� Review Article www.jpgmonline.com Microbiology of systemic fungal infections

Chakrabarti A

Department of Medical ABSTRACTABSTRACT Microbiology Postgradu­ The increased incidence of systemic fungal infections in the past two decades has been overwhelming. Earlier, ate Institute of Medical Education & Research, it was pathogenic dimorphic fungi, which were known to cause systemic infections. However, starting from Chandigarh, India the 1960s, opportunistic fungi started causing more number of infections, especially in the immunocompromised host. More recently, newer and less common fungal agents are being increasingly associated with infection in immunosuppressed hosts. Amongst dimorphic fungi, infections due to and Penicillium marneffei are increasingly reported in patients with AIDS in India. H. capsulatum is found country wide, but P. marneffei remains restricted to Manipur state. Although both varieties of C. neoformans, C. neoformans var. neoformans (serotypes A & D), and C. neoformans var. gattii (serotypes B & C) are reported in India, most of the cases reported are of serotype A. Increased incidence of is reported from all centers with the emergence of AIDS. Systemic infection due to species under Candida, and zygomycetes is widely prevalent in nosocomial setting, and outbreaks due to unusual fungi are reported occasionally from tertiary care centers. This global change in systemic fungal infections has emphasized the need to develop good diagnostic mycology laboratories in this country and to recognize this increasingly large group of potential fungal pathogens. Correspondence: Arunaloke Chakrabarti KEY WORDS: Aspergillus, Candida, disseminated fungal infections, fungi, opportunistic infections, systemic E-mail: fungal infections, Zygomycetes [email protected]

ystemic infections caused by fungi constitute a major patients have Pneumocystis carinii (jiroveci) pneumonia or public health problem in many parts of the world, both esophageal , respectively[8]; cryptococcal meningi­ S in developed and developing countries. Historically, tis is present in 30% of people with AIDS in Africa and south­ the discovery of the etiologic role played by fungi in disease east Asia[9]; and Penicillium marneffei infections are present in marked the very beginning of medical microbiology. The about 30% of people with AIDS in south-east Asia.[10] founder of the doctrine of pathogenic microbes was Agostino Bassi, a predecessor of Pasteur and Koch. In 1835, Bassi re­ The data on burden of systemic fungal infections in India are vealed a , Beauvaria bassiana, that caused devastating silk­ not clear though the climatic diversity in this country is suited worm disease. It was quickly followed by the first discoveries for a wide variety of fungal infections. However, a definite ris­ of human disease caused by fungi e.g. by Remark and ing trend has been noted. The systemic fungal infections re­ Schoenlein in 1837 and 1842, respectively, candidiasis by Gruby ported in India are included in Table 1. in 1842 and by Sluyter in 1847.[1],[2] From our center, an eleven-fold increase in candidemia was Fungi are extremely fit for survival as evidenced by their ubiq­ reported in the second half of the 1980s[11] and further 18-fold uity in nature. However, of the estimated several hundred thou­ rise was observed in the first half of the 1990s.[12] sand species of fungi, fewer than 150–200 were considered to due to unusual – Pichia anomala – was reported from the be pathogens of humans. However, in recent years, fungi are same center affecting 379 neonates and children (4.2% of all flourishing in man. The number of fungi causing systemic dis­ ease is growing and the number of systemic diseases caused by Table 1: Systemic fungal infection in India fungi is increasing. Up to 7% patients dying in teaching hospi­ Endemic mycoses Opportunistic fungal infections [3],[4] tals have invasive aspergillosis. Candida spp. accounts for Invasive candidiasis 8–15% of nosocomial blood stream infections and fourth most Invasive aspergillosis common isolate of patients of intensive care unit.[5] Specific Penicilliosis marneffei Cryptococcosis patient groups have very high frequencies of fungal infections: Invasive 15% of allogenic hemopoietic stem-cell transplant recipients Pneumocystis carinii (jiroveci) infection have a fungal infection[6]; about 20% of lung transplant recipi­ Phaeohyphomycosis Infection due to miscellaneous fungi ents are colonized and infected[7]; about 60% and 20% of AIDS

