Lessons from Fungal Outbreaks

侵襲性黴菌感染:從美國

黴菌中樞神經感染群突發之省思 (II)

陳宜君

國立臺灣大學醫學院內科教授

臺大醫院內科部感染科主任

國家衛生研究院感染症與疫苗研究所合聘研究員

Contents

Part I

1. Hidden killers

2. US meningitis outbreak

3. Healthcare-Associated Infection

Conclusion

Part II

4. Invasive fungal infections after natural disasters

5. Infections after travel or leisure activity

6. Community-acquired Infection

Conclusion

2

Fatal aspergillosis in a 39-year-old male physician with SARS who was treated with corticosteroids

Fever

CXR

Sore throat leukocytosis dyspnea leukopenia pancytopenia

CXR

Wang et al. NEJM 349:507-508 July 31, 20033

Autopsy showed SARS-associated pathologic changes

Dissemination aspergillosis: multiple lung abscesses

containing aspergillus; cerebral edema, diffuse cerebral

hemorrhage, aspergillus meningitis, and multiple brain

abscesses containing aspergillus; multiple abscesses

containing aspergillus in the heart, liver, kidney, spleen,

stomach, pancreas, and adrenal glands. A. Cut surface of a lung.

B. Extensive hyaline membranes, desquamated epithelial cells, and exuded monocytes in alveoli

(HE stain, x100).

Aspergillus mycelia were observed on microscopical examination of the abscess and were

isolated by culture as well.

Wang et al. NEJM 2003;349:507

Fatal aspergillosis in a 39-year-old male physician with SARS Who Was Treated with Corticosteroids

Increasing growth rate of Aspergillusin the presence of steroids

Doubling time for

Aspergillus: 48 hr

E. coli: 20 min

M. tuberculosis: 24 hr Denning et al. Microbiology 1994;140Michail et al. Lancet 2003;362:1828

4

Fungi and steroids should not mixIncrease susceptibility to IFI

Dual effects of corticosteroids

• Effect on host/immunity

• Effects on fungi

Increase IFI-attributable mortality

• Invasive aspergillosis in HSCT, n=51

Denning et al. Microbiology 1994;140Michail et al. Lancet 2003;362:1828Cordonnier et al. Clin Infect Dis 2006;42:955

Low-dose steroid

High-dose steroid

5

4. Invasive fungal infections after natural disasters

6

Necrotizing cutaneous mucormycosisafter a tornado in Joplin, Missouri, in 2011

What people feel

What public health officers see

What physicians see (3 June)

22 May

Sequencing of the D1-D2 region of the 28S ribosomal DNA yielded Apophysomyces trapeziformis in all 13 case patients. Whole-genome sequencing showed that the apophysomyces isolates were four separate strains.Neblett et al. NEJM 2012;367:2214

7

Invasive fungal infections after natural disastersEID 2014;20:349

8

Invasive fungal infections after natural disasters

• Fungi in our environment

• Disasters and global climate change

• Route of transmission (pattern of infection)

– Inhalation (respiratory)

– Trauma (soft tissue infection, CNS)

– Near-drowning (respiratory)

– Indoor exposures (respiratory)

– Healthcare–associated

Benedict & Park. Emerg Infect Dis 2014;20:349 9

5. Invasive fungal infections after travel or leisure activity

10

A multinational outbreak of histoplasmosis following a biology field trip in the Ugandan rainforest

Cottle et al. J Travel Med. 2013;20:83 11

Increase in Coccidioidomycosis, CA, USA

Health-care providers should maintain heightened suspicion for coccidioidomycosis in patients who live or have traveled in areas where

the disease is endemic and who have signs of ILI, pneumonia, or disseminated infection.

