Microbiology of systemic fungal infections

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Microbiology of systemic fungal infections

Chakrabarti A

Department of Medical Microbiology Postgradu ate Institute of Medical Education & Research, Chandigarh, India

Correspondence: Arunaloke Chakrabarti E-mail: akrab@sancharnet.in

ABSTRACT

The increased incidence of systemic fungal infections in the past two decades has been overwhelming. Earlier, it was pathogenic dimorphic fungi, which were known to cause systemic infections. However, starting from 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 Histoplasma capsulatum 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 cryptococcosis is reported from all centers with the emergence of AIDS. Systemic infection due to species under Candida, Aspergillus 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.

KEY WORDS: Aspergillus, Candida, disseminated fungal infections, fungi, opportunistic infections, systemic fungal infections, Zygomycetes

ystemic infections caused by fungi constitute a major

S public health problem in many parts of the world, both in developed and developing countries. Historically, the discovery of the etiologic role played by fungi in disease marked the very beginning of medical microbiology. The founder of the doctrine of pathogenic microbes was Agostino Bassi, a predecessor of Pasteur and Koch. In 1835, Bassi re vealed a mold, Beauvaria bassiana, that caused devastating silk worm disease. It was quickly followed by the first discoveries of human disease caused by fungi e.g. favus by Remark and Schoenlein in 1837 and 1842, respectively, candidiasis by Gruby in 1842 and aspergillosis by Sluyter in 1847.[1],[2]

Fungi are extremely fit for survival as evidenced by their ubiq uity in nature. However, of the estimated several hundred thou sand species of fungi, fewer than 150?200 were considered to be pathogens of humans. However, in recent years, fungi are flourishing in man. The number of fungi causing systemic dis ease is growing and the number of systemic diseases caused by fungi is increasing. Up to 7% patients dying in teaching hospi tals have invasive aspergillosis.[3],[4] Candida spp. accounts for 8?15% of nosocomial blood stream infections and fourth most common isolate of patients of intensive care unit.[5] Specific patient groups have very high frequencies of fungal infections: 15% of allogenic hemopoietic stem-cell transplant recipients have a fungal infection[6]; about 20% of lung transplant recipi ents are colonized and infected[7]; about 60% and 20% of AIDS

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patients have Pneumocystis carinii (jiroveci) pneumonia or esophageal candidiasis, respectively[8]; cryptococcal meningi tis is present in 30% of people with AIDS in Africa and south east Asia[9]; and Penicillium marneffei infections are present in about 30% of people with AIDS in south-east Asia.[10]

The data on burden of systemic fungal infections in India are not clear though the climatic diversity in this country is suited for a wide variety of fungal infections. However, a definite ris ing trend has been noted. The systemic fungal infections re ported in India are included in Table 1.

From our center, an eleven-fold increase in candidemia was reported in the second half of the 1980s[11] and further 18-fold rise was observed in the first half of the 1990s.[12] Fungemia due to unusual yeast ? Pichia anomala ? was reported from the same center affecting 379 neonates and children (4.2% of all

Table 1: Systemic fungal infection in India

Endemic mycoses

Histoplasmosis Blastomycosis Penicilliosis marneffei Sporotrichosis

Opportunistic fungal infections

Invasive candidiasis Invasive aspergillosis Cr yptococcosis Invasive zygomycosis Pneumocystis carinii (jiroveci) infection Phaeohyphomycosis Infection due to miscellaneous fungi

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admission) over a period of 23 months.[13] Systemic aspergillo sis also caused havoc as 95 patients developed intracranial as pergillosis during 1980?1993.[14] A rising trend in invasive zygomycosis was reported when 129 cases were diagnosed over the period 1990?1999[15] with the emergence of Apophysomyces elegans infection in India.[16] The annual incidence of crypto coccosis has increased about 15-fold compared to pre-AIDS era.[17] All these figures denote that at present a vast array of fungi are causing systemic disease in a large number of pa tients. Many factors account for this substantial increase in systemic fungal infections, including better management of other complications of immunosuppression, novel and more aggressive immunosuppressive regimens, enhanced survival in intensive care, a high frequency of instrumentation and cath eterization, greater awareness of clinicians, better diagnostic approaches, and increased use of broad spectrum antibiotics.