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16 CMYK Chakrabarti: Microbiology of systemic fungal infections � admission) over a period of 23 months.[13] Systemic aspergillo­ specimens. This leads to difficulty in classifying and studying sis also caused havoc as 95 patients developed intracranial as­ this group of fungal infections. To resolve this problem, Ajello pergillosis during 1980–1993.[14] A rising trend in invasive et al. proposed the term “phaeohyphomycosis’ to cover all “in­ zygomycosis was reported when 129 cases were diagnosed over fections of a cutaneous, subcutaneous, and systemic nature the period 1990–1999[15] with the emergence of Apophysomyces caused by hyphomycetous fungi that develop in host tissues elegans infection in India.[16] The annual incidence of crypto­ in the form of dark-walled dematiaceous septate mycelial ele­ coccosis has increased about 15-fold compared to pre-AIDS ments”[21] and the name “hyalohyphomycosis” was proposed era.[17] All these figures denote that at present a vast array of by Ajello and McGinnis to accommodate mycotic infections fungi are causing systemic disease in a large number of pa­ in which the tissue form of the etiological agents is septate tients. Many factors account for this substantial increase in hyphae with no pigment in the wall.[22] systemic fungal infections, including better management of other complications of immunosuppression, novel and more Candida spp aggressive immunosuppressive regimens, enhanced survival in The overall increase in candidemia in recent years is compli­ intensive care, a high frequency of instrumentation and cath­ cated by the emergence of non-C. albicans Candida (NAC) eterization, greater awareness of clinicians, better diagnostic species as both colonizers and pathogens causing nosocomial approaches, and increased use of broad spectrum antibiotics. fungal blood stream infection (BSI). Wingard in a compre­ hensive review of all published reports during 1952–1992 found The etiology of systemic fungal infections can be broadly clas­ that 12 reports showed proportionally higher (>50%) isola­ sified into two groups: endemic mycoses due to true patho­ tion of NAC species.[23] The NAC species isolated were C. genic fungi and opportunistic fungal infections due to a vast glabrata, C. krusei, C. tropicalis, and C. parapsilosis. Other array of saprophytic fungi. species like C. guilliermondii, C. lusitaniae, C. dubliniensis, C. kefyr, C. lipolytica, and C. pelliculosa were occasionally iso­ True pathogenic fungi lated. The earliest population-based surveillance study con­ ducted in 1992–1993 by CDC, USA, reported C. albicans as True pathogenic fungi produce a different form in tissue or at the most common species, followed in order by C. parapsilosis, 37°C in contrast to mycelial form in culture at 25–30°C. These C. tropicalis, and C. glabrata. Subsequent surveillance pro­ fungi are referred to as dimorphic fungi and include Histo­ grams noted an increase in the proportion of Candida BSI by plasma capsulatum, , Blastomyces NAC species and especially an increase in the frequency of dermatitidis, immitis, Paracoccidioides brasiliensis, BSI due to C. glabrata.[5] In contrast, surveillance data from Penicillium marneffei, and . These fungi other countries continue to reflect the importance of C. are usually geographically restricted. C. immitis is a geophilic parapsilosis over C. glabrata.[24] mold confined to new world and adapted to live specifically in the desert-like terrain of North, Central, and South America.[18] The importance of patient age in determining rank order of P. marneffei is restricted to south-east Asia possibly remaining Candia species causing BSI has also been noted.[23] The pre­ with its habitat bamboo rats.[10],[19] H. capsulatum and B. dominance of C. albicans and C. parapsilosis and the lack of dermatitidis have a worldwide distribution. In India, histoplas­ C. glabrata and other NAC species have been observed in mosis and blastomycosis are reported from different states, but neonatal age groups. In contrast, C. glabrata becomes an in­ penicilliosis marneffei is restricted to Manipur state. There is creasingly important pathogen with increase in age. The con­ only one report of systemic sporotrichosis due to S. schenckii tribution of individual NAC species also varies with patients var. luriei and represents the only report from an Asian coun­ and diagnostic groups. Candidemia due to C. parapsilosis is try.[20] Along with emergence of AIDS in India, histoplasmosis generally associated with catheters, hyperalimentation, or pros­ is increasingly reported. thetic devices.[25] Also, C. parapsilosis is the most common species of Candida to be isolated from the hands of health Opportunistic fungi care workers in ICU, especially those who wear gloves.[26] Thus, it is likely that the contamination of prosthetic devices with Starting in the 1960s, species under Candida, Aspergillus, Cryp­ the organism occurs via the hand of health care workers. C. tococcus, and zygomycetes began to be regularly associated with glabrata tends to affect oncology patients with solid tumor.[27] patients receiving treatment for cancer, sarcoidosis, diabetes, C. krusei is intrinsically resistant to fluconazole and increased and organ transplant. The ‘big four’ of these opportunists were infection with this organism has been reported in some bone then accounting for more pathology and more investigators’ marrow transplant units when fluconazole prophylaxis has been attention than all other fungi combined. However, in the last used.[28] Independent of antifungal prophylaxis, C. krusei in­ 30–40 years changes have occurred, and newer pathogens are fection is found predominantly in patients with hematological being recognized especially with the emergence of AIDS. Some­ malignancies, whereas the incidence of C. krusei infections in times, it is not just a single fungus, but rather a combination patients with solid tumor and ICU patients is low.[29] of fungi i.e. species under Pneumocystis, Candida, Cryptococ­ cus, Histoplasma, Coccidioides, Aspergillus, and zygomycetes, Similar to the western world, the rise in frequency of NAC which may produce concomitant and/or successive opportun­ species has been observed in tertiary care centers in India as istic systemic fungal infections. Besides, a long list of less com­ well with isolation rates ranging from 52 to 96%. However, the mon fungal pathogens is being isolated regularly from clinical predominant isolation of C. tropicalis instead of C. glabrata

