Stealthy emergence of Cryptococcus gattii in North America

What can the members of multiple animal species (cat, dog, bird, ferret, llama, alpaca, elk, goat, sheep, horse, porpoise) have in common with humans? Deeper philosophical questions aside, all of them have fallen prey to a deadly fungus spreading gradually, but steadily, in western North America (southwest Canada; US states of the Pacific Northwest, PNW) for over a decade.¹

Well, what-ho, what-ho Cryptococcus gattii (CG), I believe we have been introduced.

The disease, cryptococcosis, generally, affects the lungs first, later spreading to the brain and other organs in absence of therapy – with severe, even life-threatening, manifestations. Worldwide, the burden of cryptococcosis is predominantly due to Cryptococcus neoformans (CN). I have mentioned earlier that CN loves to get to the brain; CN serotype D (christened variety neoformans), prevalent in northern European countries, is known to also cause skin infections. The closely-related cousin, CG, is more of a systemic (i.e. affecting the whole body from inside) kind of fungus – involving lungs, blood, brain, and organs – much like CN serotype A (christened variety grubii).

Illustration ©CDC; Source: CDC Page on C. gattii sources. Click to embiggen.

CG is an inhabitant of specific tropical and subtropical regions of the world (including Australia, South America, northern and central Africa, east and southeast Asia) and wreaks significant havoc in these parts. In the US, a high prevalence of CG has been noted since late 1970s in Southern California and Hawaii; retrospective analyses have found sporadic occurrences in North Carolina, Rhode Island, New Mexico, Michigan, Georgia, and Montana. However, disease incidences were not high enough to merit concern, until now. The current North American spread is severe enough to have gained ‘outbreak’ status from the US Centers for Disease Control and Prevention (CDC).

CG and CN have similar, but slightly different, biochemical properties and effects on mammalian (human and animal) hosts. Current thinking is that CN primarily causes disease in people with reduced or suppressed immunity (for instance, cancer or organ transplant patients; people with severe metabolic disorders; and HIV-infected individuals); in contrast, CG appears to be able to cause disease both in the immune-suppressed and in apparently healthy people with presumably intact immunity [although subtle, non-apparent defects of immunity cannot be ruled out].² In addition, CG is known to require more aggressive therapy, and for a longer duration, compared to CN.

Amongst infectious diseases, fungal diseases are generally more ‘chronic’ in nature, developing over a long time and sometimes reappearing even after therapy, in contrast to bacterial diseases with more ‘acute’ or immediate manifestations. In traditional clinical practice, therefore, bacterial infections naturally get more attention compared to fungal infections. In the past several decades, however, the importance of systemic fungal infections has been highlighted by clinical observations and research. Current clinical policies, aided by modern diagnostic techniques, advocate maintaining a high ‘index of suspicion’ for fungal infections; this means that for a given set of symptoms in a patient, the possibility of a fungal pathogen’s involvement is now actively considered while determining diagnosis and therapy. This increased awareness also means that local and regional public health authorities in the US can mobilize epidemiological surveillance systems for tracking the progress of a fungal disease; such systems may immensely help in determining its source.

Epidemiologists generally place the commencement of the outbreak in 1999, a year when hospitals in Vancouver Island of British Columbia (BC) in Canada noticed a sharp increase in cases of cryptococcosis among HIV-uninfected patients, compared to mainland BC hospitals. Around the same time, starting February of 2000, the veterinary clinical community in BC became aware of an explosive increase in the number of ill animals with diagnosed cryptococcal infection. Curiously, the cases seemed to cluster around the coastal areas of Vancouver Island and the west coast of BC, as well as parts of BC mainland – spanning the Coastal Douglas Fir and Coastal Western Hemlock biogeoclimatic zones.

In contrast to 4-6 animal cryptococcosis cases previously encountered on an annual basis, the annual count continued to rise sharply in this region, expanding to 45 laboratory-confirmed cases (excluding cases with lost/incomplete records) by March 2002. This included many of the aforementioned animals, variously presenting with respiratory or neurological symptoms, with or without lymph node enlargement. In a vast majority of cases, there was no detectable immune-suppression. The fungal isolates recovered from the clinical cases (and later from the environment in these zones, as well as from nasal passageways of many cats and dogs resident in the area) were identified by biochemical and molecular techniques to be none other than CG.

