Bacterial

Antibiotics improve outcomes in those with bacterial pneumonia.[64] Antibiotic choice depends initially on the characteristics of the person affected, such as age, underlying health, and the location the infection was acquired. In the UK, empiric treatment with amoxicillin is recommended as the first line for community-acquired pneumonia, with doxycycline or clarithromycin as alternatives.[37] In North America, where the "atypical" forms of community-acquired pneumonia are more common, macrolides (such as azithromycin or erythromycin), and doxycycline have displaced amoxicillin as first-line outpatient treatment in adults.[21][65] In children with mild or moderate symptoms amoxicillin remains the first line.[59] The use of fluoroquinolones in uncomplicated cases is discouraged due to concerns about side effects and generating resistance in light of there being no greater clinical benefit.[21][66] The duration of treatment has traditionally been seven to ten days, but increasing evidence suggests that shorter courses (three to five days) are similarly effective.[67] Recommended for hospital-acquired pneumonia include third- and fourth-generation cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and vancomycin.[68] These antibiotics are often given intravenously and used in combination.[68] In those treated in hospital more than 90% improve with the initial antibiotics.[18]

Viral

Neuraminidase inhibitors may be used to treat viral pneumonia caused by influenza viruses (influenza A and influenza B).[6] No specific antiviral medications are recommended for other types of community acquired viral pneumonias including SARS coronavirus, adenovirus, hantavirus, and parainfluenza virus.[6] Influenza A may be treated with rimantadine or amantadine, while influenza A or B may be treated with oseltamivir, zanamivir or peramivir.[6] These are of most benefit if they are started within 48 hours of the onset of symptoms.[6] Many strains of H5N1 influenza A, also known as avian influenza or "bird flu," have shown resistance to rimantadine and amantadine.[6] The use of antibiotics in viral pneumonia is recommended by some experts as it is impossible to rule out a complicating bacterial infection.[6] The British Thoracic Society recommends that antibiotics be withheld in those with mild disease.[6] The use of corticosteroids is controversial.[6]

Aspiration

In general, aspiration pneumonitis is treated conservatively with antibiotics indicated only for aspiration pneumonia.[69] The choice of antibiotic will depend on several factors, including the suspected causative organism and whether pneumonia was acquired in the community or

developed in a hospital setting. Common options include clindamycin, a combination of a beta-lactam antibiotic and metronidazole, or an aminoglycoside.[70] Corticosteroids are sometimes used in aspiration pneumonia, but there is limited evidence to support their effectiveness.[69]

Prognosis

With treatment, most types of bacterial pneumonia will stabilize in 3–6 days.[71] It often takes a few weeks before most symptoms resolve.[71] X-ray finding typically clear within four weeks and mortality is low (less than 1%).[11][72] In the elderly or people who have other lung problems recover may take more than 12 weeks. In persons who require hospitalization mortality may be as high as 10% and in those who require intensive care it may reach 30–50%.[11] Pneumonia is the most common hospital-acquired infection that results in death.[18] Before the advent of antibiotics, mortality was typically 30% in those who where hospitalized.[15]

Complications may occur particularly in the elderly and those with underlying health problems.[72] This may include, among others: empyema, lung abscess, bronchiolitis obliterans, acute respiratory distress syndrome, sepsis, and worsening of underlying health problems.[72]

Clinical prediction rules

Clinical prediction rules have been developed to prognosticate more objectively outcomes in pneumonia.[18] These rules are often used in deciding whether or not to hospitalize the person.[18]

Pneumonia severity index (or PSI Score)[18]

CURB-65 score, which takes into account the severity of symptoms, any underlying diseases, and age[73]

Pleural effusion, empyema, and abscess

A pleural effusion: as seen on chest x-ray. The A arrow indicates fluid layering in the right chest. The B arrow indicates the width of the right lung. The volume of the lung is reduced because of the collection of fluid around the lung.

In pneumonia, a collection of fluid may form in the space that surrounds the lung.[74] Occasionally, microorganisms will infect this fluid, causing an empyema.[74] To distinguish an empyema from the more common simple parapneumonic effusion, the fluid may be

collected with a needle (thoracentesis), and examined.[74] If this shows evidence of empyema, complete drainage of the fluid is necessary, often requiring a drainage cathater.[74] In severe cases of empyema, surgery may be needed.[74] If the infected fluid is not drained, the infection may persist, because antibiotics do not penetrate well into the pleural cavity. If the fluid is sterile, it needs to be drained only if it is causing symptoms or remains unresolved.[74]

Rarely, bacteria in the lung will form a pocket of infected fluid called a lung abscess.[74] Lung abscesses can usually be seen with a chest X-ray but frequently require a chest CT scan to confirm the diagnosis.[74] Abscesses typically occur in aspiration pneumonia, and often contain several types of bacteria. Long term antibiotics are usually adequate to treat a lung abscess, but sometimes the abscess must be drained by a surgeon or radiologist.[74]

