Journal of Antimicrobial Chemotherapy (1991) 28, Suppl. A, 1-11
Opportunistic and pathogenic fungi Makobn D. Richardson
Medical Mycology Unit, Anderson College Building, University of Glasgow, 56 Dumbarton Road, Glasgow Gil 6NU, UK The number of fungal species reported to cause disease in man is increasing rapidly. Very few of these fungi are capable of infecting a normal host. Important progress has been achieved in an understanding of fungal pathogenicity including the mechanisms of adherence to host tissues, penetration of tissues, multiplication within the host, and the interaction of fungal cells with host effector cells. In addition to the increase in infections by opportunistic and pathogenic fungi in compromised patients, caused by Candida spp., Aspergillus spp., Cryptococcus neoformans, Histoplasma capsulation and Coccidioides immitis, many fungi that occur as saprophytes in the environment and which had previously been considered to be nonpathogenic are now being encountered as causes of human infection. The advent of these unusual infections has led to reappraisal of the diagnostic tests involved in the investigation of fungal infections and has had important implications for the choice of treatment. Many of these fungi have a similar tissue appearance and the organisms must be isolated and identified to ensure that the most appropriate treatment is given. Introduction
Fungi have a major influence on the health and livelihood of mankind. Diseases caused by fungi are termed mycoses, and range from very common mild chronic infections affecting the skin, via deep cutaneous or subcutaneous infections, to acute or chronic infections of deep tissues, many of which are potentially lethal. Fungi are eukaryotic organisms with a denned nucleus enclosed by a nuclear membrane, a plasma membrane that contains lipids, glycoproteins and sterols, mitochondria, Golgi apparatus, ribosomes bound to an endoplasmic reticulum, and a cytoskeleton with microtubules, microfilaments and intermediate filaments. The structure and function of fungal cells are very similar to those of mammalian cells. These similarities present major problems when developing antifungal compounds specific for an invading fungus. Although there are about 300,000 species of fungi, only 200 or so species have become well adapted to a parasitic mode of existence. Very few of these can infect man. Mammalian hosts may acquire a fungal infection in three ways. Firstly, they may be exposed to truly pathogenic organisms that normally occur as saprophytes in the environment. Some of these fungi have a limited natural distribution. For instance, Coccidioides immitis is found in certain semi-arid areas of the southwestern United States and similar geographic sites in Central and South America where there are hot summers, few cold periods in the winter, and alkaline soils. Paracoccidioides brasilien1 0305-7453/91/28A001 + 11 $0100/0
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sis, the causal agent of paracoccidioidomycosis, is geographically restricted to South and Central America. By contrast, Sporothrix schenckii has been isolated frequently from decaying vegetation in many different parts of the world. Secondly, individuals who are immunosuppressed may acquire a fungal infection following exposure to weakly pathogenic organisms that occur as saprophytes in the environment. Such organisms are termed opportunistic pathogens. Infections such as aspergillosis and candidosis are being seen increasingly in immunocompromised patients, particularly those with haematological malignancies or the acquired immune deficiency syndrome (AIDS). Thirdly, individuals may be exposed to infective propagules of the dermatophyte fungi, organisms which are very well adapted to parasitism and quite capable of invading the healthy host. Occasionally, dermatophyte fungi are found on the skin and scalp of individuals in the absence of symptoms: this is thought to represent transient colonization or a carrier state. Causal agents of mycoses The aetiological agents of mycoses can be classified according to their degree of parasitic adaptation (Dei Cas & Vcrnes, 1986). (1) Fungi that are able to invade and develop in the tissues of a healthy host, with no recognisable predisposition. The principal infections in this group are histoplasmosis, blastomycosis, coccidioidomycosis and paracoccidioidomycosis. The causal organisms are found in the environment and the majority of human infections are acquired by inhalation. (2) Fungi that give rise to infection following traumatic implantation into healthy tissue, e.g. those that cause chromoblastomycosis and mycetoma. (3) Environmental fungi that are able to invade the tissues of an immunocompromised host. The causal organisms of diseases such as aspergillosis, cryptococcosis and mucormycosis are widespread in the environment and commonly give rise to infection following inhalation. (4) Commensal yeasts, such as Candida spp., that cause endogenous infection. Apart from infections caused by dermatophytes, Candida infections outnumber all other mycoses. Members of the genus Candida are regarded as endogenous pathogens and can cause both superficial and deep-seated diseases which are worldwide in distribution. Of relatively low virulence by comparison with bacteria and viruses, Candida spp. are generally classified as opportunistic pathogens that cause disease only in hosts with some underlying pathological process or deficiency state. These fungi tend to cause infection in the newborn, or in debilitated, pregnant, or immunosuppressed individuals, particularly those with leukaemia. Candida spp. also cause endocarditis, pyelonephritis and other forms of visceral infection. Other yeasts cause various superficial diseases; for instance, pityriasis versicolor and white piedra. Many of the yeasts that cause disease are commensals, exerting pathogenic effects only when the balance between the host and its indigenous flora is deranged. Opportunity for yeasts to invade tissues is afforded by many of the procedures of modern medicine, such as organ transplantation, open-heart surgery, prolonged parenteral nutrition, and the use of cytotoxic and
