INFECTIOUS DISEASE/CDC UPDATE

Update on Emerging Infections: News From the Centers forDisease Control and Prevention

CommentatorManish Garg, MD

From the Department of Emergency Medicine, Temple University Hospital, Philadelphia, PA.

Editor’s note: This article is part of a regular series onemerging infection from the Centers for Disease Controland Prevention (CDC) and the EMERGEncy ID NET, anemergency department-based and CDC-collaborativesurveillance network. Important infectious diseasepublic health information with relevance to emergencyphysicians is reported. The goal of this series is toadvance knowledge about communicable diseases inemergency medicine and foster cooperation betweenthe front line of clinical medicine and public healthagencies.

Emergence of Cryptococcus gattii—Pacific Northwest,2004-2010

[Centers for Disease Control and Prevention. Emergenceof Cryptococcus gattii—Pacific Northwest 2004-2010.MMWR Morb Mortal Wkly Rep. 2010;59:865-868.]

Cryptococcus is a genus of fungi, of which 2 species, Cneoformans and C gattii, cause nearly all human and animalcryptococcal infections. Whereas C neoformans primarily affectspersons infected with HIV worldwide, C gattii primarily affectsHIV-uninfected persons in tropical and subtropical regions.1 InDecember 2004, a case of human C gattii infection was reportedin Oregon, associated with an outbreak on Vancouver Islandand in mainland British Columbia, Canada.2 A second C gattiicase was reported in Oregon in 2005, and 12 more cases werereported in 2006 and 2007. In 2008, in response to theemergence of C gattii in the United States, the Centers forDisease Control and Prevention (CDC), state and local publichealth authorities, and the British Columbia Centre for DiseaseControl formed the Cryptococcus gattii Public Health WorkingGroup.1 States began collecting epidemiologic information onpatients and sending isolates to CDC. By July 2010, a total of60 human cases had been reported to CDC from 4 states(California, Idaho, Oregon, and Washington) in the PacificNorthwest. Among 52 patients for whom travel history wasknown, 46 (88%) said they had not traveled to BritishColumbia or any other C gattii–endemic areas, suggesting theyacquired the infection locally. Among 45 patients with knownoutcomes, 9 (20%) died because of C gattii infection, and 6(13%) died with C gattii infection. Physicians should consider Cgattii as a possible cause of a cryptococcal infection amongpersons living in or traveling to the Pacific Northwest or

traveling to other C gattii–endemic areas.

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Multilocus sequence typing subcategorizes C gattii into 4genotypes: VGI, VGII, VGIII, and VGIV. Further genetic analysisdivides the VGII genotype into 3 subtypes: VGIIa, VGIIb, andVGIIc.3 Although VGII is the genotype most commonly associatedwith the outbreak in the United States and British Columbia, it isuncommon in other C gattii–endemic parts of the world, whereVGI is isolated most frequently.3

During 1999, C gattii began appearing in animals andhumans on Vancouver Island and, beginning in 2004, amongmainland British Columbia residents who had no exposure toVancouver Island.2,4 By the end of 2007, a total of 218 humancases had been reported to British Columbia Centre for DiseaseControl.5 Studies from British Columbia and elsewhere showeda median incubation period of 6 to 7 months, with a range of 2to 13 months.1 The median age of patients in British Columbiawas 59 years, with age-specific incidence highest among personsaged 70 to 79 years.5 Only 38% of patients had an identifiableimmunosuppressive condition.5 Reported case-fatality rateseither from or with C gattii infection was 9%.5 Studies onVancouver Island found C gattii spores in the environment,often in association with trees and soil.6

The 2 human infections reported from Oregon in 2004 and2005 were from C gattii subtypes VGIIa and VGIIc.3 TheVGIIc subtype had not been found previously anywhere inthe world; the VGIIa isolate was genetically distinct from theBritish Columbia VGIIa isolates.4 Neither patient had traveledto Vancouver Island or any other known C gattii–endemic area.In early 2006, a resident of Orcas Island, Washington,developed C gattii VGIIa infection with a strainindistinguishable from the British Columbia VGIIa strain.7