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CMYK 17 � Chakrabarti: Microbiology of systemic fungal infections or C. parapsilosis in all age groups in the Indian scenario is A. fumigatus is the most common cause of invasive aspergillo­ unique in this context.[12],[30]–[32] The data summarized in Ta­ sis. A. flavus, the second most common species, is isolated from ble 2 show the worldwide isolation of Candida species from systemic aspergillosis of immunosuppressed patients, as well patients with candidemia. as from lesions originating from the nasal sinuses. However, in India, Sudan, and South Africa, A. flavus is the most common Other cause of all forms of aspergillosis. A. niger is the third most Cryptococcosis is reported with increasing frequency after the common cause of invasive aspergillosis. Other species docu­ emergence of AIDS.[17] Although a decline in incidence has mented rarely include A. nidulans, A. versicolor, A. candidus, been observed in developed countries after tri-drug regimen, A. oryzae, A. sydowii, A. terreus, A. clavatus, etc. no such change is seen in developing countries due to poor affordability of the costly drugs. Several other saprophytic yeasts Fusarium species, cosmopolitan soil saprobe, can cause sys­ are reported to cause systemic infections in recent years. Those temic infection in humans. Increased incidence, often with are listed in Table 3. fatal outcome, has been seen in neutropenic patients with hematological malignancies and in patients with bone-mar­ Aspergillus spp. and other moniliaceous fungi row and solid-organ transplantation.[37] Other rare systemic Systemic aspergillosis is the second most common invasive infections are reported due to fungi belonging to genera fungal infections. In certain patient groups, such as Scedosporium, Pseudallescheria, Acremonium, Lecythophora, hematological malignancies, the condition has been reported Phialemonium, Phaeoacremonium, Paecilomyces and Emmonsia. as accounting for up to 30% of patients in postmortem se­ ries[34] and 36% of patients with pneumonia in bone-marrow Zygomycetes transplant unit.[35] Data gathered between 1980 and 1990 in a Like Aspergillus species, zygomycetes are common nosocomial cross-section of hospitals throughout USA indicated that 1.3% pathogens to cause systemic zygomycosis. However, the exact of all nosocomial infections were caused by Aspergillus spe­ incidence is difficult to ascertain due to difficulty in ante­ cies.[36] mortem diagnosis. Systemic zygomycosis can also be commu-