MMWR 2009;58:105 12

6. Community-AcquiredInvasive fungal infections

13

Healthcare-associated vs. Community-Acquired Invasive Aspergillosis

Healthcare-associated

• Due to break in, or contamination of hospital water system

• Due to break in HEPA filtration system

• Due to construction or demolition work in the hospital

Community-acquired

• Due to housing quality

• Due to occupational activities

• Due to leisure activities

• Due to exposure to Aspergillus spores (minimum effective dose not known)

Praz-Christinaz et al. Transplant Infect Dis 2007; 9: 175-181 14

CryptococcusThe most common human fungal pathogen

15

Li SS et al. Proc Am Thorac Soc, 2010; 7: 186Lin X, Heitman J. Annu. Rev. Microbiol. 2006; 60: 69-105.Lester SJ, et al. Veterinary clinical pathology / American Society for Veterinary Clinical Pathology 2011.

Avian Cryptococcosis; Feline Cryptococcosis; Canine Cryptococcosis; Koala Cryptococcosis: the role as a sentinel species for human infection

Infection cycle of Cryptococcus neoformans- C. gattiispecies complex (environment and host)

Chayakulkeeree M et al. Infect Dis Clin N Am, 2006; 20: 507* Chuang YM et al. Eur J Clin Microbiol Infect Dis, 2008; 27: 307Perfect JR et al. Clin Infect Dis, 2010; 50: 000Brouwer AE et al. Lancet, 2004; 363: 1764

Group 1 Group 2Group 3

(Non-HIV, Non-SOT)

HIV infection

Solid organ transplant-ation (SOT)

Corticosteroid use

Autoimmune diseases*

Malignancy

Monoclonal Ab, anti-TNF-α

Cirrhosis*

Diabetes mellitus*

Renal failure or peritonealdialysis

AT Risk Groups of Cryptococcosis

C. neoformans

C. gattii

16

Cryptococcosis

• Cryptococcus neoformans- C. gattii species complex

• Host: immunecompetents, immunocompromised

• Presentations: lung, CNS; FUO, sepsis; skin

– C. neoformans has been found to infect any organ of the human body

– In severely immunosuppressed patient cryptococcosis may present with involvement of multiple body sites

– Atypical presentation and fulminant course in patients with impaired T cell function and cirrhosis of liver

Chen et al. Diagn Microbiol Infect Dis 2000;36:175Shin et al. Q J Med 2000;93:245; Lee et al. JMII 2011;44:338 Jean et al. Q J Med 2002;95:511; Jean et al. J Formos Med Assoc 2005;104:39Tseng et al. Plos One 2013;8:e61921 17

Early-onset recurrent “CVA”

• A 48 year old housewife – Polymyositis, prednisolone 15 mg daily, Imuran 50 mg tid– Diabetes mellitus, hypertension

• 1st event– Acute onset of left hemiparesis with progression on 03/02 – MRI: acute cerebral infarct, left post. limb of the internal

capsule, diffuse leptomeningeal enhancement esp. at bil sides of cerebellum; meningitis is compatible

• 2nd event– Altered mental status since 04/18 – Hypercalcemia: 3.06 mmol/L – Afebrile; supple neck; negative meningeal signs– Headache, dizziness– Blurred vision and tinnitus – MRI: meningitis, multiple lacunar infarcts due to arteritis 18

HIV- (94) HIV+ (43)

incidence 0.0175% 5.13%

Male 62.8% 97%

Age 36 36

LACT 384 >512

Fungemia Relapse Subtype(NE)

13.8% 2.1%

58.3%

67.7% 11.8% 91.7

Shih et al. QJM 2000; Sheng et al. Int J STD AIDS 2002; Chen et al. DMID 2000

Non-AIDS vs. AIDS, NTUH

19

Presentations of cryptococcal meningitis in HIV-Negative patients

variable Total

(94)

Non T cell suppression

(64)

T cell suppression

(30)

Duration, days 15 29 14

Headache 86.2% 90.6% 76.7%

Vomiting 72.3% 75.0% 33.3%

Meningeal signs 69.1% 79.7% 46.7%

Fever 69.1% 70.3% 66.7%

20Shih CC, et al. Q J Med 2000;93:245-51

T cell suppression: lymphoma, transplantation, prednisolone > 700 mg in total, and/or other T cell cytotoxic agents > 2 wks

Presentations (cont.)