In October 2009, the Cryptococcus gattii Public HealthWorking Group formalized a surveillance system for C gattii andhoused it at CDC. The system includes standardized human andveterinary case report forms and isolate submission protocols.Standardized case report forms include questions about patientdemographics, health history, and illness onset and course and arecompleted by state or local health departments through interviewswith patients or their family members. For the surveillance system,a case is defined as an illness occurring on or after January 1, 2004,in a US resident or animal with a culture-confirmed isolate of Cgattii. Case report forms are completed after a patient isolate isconfirmed as C gattii at CDC. Chart reviews and patient or familymember interviews for collection of patient information are carried

out by state and local health departments to gather data on

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symptoms and illness course. For patients whose illnessoccurred before the surveillance system was initiated, isolateswere sent to CDC or British Columbia Centre for DiseaseControl at illness; chart reviews and patient or familymember interviews carried out at illness were used tocomplete the case report forms.

During January 1, 2004, to July 1, 2010, a total of 60human cases of C gattii infection were reported to CDC: 43from Oregon, 15 from Washington, 1 from California, and 1from Idaho. Approximately half (54%) of the cases were malepatients; patients ranged in age from 15 to 95 years, with thehighest proportion of patients (45%) aged 50 to 69 years.Among 47 patients for whom such information was known, 38(81%) had an underlying condition that might havepredisposed them to infection, including 3 patients with HIVinfections. Of all patient isolates, 50% were subtype VGIIa,32% were VGIIc, 10% were VGIIb, 5% were VGI, and 3%were VGIII. The most common clinical finding waspneumonia, occurring among 57% of patients.

Among the 45 patients for whom outcome was known, 9(20%) died because of C gattii infection and 6 (13%) died withC gattii infection; 2 of the 9 who died from C gattii infectionhad no predisposing condition. In addition to human cases, 52veterinary cases (among cats, dogs, ferrets, sheep, camelids, elk,horses, goats, and porpoises) were reported to CDC fromCalifornia, Hawaii, Oregon, and Washington.

Cryptococcus gattii is an emerging infection in the UnitedStates. Cryptococcus gattii appears to differ from its siblingspecies, C neoformans, both in its clinical aspects (eg, lessresponsive to antifungal drugs and more likely to causetumorlike lesions called cryptococcomas) and its ecologicniche.2,8 In addition, whereas the primary risk factor for Cneoformans cryptococcosis is severe immunosuppression (eg,from HIV infection), risk factors for C gattii infection in theUnited States appear to include both immunocompromise andexposure to specific regions of environmental fungalcolonization.2,8 Many cases of C gattii infection are likely notrecognized because distinguishing between C gattii and Cneoformans requires plating on differential media notroutinely available in clinical microbiology laboratories;therefore, many cryptococcal infections are never speciated.In addition, cryptococcal infections generally are notnotifiable diseases in the United States, although C gattii isnow reportable in 1 state, Washington, as a rare disease ofpublic health importance.

Until 1999, most human C gattii infections were reported fromAustralia and other tropical and subtropical regions, including partsof Africa, Asia, the Mediterranean, South America, and southernCalifornia.8 Fungal spores are known to colonize the nasal cavityand spread to other body sites, causing meningitis, pneumonia, andthe development of lung, brain, or muscle cryptococcomas.8 Theinfection is not known to be transmitted among or within animal

species. Although C gattii had been isolated rarely from

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environmental sources and patients in the United States before2004,2 US outbreaks had not been reported.

Because C gattii typically has been regarded as tropical orsubtropical in geographic distribution, its emergence in a temperateclimate suggests that the pathogen might have adapted to a newclimatic niche or that climatic warming might have created anenvironment in which minimum threshold conditions for C gattiispore survival and propagation are attained consistently.1,2

Alternatively, the environmental conditions supportive of C gattiimight be broader than previously suspected, or earlier propagationmight have been inhibited by low concentrations of pathogen inthe environment. In addition, infections might have occurred inthe Pacific Northwest before the recognized increase in humancases, but too rarely to attract attention. However, retrospectivespeciation of 49 cryptococcal isolates from the Pacific Northwestobtained from 1997 through 20037 and 31 isolates fromVancouver Island obtained from 1987 through 19989 revealedexclusively C neoformans, suggesting that the recent increase inreports of C gattii represents actual emergence of the species in theregion and not just an increase in disease awareness and reporting.