The etiology of systemic fungal infections can be broadly clas sified into two groups: endemic mycoses due to true patho genic fungi and opportunistic fungal infections due to a vast array of saprophytic fungi.

True pathogenic fungi

True pathogenic fungi produce a different form in tissue or at 37?C in contrast to mycelial form in culture at 25?30?C. These fungi are referred to as dimorphic fungi and include Histo plasma capsulatum, Histoplasma duboisii, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenckii. These fungi are usually geographically restricted. C. immitis is a geophilic mold confined to new world and adapted to live specifically in the desert-like terrain of North, Central, and South America.[18] P. marneffei is restricted to south-east Asia possibly remaining with its habitat bamboo rats.[10],[19] H. capsulatum and B. dermatitidis have a worldwide distribution. In India, histoplas mosis and blastomycosis are reported from different states, but penicilliosis marneffei is restricted to Manipur state. There is only one report of systemic sporotrichosis due to S. schenckii var. luriei and represents the only report from an Asian coun try.[20] Along with emergence of AIDS in India, histoplasmosis is increasingly reported.

Opportunistic fungi

Starting in the 1960s, species under Candida, Aspergillus, Cryp tococcus, and zygomycetes began to be regularly associated with patients receiving treatment for cancer, sarcoidosis, diabetes, and organ transplant. The `big four' of these opportunists were then accounting for more pathology and more investigators' attention than all other fungi combined. However, in the last 30?40 years changes have occurred, and newer pathogens are being recognized especially with the emergence of AIDS. Some times, it is not just a single fungus, but rather a combination of fungi i.e. species under Pneumocystis, Candida, Cryptococ cus, Histoplasma, Coccidioides, Aspergillus, and zygomycetes, which may produce concomitant and/or successive opportun istic systemic fungal infections. Besides, a long list of less com mon fungal pathogens is being isolated regularly from clinical

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Chakrabarti: Microbiology of systemic fungal infections

specimens. This leads to difficulty in classifying and studying this group of fungal infections. To resolve this problem, Ajello et al. proposed the term "phaeohyphomycosis' to cover all "in fections of a cutaneous, subcutaneous, and systemic nature caused by hyphomycetous fungi that develop in host tissues in the form of dark-walled dematiaceous septate mycelial ele ments"[21] and the name "hyalohyphomycosis" was proposed by Ajello and McGinnis to accommodate mycotic infections in which the tissue form of the etiological agents is septate hyphae with no pigment in the wall.[22]

Candida spp The overall increase in candidemia in recent years is compli cated by the emergence of non-C. albicans Candida (NAC) species as both colonizers and pathogens causing nosocomial fungal blood stream infection (BSI). Wingard in a compre hensive review of all published reports during 1952?1992 found that 12 reports showed proportionally higher (>50%) isola tion of NAC species.[23] The NAC species isolated were C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis. Other species like C. guilliermondii, C. lusitaniae, C. dubliniensis, C. kefyr, C. lipolytica, and C. pelliculosa were occasionally iso lated. The earliest population-based surveillance study con ducted in 1992?1993 by CDC, USA, reported C. albicans as the most common species, followed in order by C. parapsilosis, C. tropicalis, and C. glabrata. Subsequent surveillance pro grams noted an increase in the proportion of Candida BSI by NAC species and especially an increase in the frequency of BSI due to C. glabrata.[5] In contrast, surveillance data from other countries continue to reflect the importance of C. parapsilosis over C. glabrata.[24]