21

Shih CC, et al. Q J Med 2000;93:245-51

variable Total

(94)

Non T cell suppression

(64)

T cell suppression

(30)

CT findings

Leptomeningeal enhancement

48% 57% 24%

Hydrocephalus 42% 49% 23%

Hypodense lesions 14% 24% 0

Lab findings

Extraneural involvement 21% 17% 30%

Fungemia 14% 9% 23%

20 of 94 patients had C. neoformans isolated from 21 specimens other than CSF, including blood

(13), sputum (4), urine (2), lung tissue (1), and brain mass aspirate (1).

Cryptococcal meningitis in HIV-Negative patients

CSF findings

variable Total

(94)

Non T cell suppression

(64)

T cell suppression

(30)

Pressure > 200 mmH2O 82% 83% 80%

Hypoglycorrhachia 48% 42% 62%

Cell count, median (range)

49 (0-1098)

76.5 (0-1098)

20 (0-306)

Cryptococcal antigen titer

384 (0-16348)

192 (0-16348)

512 (8-16348)

22Shih CC, et al. Q J Med 2000;93:245-51

A 56-year-old female, HBV and HCV infection, cirrhosis

of liver with esophageal varices bleeding

Fever and hypotension were noted on Oct 16 at ES and

condition improved after 2nd generation

cephalosporin.

However, CXR revealed RUL infiltration and anti-TB were given after diagnostic approach.

After discharge, fever and poor appetite persisted.

Headache aggravated and vomiting became projectile.

She visited ES again on Nov 10 and neck stiffness was noted.

Cryptococcosis or TB

23

Of all cases of cryptococcemia, 21%~36% occur in patients with liver cirrhosis.1-3

Cirrhosis-associated cryptococcosis, presented with 4

1. Peritonitis (45%)2. Meningoencephalitis (39%)3. Pulmonary infection (18%)4. Skin, soft tissue 5. Osetoarticular disease

1 Jean SS et al. QJM 2002; 95: 511-5182 Tseng HK et al. PLoS ONE 2013; 8: e619213 Eur J Clin Microbiol Infect Dis 2008; 27: 307-3104 Medicine 2004; 83: 188-192

Multivariate analysis of factors predicting 30-day mortality in patients with cryptococcemia, NTUH, 1981-2001, N=52 1

Cryptococcemiain patients with cirrhosis of liver

24

Cryptococcosis, Taiwan, 1997-2010

Variety North Middle South East

All (219) 121 (55.3%) 66 (30.1%) 24 (11.0%) 8 (3.7%)

VG (9) 1 (11.1%) 5 (55.6%) 1 (11.1%) 2 (22.2%)

VN (210) 120 (57.1%) 61(29%) 23 (11%) 6 (2.9%)

CSF Blood/Marrow BAL/BAW/S Tissue (lung) Effusion (Pleural) Urine Ascites Others

45.3% 29.1% 7.9% 7.9% 2.5% 2.5% 1.1% 3.6%

PLoS ONE 2013;8: e61921

Host profiles: HBV carrier or cirrhosis, 30.2%; HIV 24.6%; no, 15.4%

Presentations: CNS 58.9%; pulmonary 19.6%, others (cryptococcemia etc.) 18.7%

Microbiology: The predominant genotype was VNI (206 isolates).

Ag serum

≥ 512Ag CSF

≥ 512ICP ≥25 cmH20

NS intervention

M2 week (%) M10 week (%)

All (219) 72 (32.9%) 80 (36.5%) 54 (24.7%) 14 (6.4%) 25(11.4%) 63 (28.8%)

VG (9) 4 (44.4%) 6 (66.7%) 6 (66.7%) 3 (33.3%) 2 (22.2%) 4 (44.4%)

VN (210) 68 (32.4%) 72 (34.3%)* 48(22.9%)* 11 (5.2%)* 23 (11%) 59 (28.1%)

25

Antifungal susceptibility of 216 cryptococcal clinical isolates in Taiwan, 1997–2010

MIC > epidemiologic cutoff values (ECVs): 9 VNI isolates (7 for amphotericin B)

26Tseng et la. PLoS ONE 2013;8: e61921

(90%)

(10%)

Datta K et al. Emerg Infect Dis, 2009; 15: 1185Galanis E et al. Emerg Infect Dis, 2010; 16: 251