Additional systematic surveillance is needed to track C gattiiinfection, along with increased awareness of the infectionamong public health practitioners, physicians, and veterinarians.In 2010, for the first time, surveillance data for C gattii werereported at the Council of State and Territorial Epidemiologistsmeeting. The Cryptococcus gattii Public Health Working Groupis continuing disease surveillance and planning to conductspeciation of banked isolates of Cryptococcus. Improvedsurveillance should enable better assessment of the incidence ofthe disease and also its clinical manifestation and course.

Physicians should consider C gattii as a possible cause ofinfection when treating patients (particularly those who are HIVnegative) who have signs and symptoms of cryptococcalinfection and should ask patients about recent travel to thePacific Northwest, British Columbia, or other C gattii–endemicareas. Physicians, particularly in the Pacific Northwest, shouldreport suspected C gattii infections and submit clinical isolatesto their state health departments when requested.

REFERENCES1. Dixit A, Carroll SF, Qureshi ST. Cryptococcus gattii: an emerging

cause of fungal disease in North America. Interdiscip PerspectInfect Dis. 2009:840452.

2. Datta K, Bartlett KH, Baer R, et al. Spread of Cryptococcus gattiiinto Pacific Northwest region of the United States. Emerg InfectDis. 2009;15:1185-1191.

3. Byrnes EJ III, Bildfell RJ, Frank SA, et al. Molecular evidence thatthe range of the Vancouver Island outbreak of Cryptococcus gattiiinfection has expanded into the Pacific Northwest in the UnitedStates. J Infect Dis. 2009;199:1081-1086.

4. MacDougall L, Kidd SE, Galanis E, et al. Spread of Cryptococcusgattii in British Columbia, Canada, and detection in the PacificNorthwest, USA. Emerg Infect Dis. 2007;13:42-50.

5. Galanis E, Macdougall L. Epidemiology of Cryptococcus gattii, BritishColumbia, Canada, 1999-2007. Emerg Infect Dis. 2010;16:251-257.

6. Kidd SE, Chow Y, Mak S, et al. Characterization of environmental

sources of the human and animal pathogen Cryptococcus gattii in

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British Columbia, Canada, and the Pacific Northwest of the UnitedStates. Appl Environ Microbiol. 2007;73:1433-1443.

7. Upton A, Fraser JA, Kidd SE, et al. First contemporary case ofhuman infection with Cryptococcus gattii in Puget Sound: evidencefor spread of the Vancouver Island outbreak. J Clin Microbiol.2007;45:3086-3088.

8. Sorrell TC. Cryptococcus neoformans variety gattii. Med Mycol.2001;39:155-168.

9. Fyfe M, MacDougall L, Romney M, et al. Cryptococcus gattiiinfections on Vancouver Island, British Columbia, Canada:emergence of a tropical fungus in a temperate environment. CanCommun Dis Rep. 2008;34:1-12.

COMMENTARY

[Ann Emerg Med. 2011;57:62-63.]

Emergency physicians are the front-line providers fordiagnosis and initial empiric treatment of meningoencephalitis.The diagnosis of subacute central nervous system infections isoften difficult, and additional consideration of these infections isgiven to patients with impaired immune function. For example,meningitis caused by C neoformans would be a consideration inan HIV-infected patient with a new or unusual headache. Theemergence of C gattii in the Pacific Northwest represents aconcerning challenge to this approach because C gattii primarilyaffects nonimmunocompromised individuals and is associatedwith serious morbidity and mortality.1