Table 2: Candida species causing blood stream infection worldwide Species USA Canada Europe Hungary Latin America The Netherlands Northern Ireland India 1997 1997 1997 1996–2000 1997 1995 1996–2000 1991–2000 C. albicans 56 53 53 77 41 60 53 14 C. parapsilosis 9 23 21 7 38 2 11 2 C. glabrata 19 11 12 3 2 17 27 3 C. tropicalis 7 8 6 4 12 4 6 38 C. guilliermondii 1–4– 2 2 – 12 C. krusei 2 2 1 6 – 2 – 5 Other Candida species 6 3 3 3 5 13 3 26

Table 3: Other yeasts or yeast-like organisms causing systemic fungal infections Genus Species Occurrence Remarks Cryptococcus C. neoformans Common Increased number of cases due to emergence of AIDS (C. neoformans var. neoformans C. neoformans var. gattii) Rare Habitat – C. neoformans var. neoformans in bird droppings, C. neoformans var. gattii in Eucalyptus trees, but recently both varieties isolated from debris in hollows of several big trees (Jamun, Pipal, etc.) C. albidus, C. laurentii Geotrichum G. candidum Very rare Only in extremely debilitated individuals Prototheca P. wickerhamii Extremely rare Blastoschizomyces B. capitatus Rare In patients with leukemia, endocarditis and other immunosuppressive conditions Pichia (Hansenula) P. anomala Outbreak Three outbreaks reported mainly in pediatric units P. augusta Rare From mediastinal lymphadenitis M. furfur, M. globosa, Rare outbreak Usually present on skin M. pachydermatis, M. obtusa, M. furfur, M. pachydermatis in neonatal intensive care M. restricta, M. slooffiae, M. sympoidalis unit Associated risk factor – parenteral lipid formulation Rhodotorula R. rubra Extremely rare From indwelling central venous catheters Saccharomyces S. cerevisiae Extremely rare Associated with health food, baking T. asahii, T. asteroides, T. cutaneum, Rare T. inkin, T. mucoides, T. ovides T. asahii and less often T. mucoides cause disseminated infection in patients with hematological malignancies or immunosuppression

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nity acquired especially in patients with uncontrolled diabe­ Conclusion tes mellitus, other forms of metabolic acidosis, burns, and malignant hematological disorders. This review emphasizes the fact that the clinical mycology labo­ ratory must be able to recognize this increasingly large group Many different zygomycetes have been implicated, but the of potential pathogens. Organisms once thought to be con­ most common causes of systemic zygomycosis, listed in order taminants are now confirmed pathogens causing systemic in­ of apparent incidence, are Rhizopus arrhizus and Rhizopus fection in immunocompromised patients. In addition, there microsporus var. rhizopodoformis. Other less frequent etiological is a critical need to recognize that even though a given isolate agents, but for which a major pathogenic role in humans has may not be a documented fungal pathogen in textbooks, its been established, include Absidia corymbifera, Apophysomyces isolation from a normally sterile site and its ability to grow at elegans, Cunninghamella bertholletiae, Mucor species, 37°C require that it be considered a possible pathogen. Rhizomucor pusillus, and Saksenaea vasiformis. These are ubiquitous and thermotolerant and can be isolated in large References numbers from soil or decomposing organic matter, such as fruit 1. Kisch B. Forgotten leaders in modern medicine: Valentin, Gruby, Remark, and bread. The spores can often be found in hospital and out­ Auerback. Trans Am Philos Soc 1954;44:139-317. 2. Ajello L. Systemic mycoses in modern medicine. Contr Microbiol Immunol side air. 1977;3:2-6. 3. Groll AH, Shah PM, Mentzel C,Schneider M, Just-Nuebling G, Huebner K. 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