Respiratory and circulatory failure

Pneumonia can cause respiratory failure by triggering acute respiratory distress syndrome (ARDS), which results from a combination of infection and inflammatory response. The lungs quickly fill with fluid and become stiff. This stiffness, combined with severe difficulties extracting oxygen due to the alveolar fluid, may require long periods of mechanical ventilation for survival.[22]

Sepsis is a potential complication of pneumonia but occurs typically only in people with poor immunity or hyposplenism. The organisms most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae. Other causes of the symptoms should be considered such as a myocardial infarction or a pulmonary embolism.[75]

Epidemiology

Main article: Epidemiology of pneumonia

Age-standardized death rate: lower respiratory tract infections per 100,000 inhabitants in 2004.[76] no data <100 100–700 700–1400 1400–2100 2100–2800 2800–3500

3500–4200 4200–4900 4900–5600 5600–6300 6300–7000 >7000

Pneumonia is a common illness affecting approximately 450 million people a year and occurring in all parts of the world.[6] It is a major cause of death among all age groups resulting in 4 million deaths (7% of the world's total death) yearly.[6][64] Rates are greatest in children less than five, and adults older than 75 years.[6] It occurs about five times more frequently in the developing world than in the developed world.[6] Viral pneumonia accounts

for about 200 million cases.[6] In the United States, as of 2009, pneumonia is the 8th leading cause of death.[11]

Children

In 2008, pneumonia occurred in approximately 156 million children (151 million in the developing world and 5 million in the developed world).[6] It resulted in 1.6 million deaths, or 28–34% of all deaths in those under five years, of which 95% occurred in the developing world.[6][10] Countries with the greatest burden of disease include: India (43 million), China (21 million) and Pakistan (10 million).[77] It is the leading cause of death among children in low income countries.[6][64] Many of these deaths occur in the newborn period. The World Health Organization estimates that one in three newborn infant deaths is due to pneumonia.[78]

Approximately half of these deaths can theoretically be prevented, as they are caused by the bacteria for which an effective vaccine is available.[79]

History

WPA poster, 1936/1937

Pneumonia has been a common disease throughout human history.[80] The symptoms were described by Hippocrates (c. 460 BC – 370 BC):[80] "Peripneumonia, and pleuritic affections, are to be thus observed: If the fever be acute, and if there be pains on either side, or in both, and if expiration be if cough be present, and the sputa expectorated be of a blond or livid color, or likewise thin, frothy, and florid, or having any other character different from the common... When pneumonia is at its height, the case is beyond remedy if he is not purged, and it is bad if he has dyspnoea, and urine that is thin and acrid, and if sweats come out about the neck and head, for such sweats are bad, as proceeding from the suffocation, rales, and the violence of the disease which is obtaining the upper hand."[81] However, Hippocrates referred to pneumonia as a disease "named by the ancients." He also reported the results of surgical drainage of empyemas. Maimonides (1135–1204 AD) observed: "The basic symptoms that occur in pneumonia and that are never lacking are as follows: acute fever, sticking pleuritic

pain in the side, short rapid breaths, serrated pulse and cough."[82] This clinical description is quite similar to those found in modern textbooks, and it reflected the extent of medical knowledge through the Middle Ages into the 19th century.

Edwin Klebs was the first who observed bacteria in the airways of persons who died of pneumonia in 1875.[83] Initial work identifying the two common bacterial causes Streptococcus pneumoniae and Klebsiella pneumoniae was performed by Carl Friedländer [84] and Albert Fränkel [85] in 1882 and 1884, respectively. Friedländer's initial work introduced the Gram stain, a fundamental laboratory test still used today to identify and categorize bacteria. Christian Gram's paper describing the procedure in 1884 helped to differentiate the two bacteria, and showed that pneumonia could be caused by more than one microorganism.[86]

Sir William Osler, known as "the father of modern medicine," appreciated the death and disability caused by pneumonia, describing it as the "captain of the men of death" in 1918, as it had overtaken tuberculosis as one of the leading causes of death in this time. This phrase was originally coined by John Bunyan in reference to "consumption" (tuberculosis).[87][88] Osler also described pneumonia as "the old man's friend" as death was often quick and painless when there were many slower more painful ways to die.[15]

Several developments in the 1900s improved the outcome for those with pneumonia. With the advent of penicillin and other antibiotics, modern surgical techniques, and intensive care in the 20th century, mortality from pneumonia, had approached 30%, dropped precipitously in the developed world. Vaccination of infants against Haemophilus influenzae type B began in 1988 and led to a dramatic decline in cases shortly thereafter.[89] Vaccination against Streptococcus pneumoniae in adults began in 1977, and in children in 2000, resulting in a similar decline.[90]

Society and culture

See also: List of notable pneumonia cases

Due to the high burden of disease in developing countries and a relatively low awareness of the disease in developed countries, the global health community has declared 12th November the World Pneumonia Day, a day for concerned citizens and policy makers to take action against the disease.[91] The global economic cost of community acquired pneumonia has been estimated at $17 billion.[11]

References

1. ^ a b McLuckie, [editor] A. (2009). Respiratory disease and its management. New York: Springer. p. 51. ISBN 978-1-84882-094-4.