Vancouver island, British Columbia, Northwest US

AmB, 5-FC, vori, cidal; fluconazole, staticCNS penetration: L-AmB, 5-FC, flu,vori

multivariate analysis

Risk factors associated with 10-week mortality195 patients with cryptococcosis in Taiwan

27PLoS ONE 2013;8: e61921

Fungi capable of crossing kingdoms to infect plants and humans

• The predominant pathogen of a recent outbreak associated with contaminated methylprednisolone acetate, Exserohilum rostratum(teleomorph: Setosphaeria rostrata), is a dematiaceous fungus that infects grasses and rarely humans.

• Most crossover or trans-kingdom pathogens are soil saprophytes and include fungi in Ascomycota and Mucormycotina phyla.

Gauthier & Keller. Fungal Genet Biol. 2013;61:146

Ascomycota Plant disease Human disease

Aspergillus flavus Seedling blight Ocular (trauma); otitis externa (trauma); sinus, lung, and SSTI infections (Trauma, SOT, HSCT, PI, Malignancy)

Aspergillus niger Rot, seedling blight

Otitis externa (trauma), cutaneous (HSCT, ALL, AML, AA), lung (PI, pre-existing cavity)

Fusariumoxysporum, F. solani

Wilt disease, stem canker, rot

Ocular (trauma); sinus, lung, SSTI, and disseminated infections (Trauma, SOT, HSCT, PI, Malignancy)

28

Invasive infections in plants and humans caused by crossover fungal pathogens (cont.)

Ascomycota Plant disease Human disease

Dematiaeceous

Acrophialophorausispora

Secondary invader of plants

Keratitis (trauma), brain abscess (ALL), lung infection (SOT)

Exserohilumrostratum

Leaf spot, blight, rot (root, crown)

Keratitis (post-operative, trauma), sinusitis (AA, healthy), SSTI (trauma, lymphoma),disseminated (AA, ALL); meningitis, bone, joint, soft tissue due to contaminatedmethylprednisolone

Mucoromycotina

Rhizopus, Rhizomucor Rot CNS, sinus, lung, SSTI, GI and disseminated infections (Trauma, DM, SOT, HSCT, PI,Malignancy)

Gauthier GM, Keller NP. Fungal Genet Biol. 2013 Dec;61:146 29

Agricultural fungicides and invasive fungal infections in humans

• To minimize agricultural losses from fungal diseases, fungicides are routinely applied to economically valuable crops.

• In the Netherlands, the prevalence of itraconazole resistance of A. fumigatus isolated from humans has increased from 1.7% to 6.0%, and 90% to 94% of these resistant isolates contain a 34-base pair tandem repeat and a point mutation in cyp51A (TR34/L98H mutation).

• The TR34/L98H mutant also confers reduced susceptibility or resistance to voriconazole and posaconazole.

• A. fumigatus TR34/L98H mutants have also been isolated from humans in several other European countries and Asia.

Gauthier GM, Keller NP. Fungal Genet Biol. 2013;61:146 30

Catastrophes from the past will strike again — we just do not know when

Fungi have not received enough attention from

researchers and governments• Although viruses and bacteria grab more attention, fungi are the

planet's biggest killers. Of all the pathogens being tracked, fungi have caused more than 70% of the recorded global and regional extinctions, and now threaten amphibians, bats and bees.

• The Irish potato famine in the 1840s showed just how devastating such pathogens can be. Modern agriculture has exacerbated societies' vulnerability by encouraging farmers to plant the same strains of high-yield crops, limiting the variety of resistance genes among the plants.

• In the past decade, Cryptococcus gattii has adapted to thrive in cooler climes and invaded the forests of North America's Pacific Northwest. By 2010, it had infected some 280 people, dozens of whom died.

Jones N. Nature. 2013;493:15431

Conclusion

32

Entry

Proliferation

Tissue damage

Inflammatory response

Organ dysfunction

Be vigilant! Be aware of the risk and potential etiologies

What the mind does not know, the eye does not see.

Expanded spectrum of opportunistic fungal pathogens

Sci Transl Med 2012;4