The Center for Disease Control at BC (BC-CDC), taking cognizance of the increasing numbers, made cryptococcosis reportable in 2003. By 2004, CG was reported in BC mainland residents who never visited Vancouver island – an indication that the fungus was spreading. As an indication of the extent of the problem, a retrospective analyses of disease surveillance data through 2006 estimated the incidence rate of human CG infections on Vancouver Island at 27.9 cases/million population annually; this rate is much higher than the rates seen in known habitats (‘endemic regions’) of CG such as Australia. The corresponding number for BC mainland stood at 6.5 cases/million. By the end of 2007, BC-CDC had recorded a total of 218 human cases. Importantly, a majority of these patients had no identifiable immune suppression.

Perhaps not surprisingly, the spread continued southward into PNW US states Washington and Oregon, with climate and ecology similar to coastal BC. In December 2004 and 2005, Oregon reported the first two human C. gattii infection cases; later molecular analysis revealed that CG strains in these were genetically different from CG seen in BC. Not long thereafter, the first contemporary ‘index’ CG (involving the ‘outbreak strain(s)’ from BC) case was recorded in January 2006 on Orcas Island in Washington. A 2010 report from CDC, the first comprehensive public health study of CG outbreak within US, documented 60 human and 52 veterinary cases of cryptococcosis, spanning 2004-2010 and covering five states, California, Idaho, Hawaii, Oregon, and Washington.³ Close to 80% of these patients appeared to have contracted the infection locally. CG numbers continue to rise in PNW; sporadic reports have appeared from regions beyond PNW (such as, Florida), indicating the spread.

The CDC report also provided evidence for some marked differences between clinical observations in the US and Canada. In the US, the mortality rates in these cryptococcosis patients were alarmingly high (up to 33%; compared to 9% in Canada), and a majority of patients (~80%) had mild to severely reduced immunity (including a documented few with HIV).

The CG outbreak in the US and Canada has affected hundreds of humans and animals over more than a decade. Epidemiological surveillance studies indicate the presence of the fungus in the soil, water, and air, and in association with a variety of indigenous tree species; the spread likely occurs as a result of human activities, as well as via natural dispersal.^{4, 5} The fact that CG – hitherto restricted to tropical/subtropical climates – continues to survive and thrive in the dry, temperate climate of North America is somewhat of a mystery. It is possible that long term climate changes towards elevated temperatures may have created in this region small pockets of climates conducive to Cg habitat, a hypothesis that seems to be corroborated by predictive ecological niche modeling.⁴

Continuously accruing knowledge about CG, from clinical, epidemiological, and laboratory research initiatives, has been constructive. Clinical decisions are aided by the recognition that Cg disease is different, and more severe, from the more common C. neoformans disease, and that various strains/molecular types of Cg differ in virulence and are less susceptible to many available antifungal drugs. However, clinical outcomes are largely poor. Two areas need urgent work, namely, the inclusion of molecular typing in routine diagnostic testing of CG, and evidence-based revisions of the existing therapeutic guidelines for CG disease. These steps would benefit the efforts to combat this public health menace successfully.

Death from CG disease is not merely due to treatment failure, but a combination of many factors including the host immune system. Ongoing research seeks to find better drugs as well as preventive vaccines. However, early detection may enhance the chance of a positive outcome manifold. Therefore, know thy fungus and get thee to a doctor should you experience the symptoms of a possible cryptococcal disease. Also, don’t disregard illness in your pets either; remember, CG disease in domestic pets and other animals have served as indicators for zones of human infections.

Sources:

1. Datta K, Bartlett KH, Baer R, Byrnes E, Galanis E, Heitman J, Hoang L, Leslie MJ, MacDougall L, Magill SS, Morshed MG, Marr KA, & Cryptococcus gattii Working Group of the Pacific Northwest (2009). Spread of Cryptococcus gattii into Pacific Northwest region of the United States. Emerging infectious diseases, 15 (8), 1185-91 PMID: 19757550
2. Marr KA, Datta K, Pirofski LA, & Barnes R (2012). Cryptococcus gattii infection in healthy hosts: a sentinel for subclinical immunodeficiency? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 54 (1), 153-4 PMID: 22075791
3. Centers for Disease Control and Prevention (CDC) (2010). Emergence of Cryptococcus gattii– Pacific Northwest, 2004-2010. MMWR. Morbidity and mortality weekly report, 59 (28), 865-8 PMID: 20651641
4. Datta K, Bartlett KH, & Marr KA (2009). Cryptococcus gattii: Emergence in Western North America: Exploitation of a Novel Ecological Niche. Interdisciplinary perspectives on infectious diseases, 2009 PMID: 19266091
5. Kidd SE, Bach PJ, Hingston AO, Mak S, Chow Y, MacDougall L, Kronstad JW, & Bartlett KH (2007). Cryptococcus gattii dispersal mechanisms, British Columbia, Canada. Emerging infectious diseases, 13 (1), 51-7 PMID: 17370515