2. ̂ Leach, Richard E. (2009). Acute and Critical Care Medicine at a Glance (2nd ed.). Wiley-Blackwell. ISBN 1-4051-6139-6. Retrieved 2011-04-21.

3. ̂ Jeffrey C. Pommerville (2010). Alcamo's Fundamentals of Microbiology (9th ed.). Sudbury MA: Jones & Bartlett. p. 323. ISBN 0-7637-6258-X.

4. ̂ Ashby, Bonnie; Turkington, Carol (2007). The encyclopedia of infectious diseases (3rd ed.). New York: Facts on File. p. 242. ISBN 0-8160-6397-4. Retrieved 2011-04-21.

5. ̂ Osler, William (1901). Principles and Practice of Medicine, 4th Edition. New York: D. Appleton and Company. pp. 108.

6. ^ a b c d e f g h i j k l m n o p q r s t u v w x Ruuskanen, O; Lahti, E, Jennings, LC, Murdoch, DR (2011-04-09). "Viral pneumonia". Lancet 377 (9773): 1264–75. doi:10.1016/S0140-6736(10)61459-6. PMID 21435708.

7. ̂ George, Ronald B. (2005). Chest medicine : essentials of pulmonary and critical care medicine (5th ed. ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 353. ISBN 9780781752732.

8. ^ a b Tintinalli, Judith E. (2010). Emergency Medicine: A Comprehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. pp. 480. ISBN 0-07-148480-9.

9. ^ a b c d e f Hoare Z; Lim WS (2006). "Pneumonia: update on diagnosis and management" (PDF). BMJ 332 (7549): 1077–9. doi:10.1136/bmj.332.7549.1077. PMC 1458569. PMID 16675815.

10. ^ a b c d e f g h i j k l Singh, V; Aneja, S (March 2011). "Pneumonia — management in the developing world". Paediatric respiratory reviews 12 (1): 52–9. doi:10.1016/j.prrv.2010.09.011. PMID 21172676.

11. ^ a b c d e f g h i j k l m n o p q r s t Nair, GB; Niederman, MS (November 2011). "Community-acquired pneumonia: an unfinished battle". The Medical clinics of North America 95 (6): 1143–61. doi:10.1016/j.mcna.2011.08.007. PMID 22032432.

12. ^ a b c d e f g "Pneumonia (Fact sheet N°331)". World Health Organization. August 2012.13. ̂ Darby, J; Buising, K (October 2008). "Could it be Legionella?". Australian family physician

37 (10): 812–5. PMID 19002299.14. ̂ Ortqvist, A; Hedlund, J, Kalin, M (December 2005). "Streptococcus pneumoniae:

epidemiology, risk factors, and clinical features". Seminars in respiratory and critical care medicine 26 (6): 563–74. doi:10.1055/s-2005-925523. PMID 16388428.

15. ^ a b c d e f g h i Ebby, Orin (Dec 2005). "Community-Acquired Pneumonia: From Common Pathogens To Emerging Resistance". Emergency Medicine Practice 7 (12).

16. ̂ Lowe, J. F.; St

AsthmaFrom Wikipedia, the free encyclopediaJump to: navigation, search For other uses, see Asthma (disambiguation).

AsthmaClassification and external resources

Peak flow meters are used to measure the peak expiratory flow rate, important in both monitoring and diagnosing

asthma.[1]

ICD-10 J 45 ICD-9 493OMIM 600807DiseasesDB 1006MedlinePlus 000141eMedicine article/806890MeSH D001249

Asthma (from the Greek ἅσθμα, ásthma, "panting") is a common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow

obstruction, and bronchospasm.[2] Common symptoms include wheezing, coughing, chest tightness, and shortness of breath.[3]

Asthma is thought to be caused by a combination of genetic and environmental factors.[4] Its diagnosis is usually made based on the pattern of symptoms, response to therapy over time, and spirometry.[5] It is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate.[6] Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic).[7]

Treatment of acute symptoms is usually with an inhaled short-acting beta-2 agonist (such as salbutamol).[8] Symptoms can be prevented by avoiding triggers, such as allergens [9] and irritants, and by the use of inhaled corticosteroids.[10] Leukotriene antagonists are less effective than corticosteroids and thus less preferred.[11] The prevalence of asthma has increased significantly since the 1970s. As of 2010, 300 million people were affected worldwide. In 2009 asthma caused 250,000 deaths globally.[12]