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immunosuppressive drugs, as well as by antibiotics that suppress the normal bacterial flora. Deep-seated infections caused by these fungi are serious and life-threatening, for all have an extremely grave prognosis if not diagnosed or predicted promptly. It is also important to note, however, that certain species of Candida possess morphological and biochemical attributes that may enhance the ability to invade susceptible hosts. For instance, the high incidence of Candida albicans isolated from cases of systemic infection, compared with other species of Candida, may be due to a number of virulence determinants not possessed or expressed by these other species. (5) The dermatophytes, which cause cutaneous infections that primarily involve keratinized tissues of the epidermis, pilosebaceous follicles and nail. Fungal infections can be classified according to the sites of the body that are primarily affected. Superficial mycoses are infections limited to the keratinized layers of the skin, nail and hair. Many are mild and readily diagnosed, and respond well to therapy. The subcutaneous mycoses are caused by a distinctive group of fungi which are virtually confined to the tropics; although these infections are not common they are difficult to diagnose and treat adequately. Systemic mycoses are infections of the internal organs of the body. It is convenient to differentiate between the systemic mycoses caused by primary pathogens, such as Histoplasma capsulation or C. immitis, which can occur in healthy individuals, and those caused by opportunistic fungi, such as C. albicans, which generally tend to occur in debilitated hosts. Most individuals affected by the truly pathogenic fungi have mild signs or subclinical manifestations. In contrast, opportunistic fungal infections by definition almost always produce significant disease. Patbogenesb of fungal disease A pathogenic fungus has to complete a number of steps in order to initiate an infection and has to counteract a range of non-specific and specific host defence mechanisms (Richardson & Shankland, 1991). Few fungi that fail to accomplish these steps are successful pathogens. There are many ways in which fungi can express determinants of virulence which enable the host to be invaded and the fungus to survive in the host's internal environment, e.g. by perturbing or avoiding host defences. The basis of the pathogenicity of medically important fungi is multifactorial, but the following components are contributory in many cases. (1) Adherence to the stratum corneum or mucous surfaces of the host is a necessary step for colonization and is a prelude to tissue penetration. Intensive study has been carried out on the adhesion of Candida cells to epithelial cells of the oral cavity, the gut lining and the vagina. Experiments in animals have shown that Candida cells adhere to the basement membrane of endothelial cells of blood vessels (Douglas, 1987; Kennedy, 1988). (2) Penetration of host tissues is necessary to facilitate access to target organs or body fluids. Structures that penetrate host tissues are rarely formed by zooparasitic fungi, unlike the numerous examples seen in species pathogenic to plants. However, a few human pathogens undergo transition from a filamentous growth form to a yeast form when they invade tissues. The truly pathogenic fungi such as C. immitis and H.
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capsulation exhibit this type of dimorphism; it probably results from a metabolic alteration of the fungal cells following contact with the tissues of the host. The acquisition of a yeast-like morphology is not, however, always associated with enhanced pathogenicity. The pathogenic potential of C. albicans appears to be linked to the formation of germ tubes and the development of pseudohyphae and true mycelium. All the various growth forms of C. albicans are usually seen in host tissues. (3) To multiply in vivo the fungus must be thermotolerant, able to adapt to the physicochemical conditions of the host, able to utilize available nutrients, and able to compete with other microorganisms for essential food materials. However, to penetrate host tissues and multiply, pathogenic fungi also require mechanisms that enable them to resist a wide variety of host defences. Fungi appear to exploit and acquire a number of mechanisms that enable them to do this once they have become established. These attributes are directly connected with the morphological form assumed in tissue, growth rate, and cell wall structure. (4) Fungi appear to be quite adept at avoiding or perturbing host defences. Examples include: the secretion of cytotoxins against immunocompetent cells; and the secretion of cortisone-like substances that stabilize biological membranes therefore allowing the growth of H. capsulation within pulmonary macrophages, for example. (5) The successful completion of the pathogenic process includes damage to tissue. As far as is known fungi that cause invasive disease do not secrete toxins that harm the host. Tissue damage most probably results from direct invasion with displacement or destruction of vital structures, and toxic effects of the inflammatory response. Fungi may also grow as masses of cells (fungal balls) that occlude bronchi in the lungs or tubules and ureters in the kidneys, leading to obstruction, secondary infection and tissue damage. Aspergillus and Rhizopus spp. have a propensity to grow in the walls of arteries or veins, leading to occlusion and ischaemic tissue necrosis. Fungal vegetations are formed on heart valves in fungal endocarditis. Detached pieces of fungal growth may localize in any organ and cause arterial occlusion with resultant tissue necrosis.