The importance of patient age in determining rank order of Candia species causing BSI has also been noted.[23] The pre dominance of C. albicans and C. parapsilosis and the lack of C. glabrata and other NAC species have been observed in neonatal age groups. In contrast, C. glabrata becomes an in creasingly important pathogen with increase in age. The con tribution of individual NAC species also varies with patients and diagnostic groups. Candidemia due to C. parapsilosis is generally associated with catheters, hyperalimentation, or pros thetic devices.[25] Also, C. parapsilosis is the most common species of Candida to be isolated from the hands of health care workers in ICU, especially those who wear gloves.[26] Thus, it is likely that the contamination of prosthetic devices with the organism occurs via the hand of health care workers. C. glabrata tends to affect oncology patients with solid tumor.[27] C. krusei is intrinsically resistant to fluconazole and increased infection with this organism has been reported in some bone marrow transplant units when fluconazole prophylaxis has been used.[28] Independent of antifungal prophylaxis, C. krusei in fection is found predominantly in patients with hematological malignancies, whereas the incidence of C. krusei infections in patients with solid tumor and ICU patients is low.[29]

Similar to the western world, the rise in frequency of NAC species has been observed in tertiary care centers in India as well with isolation rates ranging from 52 to 96%. However, the predominant isolation of C. tropicalis instead of C. glabrata

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Chakrabarti: Microbiology of systemic fungal infections

or C. parapsilosis in all age groups in the Indian scenario is unique in this context.[12],[30]?[32] The data summarized in Ta ble 2 show the worldwide isolation of Candida species from patients with candidemia.

Other yeasts Cryptococcosis is reported with increasing frequency after the emergence of AIDS.[17] Although a decline in incidence has been observed in developed countries after tri-drug regimen, no such change is seen in developing countries due to poor affordability of the costly drugs. Several other saprophytic yeasts are reported to cause systemic infections in recent years. Those are listed in Table 3.

Aspergillus spp. and other moniliaceous fungi Systemic aspergillosis is the second most common invasive fungal infections. In certain patient groups, such as hematological malignancies, the condition has been reported as accounting for up to 30% of patients in postmortem se ries[34] and 36% of patients with pneumonia in bone-marrow transplant unit.[35] Data gathered between 1980 and 1990 in a cross-section of hospitals throughout USA indicated that 1.3% of all nosocomial infections were caused by Aspergillus spe cies.[36]

A. fumigatus is the most common cause of invasive aspergillo sis. A. flavus, the second most common species, is isolated from systemic aspergillosis of immunosuppressed patients, as well as from lesions originating from the nasal sinuses. However, in India, Sudan, and South Africa, A. flavus is the most common cause of all forms of aspergillosis. A. niger is the third most common cause of invasive aspergillosis. Other species docu mented rarely include A. nidulans, A. versicolor, A. candidus, A. oryzae, A. sydowii, A. terreus, A. clavatus, etc.

Fusarium species, cosmopolitan soil saprobe, can cause sys temic infection in humans. Increased incidence, often with fatal outcome, has been seen in neutropenic patients with hematological malignancies and in patients with bone-mar row and solid-organ transplantation.[37] Other rare systemic infections are reported due to fungi belonging to genera Scedosporium, Pseudallescheria, Acremonium, Lecythophora, Phialemonium, Phaeoacremonium, Paecilomyces and Emmonsia.

Zygomycetes Like Aspergillus species, zygomycetes are common nosocomial pathogens to cause systemic zygomycosis. However, the exact incidence is difficult to ascertain due to difficulty in ante mortem diagnosis. Systemic zygomycosis can also be commu-