Contents

1 Signs and symptoms o 1.1 Associated conditions

2 Causes o 2.1 Environmental o 2.2 Genetic o 2.3 Medical conditions o 2.4 Exacerbation

3 Pathophysiology 4 Diagnosis

o 4.1 Spirometry o 4.2 Other o 4.3 Classification o 4.4 Differential diagnosis

5 Prevention 6 Management

o 6.1 Lifestyle modification o 6.2 Medications o 6.3 Other o 6.4 Alternative medicine

7 Prognosis 8 Epidemiology 9 History 10 Notes 11 External links

Signs and symptoms

Wheezing

Menu0:00The sound of wheezing as heard with a stethoscope.

Problems listening to this file? See media help.

Asthma is characterized by recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing.[13] Symptoms are often worse at night and in the early morning or in response to exercise or cold air.[14] Some people with asthma only rarely experience symptoms, usually in response to triggers, whereas others may have marked and persistent symptoms.[15]

Associated conditions

A number of other health conditions occur more frequently in those with asthma including: gastro-esophageal reflux disease (GERD), rhinosinusitis, and obstructive sleep apnea.[16] Psychological disorders are also more common.[17]

Causes

Asthma is caused by a combination of environmental and genetic factors.[4] These factors influence both its severity and how responsive it is to treatment.[18] The interaction between environmental and genetic factors is complex and not fully understood.[19] It is believed that the recent increased rates of asthma are due to a combination of these environmental and epigenetic changes.[20]

Environmental

Many environmental factors have been associated with asthma's development and exacerbation including: allergens, air pollution, and other environmental chemicals.

There is a relationship between exposure to air pollutants and the development of asthma.[21] Smoking during pregnancy and after delivery is associated with a greater risk of asthma-like symptoms.[22] Low air quality, from traffic pollution or high ozone levels,[23] has been associated with both asthma development and increase asthma severity.[24]

Exposure to indoor volatile organic compounds may be a trigger for asthma; formaldehyde exposure, for example, has a positive association.[25] Also, phthalates in PVC are associated with asthma in children and adults[26][27] as are high levels of endotoxin exposure.[28]

Asthma is associated with exposure to indoor allergens.[29] Common indoor allergens include: dust mites, cockroaches, animal dander, and mold.[30][31] Efforts to decrease dust mites have been found to be ineffective.[32] Certain viral respiratory infections may increase the risk of

developing asthma when acquired as a young children including:[33] respiratory syncytial virus and rhinovirus.[34] Certain other infections however may decrease the risk.[34]

Hygiene hypothesis

The hygiene hypothesis is a theory which attempts to explain the increase rates of asthma worldwide—increased rates of asthma are a direct and unintended result of reduced exposure, during childhood, to non infectious bacteria and viruses in modern societies.[35][36] It's been proposed that the reduced exposure to bacteria and viruses is due, in part, to increased cleanliness and decreased family size.[37] Evidence supporting the hygiene hypothesis includes observations of lower rates of asthma seen on farms and in households with pets; however, there are still many uncertainties.[37]

Antibiotic use early in life has been linked to the development of asthma.[38] Also, delivery via caesarean sections is associated[39] with an increased risk (estimated at 20-80%) of asthma—this increased risk is attributed to the lack of healthy bacterial colonization that the newborn would have acquired from passage through the birth canal.[40] There is a link between asthma and the degree of affluence.[41]

GeneticCD14-endotoxin interaction based on CD14 SNP C-159T[42]

Endotoxin levels CC genotype TT genotypeHigh exposure Low risk High riskLow exposure High risk Low risk

Family history is a risk factor for asthma with many different genes being implicated.[43] If one identical twin is affected, the probability of the other having the disease is ~25%.[43] By the end of 2005, 25 genes had been associated with asthma in six or more separate populations including: GSTM1, IL10, CTLA-4, SPINK5, LTC4S, IL4R and ADAM33 among others.[44] Many of these genes are related to the immune system or to modulating inflammation. Even among this list of genes supported by highly replicated studies, results have not been consistent among all populations tested.[44]. In 2006 over 100 genes where associated with asthma in one genetic association study alone;[44] more continue to be found.[45]

Some genetic variants may only cause asthma when they are combined with specific environmental exposures.[4] The genetic trait CD14 single nucleotide polymorphism (SNP) C-159T and exposure to endotoxin (a bacterial product) is an example. Endotoxin exposure can come from several environmental sources including tobacco smoke, dogs, and farms. Risk for asthma, then, is determined by both a persons genotype and the level of endotoxin exposure.[42]