Cryptococcus gattii is an encapsulated yeast that has beencultured from eucalyptus trees exported from Australia toCalifornia and the Pacific Northwest.2 Fungal spores arereleased into the environment and come into direct contact withthe human nasal passageway through contaminated soil and air.Cryptococcus gattii infections in humans typically begin asprimary pulmonary infection from spore inhalation, leading topneumonia and pulmonary cryptococcomas. The primaryinfection disseminates in the blood to other organs, includingthe central nervous system (CNS) and causesmeningoencephalitis or brain cryptococcomas.3

Cryptococcomas represent infectious granulomas of denselyconcentrated cryptococcal organisms. They are commonly seenin the lung, brain, and soft tissues. Because C gattii primarilyaffects immunocompetent individuals, it is believed that thesehealthy hosts are able to contain the foci of infection intogranulomas by immune response. Cryptococcus gattii–infectedhealthy hosts thus have higher prevalence rates ofcryptococcomas, particularly in the lung and CNS. Theselesions have significant effect on patient symptoms andsubsequent management because they are more indolent andless responsive to therapy. Cryptococcomas represent space-occupying lesions and can lead to localized pneumonia orabscesses in the lung and obstructing hydrocephalus or abscessesin the brain.

The clinical course of C gattii infection resembles Cneoformans infection. Patients present with a vague constellationof symptoms related to constitutional, pulmonary, central

nervous, and gastrointestinal systems during weeks to months.

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The most common symptoms in this report were cough,headache, dyspnea, nausea, and fever. In British Columbia,90.8% of C gattii–infected persons sought treatment for arespiratory syndrome with or without neurologic findings.3 Incontrast, an Australian study showed that 85% of Cgattii–infected patients had meningitis, and 59% of patientspresented with headache.4 The most common clinical findingsin this report were pneumonia, meningitis, lungcryptococcomas, brain cryptococcomas, and encephalitis,consistent with those of other studies.1,3,4 Thus, the emergencyphysician should suspect a C gattii infection in patients whohave had exposure to an endemic area and a slow indolentcourse of symptoms with pulmonary and CNS findings. Correctdiagnosis is important, as evidenced by the extremely highmortality rate observed in this study; 20% (1 of 5 patients) dieddirectly from C gattii infection, and 13% (1 of 8 patients) diedas a result of other complicating factors. Taken together, 33%(1 of 3 patients) died in this study directly or indirectly becauseof C gattii. In previous studies, abnormal mental status atpatient presentation is a poor prognostic indicator of mortality.5

Radiologic imaging can be extremely helpful to theemergency physician for the diagnosis of C gattii lung and brainmanifestations. Chest radiography or contrast computedtomography (CT) can show single or multiple pulmonarynodules, segmental or lobar consolidation, or a reticulonodularpattern of opacities. Furthermore, pulmonary cavitations,lymphadenopathy, or pleural effusions may also be present.6

Contrast CT scan or magnetic resonance imaging (MRI) of thebrain can show hydrocephalus, abscess, or ring-enhancinglesions representing brain cryptococcomas.7 Diagnosis ofpulmonary and brain cryptococcomas will have implications forantifungal medications and medical versus surgical treatment.

For the emergency physician, initial management andtreatment for C gattii will be similar to that of treatment for Cneoformans, with special attention to sepsis care if the patientclinically meets criteria. Historical questions should includetravel history to endemic areas and clinical symptoms previouslymentioned. Laboratory investigations should include bloodculture and cerebrospinal fluid analysis. India ink staining of thecerebrospinal fluid can quickly identify the presence of thecryptococcal polysaccharide capsule, which appears as a haloaround the organism. Cryptococcal antigen tests of blood andcerebrospinal fluid are more sensitive than India ink staining,but results may not be immediately available. The cryptococcalantigen test will not differentiate C gattii from C neoformans butwill be helpful to support the diagnosis. Initial diagnosticimaging should include chest radiography and CT of the brain.

The Infectious Diseases Society of America has justpublished its 2010 updated clinical practice guidelines for themanagement of cryptococcal disease.7 It specifically highlightsnew recommendations for management and treatment of Cgattii. For the emergency physician, the following are relevantclinical recommendations: (1) for CNS and disseminated

disease caused by C gattii, induction treatment is the same as for

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