Table 2: Candida species causing blood stream infection worldwide

Species

C. albicans C. parapsilosis C. glabrata C. tropicalis C. guilliermondii C. krusei Other Candida species

USA 1997

56 9 19 7 1 2 6

Canada 1997

53 23 11 8 ? 2 3

Europe 1997

53 21 12 6 4 1 3

Hungary 1996?2000

77 7 3 4 ? 6 3

Latin America 1997

41 38 2 12 2 ? 5

The Netherlands 1995

60 2 17 4 2 2 13

Northern Ireland 1996?2000

53 11 27 6 ? ? 3

India 1991?2000

14 2 3 38 12 5

26

Table 3: Other yeasts or yeast-like organisms causing systemic fungal infections

Genus Cryptococcus

Species

C. neoformans (C. neoformans var. neoformans C. neoformans var. gattii)

Occurrence Common

Rare

Geotrichum Prototheca Blastoschizomyces

C. albidus, C. laurentii G. candidum P. wickerhamii B. capitatus

Pichia (Hansenula) P. anomala

P. augusta

Malassezia

M. furfur, M. globosa,

M. pachydermatis, M. obtusa,

M. restricta, M. slooffiae, M. sympoidalis

Rhodotorula Saccharomyces Trichosporon

R. rubra S. cerevisiae T. asahii, T. asteroides, T. cutaneum, T. inkin, T. mucoides, T. ovides

Very rare Extremely rare Rare

Outbreak Rare Rare outbreak

Extremely rare Extremely rare Rare

Remarks

Increased number of cases due to emergence of AIDS

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.)

Only in extremely debilitated individuals

In patients with leukemia, endocarditis and other immunosuppressive conditions Three outbreaks reported mainly in pediatric units From mediastinal lymphadenitis Usually present on skin M. furfur, M. pachydermatis in neonatal intensive care unit Associated risk factor ? parenteral lipid formulation From indwelling central venous catheters Associated with health food, baking

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 tes mellitus, other forms of metabolic acidosis, burns, and malignant hematological disorders.

Many different zygomycetes have been implicated, but the most common causes of systemic zygomycosis, listed in order of apparent incidence, are Rhizopus arrhizus and Rhizopus microsporus var. rhizopodoformis. Other less frequent etiological agents, but for which a major pathogenic role in humans has been established, include Absidia corymbifera, Apophysomyces elegans, Cunninghamella bertholletiae, Mucor species, Rhizomucor pusillus, and Saksenaea vasiformis. These molds are ubiquitous and thermotolerant and can be isolated in large numbers from soil or decomposing organic matter, such as fruit and bread. The spores can often be found in hospital and out side air.

Dematiaceous fungi Dematiaceous fungi often are thought of as being exclusively hyphomycetes, but some ascomycetes, basidiomycetes, and zygomycetes are also dematiaceous by the presence of a brown or black color in the cell wall. It has been suggested that the term "dematiaceous" is a misnomer and the term "phaeoid" should be used as a replacement.[38]

Although Ajello et al.[21] proposed the term "phaeohyphomycosis" to cover all infections caused by hyphomycetous fungi having dark-walled dematiaceous sep tate mycelial elements in tissue, it presently encompasses all fungi having dematiaceous cells in infected tissue, regardless of the taxonomic classification of the etiological agent. More than 100 species of fungi can cause systemic infection, but the disease is still rare.

Pneumocystis sp. In the late 1980s, phylogenetic analyses based on the nuclear small-subunit rRNA sequence alignments showed conclusively that P. carinii is a member of the fungal kingdom.[39] P. carinii was thought to represent a single zoonotic species. However, it is now clear that the organism first identified as "P. carinii" is actually a family of related organisms that exhibit mammalian host specificity. The first species of Pneumocystis for human derived organisms, is now known as P. jiroveci replacing P. carinii f. sp. hominis.[40]

P. jiroveci is a leading agent to cause pneumonia in AIDS and other immunocompromised states. However, it can cause sys temic infection as well. The incidence of Pneumocystis infec tion in sites other than lung has been reported to be 1?3% in postmortem examinations of patients with pulmonary Pneumocystis infection.[41],[42] This is likely an underestimate due to the lack of suspicion of extra-pulmonary pneumocystosis. The lymph modes were the most frequent site (44%) of extra-pulmonary infection in that series of 52 patients followed by the spleen, bone marrow, and liver (33%). It is also detected in the adrenal glands, gastrointestinal tract, genitourinary tract, thyroid, ear, pancreas, eyes, skin, and other sites.[41]

Chakrabarti: Microbiology of systemic fungal infections

Conclusion

This review emphasizes the fact that the clinical mycology labo ratory must be able to recognize this increasingly large group of potential pathogens. Organisms once thought to be con taminants are now confirmed pathogens causing systemic in fection in immunocompromised patients. In addition, there is a critical need to recognize that even though a given isolate may not be a documented fungal pathogen in textbooks, its isolation from a normally sterile site and its ability to grow at 37?C require that it be considered a possible pathogen.

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