Medical conditions

A triad of atopic eczema, allergic rhinitis, and asthma is called atopy.[46] The strongest risk factor for developing asthma is a history of atopic disease;[33] with asthma occuring at a much greater rate in those who have either eczema or hay fever.[47] Asthma has been associated with the autoimmune disease vasculitis, Churg–Strauss syndrome. Individuals with certain types of urticaria may also experience symptoms of asthma.[46]

There is a correlation between obesity and the risk of asthma with both having increased in recent years.[48][49] Several factors may be at play including decreased respiratory function due to a buildup of fat and the fact that adipose tissue leads to a pro-inflammatory state.[50]

Beta blocker medications such as propranolol may trigger asthma in those who are susceptible.[51] Cardioselective beta-blockers, however, appear safe in those with mild or moderate disease.[52] Other medications that can cause problems include: ASA, NSAIDs, and angiotensin-converting enzyme inhibitors.[53]

Exacerbation

Some individuals will have stable asthma for weeks or months and then suddenly develop an episode of acute asthma. Different individuals react differently to various factors.[54] Most individuals can develop severe exacerbation from a number of triggering agents.[54]

Home factors that can lead to exacerbation of asthma include dust, animal dander (especially cat and dog hair), cockroach allergens and mold.[54] Perfumes are a common cause of acute attacks in women and children. Both virus and bacterial infections of the upper respiratory tract infection can worsen the disease.[54] Psychological stress may worsen symptoms—it's thought that stress alters the immune system and thus increases the airway inflammatory response to allergens and irritants.[24][55]

Pathophysiology

Obstruction of the lumen of a bronchiole by mucoid exudate, goblet cell metaplasia, and epithelial basement membrane thickening in a person with asthma.

Asthma is the result of chronic inflammation of the airways which subsequently results in increased contractability of the surrounding smooth muscles. This among other factors leads to bouts of narrowing of the airway and the classic symptoms of wheezing. The narrowing is typically reversible with or without treatment. Occasionally the airways themselves change.[13] The typical changes in the airway include an increase in eosinophils and thickening of the lamina reticularis. Chronically airway smooth muscle may increase in size along with an increase in the numbers of mucous glands in the airways. Other cell types involved include: T lymphocytes, macrophages, and neutrophils. There may also be involvement of other components of the immune system including: cytokines, chemokines, histamine, and leukotrienes among others.[34]

Diagnosis

There is currently no precise test for asthma[34] with the diagnosis typically made based on the pattern of symptoms and response to therapy over time.[5] A diagnosis of asthma should be suspected if there is a history of: recurrent wheezing, coughing or difficulty breathing and these symptoms occur or worsen due to exercise, viral infections, allergens or air pollution.[56]

Spirometry is than used to confirm the diagnosis.[56] In children under the age of six the diagnosis is more difficult as they are too young for spirometry.[57]

Spirometry

Spirometry is recommended to aid in diagnosis and management.[58][59] It is the single best test for asthma. If the FEV1 measured by this technique improves more than 12% following administration of a brochodilator such as salbutamol this is supportive of the diagnosis. It however may be normal in those with a history of mild asthma, not currently acting up. Single-breath diffusing capacity can help differentiate asthma from COPD.[34] It is reasonable to perform spirometry every 1 or 2 years to follow how well a person's asthma is controlled.[60]

Other

The methacholine challenge involves the inhalation of increasing concentrations of a substance that causes airway narrowing in those predisposed. If negative it means that a person does not have asthma; if positive, however, it is not specific for the disease.[34]

Other supportive evidence includes: a ≥20% difference in peak expiratory flow rate on at least three days in a week for at least two weeks, a ≥20% improvement of peak flow following treatment with either salbutamol, inhaled corticosteroids or prednisone, or a ≥20% decrease in peak flow following exposure to a trigger.[61] Testing peak expiratory flow is more variable than spirometry, however, and thus not recommended for routine diagnosis. It may be useful for daily self-monitoring in those with moderate to severe disease and for checking the effectiveness of new medications. It may also be helpful in guiding treatment in those with acute exacerbations.[62]

ClassificationClinical classification (≥ 12 years old)[6]

Severity Symptom frequency

Night time symptoms

%FEV1 of predicted

FEV1

VariabilitySABA use

Intermittent ≤2/week ≤2/month ≥80% <20% ≤2 days/weekMild persistent >2/week 3–4/month ≥80% 20–30% >2 days/week

Moderate persistent Daily >1/week 60–80% >30% dailySevere persistent Continuously Frequent (7×/week) <60% >30% ≥twice/day

While asthma is a well recognized condition, there is not one universal agreed upon definition.[34] It is defined by the Global Initiative for Asthma as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning. These episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment".[13]

Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in one second (FEV1), and peak expiratory flow rate.[6] Asthma may also be classified as atopic (extrinsic) or non-atopic (intrinsic), based on whether symptoms are precipitated by allergens (atopic) or not (non-atopic).[7] While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system.[63] Finding ways to identify subgroups that respond well to different types of treatments is a current critical goal of asthma research.[63]

Although asthma is a chronic obstructive condition, it is not considered as a part of chronic obstructive pulmonary disease as this term refers specifically to combinations of disease that are irreversible such as bronchiectasis,chronic bronchitis, and emphysema.[64] Unlike these diseases, the airway obstruction in asthma is usually reversible; however, if left untreated, the chronic inflammation from asthma can lead the lungs to become irreversibly obstructed due to airway remodeling.[65] In contrast to emphysema, asthma affects the bronchi, not the alveoli.[66]

Asthma exacerbationSeverity of an acute exacerbation[67]

Near-fatal High PaCO2 and/or requiring mechanical ventilation

Life threatening(any one of)

Clinical signs Measurements

Altered level of consciousness Peak flow < 33%

Exhaustion Oxygen saturation < 92%

Arrhythmia PaO2 < 8 kPa

Low blood pressure "Normal" PaCO2

Cyanosis

Silent chest

Poor respiratory effort

Acute severe(any one of)

Peak flow 33–50%

Respiratory rate ≥ 25 breaths per minute

Heart rate ≥ 110 beats per minute

Unable to complete sentences in one breath

Moderate

Worsening symptoms

Peak flow 50–80% best or predicted

No features of acute severe asthma

An acute asthma exacerbation is commonly referred to as an asthma attack. The classic symptoms are shortness of breath, wheezing, and chest tightness.[34] While these are the primary symptoms of asthma,[68] some people present primarily with coughing, and in severe cases, air motion may be significantly impaired such that no wheezing is heard.[67]

Signs which occur during an asthma attack include the use of accessory muscles of respiration (sternocleidomastoid and scalene musclesof the neck), there may be a paradoxical

pulse (a pulse that is weaker during inhalation and stronger during exhalation), and over-inflation of the chest.[69] Ablue color of the skin and nails may occur from lack of oxygen.[70]

In a mild exacerbation the peak expiratory flow rate (PEFR) is ≥200 L/min or ≥50% of the predicted best.[71] Moderate is defined as between 80 and 200 L/min or 25% and 50% of the predicted best while severe is defined as ≤ 80 L/min or ≤25% of the predicted best.[71]

Acute severe asthma, previously known as status asthmaticus, is an acute exacerbation of asthma that does not respond to standard treatments of bronchodilators and steroids.[72] Half of cases are due to infections with others caused by allergen, air pollution, or insufficient or inappropriate medication use.[72]

Brittle asthma is a kind of asthma distinguishable by recurrent, severe attacks.[67] Type 1 brittle asthma is a disease with wide peak flow variability, despite intense medication. Type 2 brittle asthma is background well-controlled asthma with sudden severe exacerbations.[67]

Exercise-inducedMain article: Exercise-induced bronchoconstriction

Exercise can trigger bronchoconstriction in both people with and without asthma.[73] It occurs in most people with asthma and up to 20% of people without asthma.[73] In athletes it occurs more common in elite athletes with rates varying from 3% for bobsled racer to 50% for cycling and 60% for cross-country skiing.[73] Inhaled beta2-agonists do not appear to improve athletic performance among those without asthma[74] however oral doses may improve endurance and strength.[75][76]

OccupationalMain article: Occupational asthma

Asthma as a result of (or worsened by) workplace exposures is a commonly reported occupational disease.[77] Many cases however are not reported or recognized as such.[78][79] It is estimated that 5–25% of asthma cases in adults are work related. A few hundred different agents have been implicated with the most common being: isocyanates, grain and wood dust, colophony, soldering flux, latex, animals, and aldehydes. The employment associated with the highest risk of problems include: those who spray paint, bakers and those who process food, nurses, chemical workers, those who work with animals, welders, hairdressers and timber workers.[77]

Differential diagnosis

Many other conditions can cause symptoms similar to those of asthma. In children other upper airway diseases such as allergic rhinitis and sinusitis should be considered as well as other causes of airway obstruction including: foreign body aspiration, tracheal stenosis or laryngotracheomalacia, vascular rings, enlarged lymph nodes or neck masses. In adults, COPD, congestive heart failure, airway masses, as well as drug induced coughing due to ACE inhibitors should be considered. In both populations vocal cord dysfunction may present similarly.[80]

Chronic obstructive pulmonary disease can coexist with asthma and can occur as a complication of chronic asthma. After the age of 65 most people with obstructive airway

disease will have asthma and COPD. In this setting, COPD can be differentiated by increased airway neutrophils, abnormally increased wall thickness, and increased smooth muscle in the bronchi. However, this level of investigation is not performed due to COPD and asthma sharing similar principles of management: corticosteroids, long acting beta agonists, and smoking cessation.[81] It closely resembles asthma in symptoms, is correlated with more exposure to cigarette smoke, an older age, less symptom reversibility after bronchodilator administration, and decreased likelihood of family history of atopy.[82][83]

Prevention

The evidence for the effectiveness of measures to prevent the development of asthma is weak.[84] Some show promise including: limiting smoke exposure both in utero and after delivery, breastfeeding, and increased exposure to daycare or large families but none are well supported enough to be recommended for this indication.[84] Early pet exposure may be useful.[85] Results from exposure to pets at other times are inconclusive[86] and it is only recommended that pets be removed from the home if a person has allergic symptoms to said pet.[87] Dietary restrictions during pregnancy or when breast feeding have not been found to be effective and thus are not recommended.[87] Reducing or eliminating compounds known to sensitive people from the work place may be effective.[77]

Management

While there is no cure for asthma, symptoms can typically be improved.[88] A specific, customized plan for proactively monitoring and managing symptoms should be created. This plan should include the reduction of exposure to allergens, testing to assess the severity of symptoms, and the usage of medications. The treatment plan should be written down and advise adjustments to treament according to changes in symptoms.[89]

The most effective treatment for asthma is identifying triggers, such as cigarette smoke, pets, or aspirin, and eliminating exposure to them. If trigger avoidance is insufficient, the use of medication is recommended. Pharmaceutical drugs are selected based on, among other things, the severity of illness and the frequency of symptoms. Specific medications for asthma are broadly classified into fast-acting and long-acting categories.[90][91]

Bronchodilators are recommended for short-term relief of symptoms.> In those with occasional attacks, no other medication is needed. If mild persistent disease is present (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene antagonist or a mast cell stabilizer is recommended. For those who have daily attacks, a higher dose of inhaled glucocorticoid is used. In a moderate or severe exacerbation, oral glucocorticoids are added to these treatments.[8]

Lifestyle modification

Avoidance of triggers is a key component of improving control and preventing attacks. The most common triggers include allergens, smoke (tobacco and other), air pollution, non selective beta-blockers, and sulfite-containing foods.[92][93] Cigarette smoking and second-hand smoke (passive smoke) may reduce the effectiveness of medications such as steroids.[94] Dust mite control measures, including air filtration, chemicals to kill mites, vacuuming, mattress covers and others methods had no effect on asthma symptoms.[32]

Medications

Medications used to treat asthma are divided into two general classes: quick-relief medications used to treat acute symptoms; and long-term control medications used to prevent further exacerbation.[90]

Fast acting

Salbutamol metered dose inhaler commonly used to treat asthma attacks.

Short acting beta2-adrenoceptor agonists (SABA), such as salbutamol (albuterol USAN) are the first line treatment for asthma symptoms.[8]

Anticholinergic medications, such as ipratropium bromide, provide additional benefit when used in combination with SABA in those with moderate or severe symptoms.[8] Anticholinergic bronchodilators can also be used if a person cannot tolerate a SABA.[64]

Older, less selective adrenergic agonists, such as inhaled epinephrine, have similar efficacy to SABAs.[95] They are however not recommended due to concerns regarding excessive cardiac stimulation.[96]

Long term control

Fluticasone propionate metered dose inhaler commonly used for long term control.

Glucocorticoids are generally considered the most effective treatment available for long term control.[90] Inhaled forms are usually used except in the case of severe persistent disease, in which oral steroids may be needed.[90] It is usually recommended that inhaled formulations be used once or twice daily, depending on the severity of symptoms.[97]

Long acting beta-adrenoceptor agonists (LABA) have at least a 12-hour effect. They however should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation of asthma in both children and adults.[11][98][99][100]

Leukotriene antagonists (such as zafirlukast) are an alternative to inhaled glucocorticoids, but are not preferred. They may also be used in addition to inhaled glucocorticoids but in this role are second line to LABA.[90]

Mast cell stabilizers (such as cromolyn sodium) are another non-preferred alternative to glucocorticoids.[90]

Delivery methods

Medications are typically provided as metered-dose inhalers (MDIs) in combination with an asthma spacer or as a dry powder inhaler. The spacer is a plastic cylinder that mixes the medication with air, making it easier to receive a full dose of the drug. A nebulizer may also be used. Nebulizers and spacers are equally effective in those with mild to moderate symptoms however insufficient evidence is available to determine whether or not a difference exists in those severe symptomatology.[101]

Adverse effects

Long-term use of inhaled glucocorticoids at conventional doses carries a minor risk of adverse effects.[102] Risks include the development of cataracts and a mild regression in stature.[102][103]

Other

When asthma is unresponsive to usual medications, other options are available for both emergency management and prevention of flareups. For emergency management other options include:

Oxygen is used to alleviate hypoxia if saturations fall below 92%.[104]

Magnesium sulfate intravenous treatment has been shown to provide a bronchodilating effect when used in addition to other treatment in severe acute asthma attacks.[105][106]

Heliox , a mixture of helium and oxygen, may also be considered in severe unresponsive cases.[106]

Intravenous salbutamol is not supported by available evidence and is thus used only in extreme cases.[104]

Methylxanthines (such as theophylline) were once widely used, but do not add significantly to the effects of inhaled beta-agonists.[104]

The dissociative anesthetic ketamine is theoretically useful if intubation and mechanical ventilation is needed in people who are approaching respiratory arrest; however, there is no evidence from clinical trials to support this.[107]

For those with severe persistent asthma not controlled by inhaled corticosteroids and LABAs bronchial thermoplasty can lead to clinical improvements.[108] It involves the delivery of controlled thermal energy to the airway wall during a series of bronchoscopies and result in a prolonged reduction in airway smooth muscle mass.[108]

Alternative medicine

Many people with asthma, like those with other chronic disorders, use alternative treatments; surveys show that roughly 50% use some form of unconventional therapy.[109][110] There is little data to support the effectiveness of most of these therapies. Evidence is insufficient to support the usage of Vitamin C.[111] Acupuncture is not recommended for the treatment as there is insufficient evidence to support its use.[112][113] Air ionisers show no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.[114]

"Manual therapies", including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, have insufficient evidence to support their use in treating asthma.[115] The Buteyko breathing technique for controlling hyperventilation may result in a reduction in medications use however does not have any effect on lung function.[91] Thus an expert panel felt that evidence was insufficient to support its use.[112]

Prognosis

Disability-adjusted life year for asthma per 100,000 inhabitants in 2004.[116] no data 350–400

<100 100–150 150–200 200–250 250–300 300–350

400–450 450–500 500–550 550–600 >600

The prognosis for asthma is generally good, especially for children with mild disease.[117] Mortality has decreased over the last few decades due to better recognition and improvement in care.[118] Globally it causes moderate or severe disability in 19.4 million people as of 2004 (16 million of which are in low and middle income countries).[119] Of asthma diagnosed during childhood, half of cases will no longer carry the diagnosis after a decade.[43] Airway remodeling is observed, but it is unknown whether these represent harmful or beneficial changes.[120] Early treatment with glucocorticoids seems to prevent or ameliorates a decline in lung function.[121]

Epidemiology

Main article: Epidemiology of asthma

As of 2011, ~235 million people worldwide are affected by asthma,[122] and approximately 250,000 people die per year from the disease.[13] Rates vary between countries with prevalences between 1 and 18%.[13] It is more common in developed than developing countries.[13] One thus sees lower rates in Asia, Eastern Europe and Africa.[34] Within developed countries it is more common in those who are economically disadvantage while in contrast in developing countries it is more common in the affluent.[13] The reason for these differences is not well know.[13] Low and middle income countries make up more than 80% of the mortality.[123]

While asthma is twice as common in boys as girls,[13] severe asthma occurs at equal rates.[124] In contrast adult women have a higher rate of asthma than men[13] and it is more common in the young than the old.[34]

Global rates of asthma have increased significantly between the 1960s and 2008[125][126] with it being recognized as a major public health problem since the 1970s.[34] Rates of asthma have plateaued in the developed world since the mid 1990s with recent increases primarily in the developing world.[127] Asthma affects approximately 7% of the population of the United States[11] and 5% of people in the United Kingdom.[128] Canada, Australia and New Zealand have rates of about 14-15%.[129]

History

Asthma was recognized in Ancient Egypt and was treated by drinking an incense mixture known as kyphi [130] It was officially named as a specific respiratory problem by Hippocrates circa 450 BC, with the Greek word for "panting" forming the basis of our modern name.[34]

In 1873 one of the first papers in modern medicine on the subject tried to explain the pathophysiology of the disease [131] while one in 1872, concluded that asthma can be cured by

rubbing the chest with chloroform liniment.[132] Medical treatment in 1880, included the use of intravenous doses of a drug called pilocarpin.[133] In 1886, F.H. Bosworth theorized a connection between asthma and hay fever.[134] Epinephrine was first referred to in the treatment of asthma in 1905.[135] Oral steroids began to be used for this condition in the 1950s[136] while inhaled corticosteroids and selective short acting beta agonist came into wide us in the 1960s.[137]

During the 1930s–50s, asthma was considered to one of the 'holy seven' psychosomatic illnesses. Its cause was considered to be psychological, with treatment often based on psychoanalysis and other talking cures.[138] As these psychoanalysts interpreted the asthmatic wheeze as the suppressed cry of the child for its mother, they considered that the treatment of depression was especially important for individuals with asthma.[138]

Notes