Changes in the incidence and spectrum of mycoses and emerging opportunists The number of infections due to pathogenic and opportunistic fungi has increased over the past few years. This increase is mainly attributable to modern techniques in the management of seriously ill and debilitated patients, i.e. iatrogenic causes. Numerous reviews have documented this rising incidence among cancer patients, transplant recipients, intravenous drug abusers, patients receiving antibiotics or parenteral nutrition, those with chronic obstructive or destructive lung diseases, and individuals with impairment of phagocytic or lymphocytic cell function. Estimates of these infections are likely to be quite conservative in comparison with the true magnitude of disease, because many infections are not notifiable or are not recorded and many infections are only diagnosed post mortem.
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Nosocomial infections
Nosocomial fungal infections have emerged as a frequent cause of morbidity and mortality in recent years. Both candidosis and aspergillosis have increased in incidence by some 300% over the ten year period from 1980 to 1990. Many other fungi have also been reported to cause infection in hospitalized patients. Walsh & Pizzo (1988) have defined a nosocomial fungal infection as any superficial, locally invasive, or disseminated mycosis acquired from the hospital environment (Type I, hospital-acquired) or developing during the course of a patient's hospitalization from a fungus previously colonizing or latently infecting a patient (Type n, hospital-associated). Walsh & Pizzo (1988) further subdivided Type II infections into those developing from endogenous colonizing fungi (Subtype IIA) and those developing from reactivation of latently infecting fungi (Subtype IIB). Significant risk factors for nosocomial fungal infections include increasing age, T-cell depletion, the use of prednisone as prophylaxis for graftversus-host disease, and profound and prolonged neutropenia. For instance, a group of cancer patients who developed aspergillus sinusitis had been granulocytopenic for a mean period of 42 days (Viollier et al., 1986). Aspergillosis The frequency of aspergillosis has increased substantially in recent years, primarily as a consequence of the use of more intensive therapeutic regimens in patients with acute leukaemia or other haematologjcal malignancies and in organ transplant recipients (Bodey & Vartivarian, 1989; Smith, 1989; Cohen, 1991). Spores of Aspergillus species are ubiquitous in the environment and may reach very high numbers in enclosed areas particularly adjacent to hospital construction work. Several point source outbreaks of invasive aspergillosis in immunocompromised patients have demonstrated the need for filtered air and efficient ventilation systems in hospital environments. Invasive aspergillosis typically occurs in patients with suppressed host defences, such as those receiving bone marrow transplants and leukaemic patients undergoing induction treatment. Such infections in the neutropenic patient are most commonly caused by Aspergillus fumigatus, the commonest sites of infection being the lungs and upper respiratory tract. Less frequently described sites of infection include the sinuses (Peterson & Schimpff, 1989). Cutaneous aspergillosis may be associated with intravenous catheters. Ctndidosis
The incidence of candidosis has increased dramatically in the last few decades. New clinical manifestations have appeared, new approaches to diagnosis have been described and a number of new species have been associated with clinical disease (Odds, 1988; Meunier, 1989; Smith, 1989; Samaranayake & MacFarlane, 1990; Dupont, 1991). New clinical entities include the chronic candidosis syndrome (hepatosplenic candidosis) in leukaemic patients (Bodey & Anaissie, 1989) and pulmonary vascular candidosis in infants receiving prolonged parenteral feeding and multiple antibiotics (Knox, Hooton & Barson, 1987). Oral Candida infection has emerged as a major problem in AIDS patients; it is frequently followed by other, more serious, opportunistic infections. A high proportion of AIDS patients with oral candidosis also develop oesophageal candidosis, although this rarely leads to systemic infection.
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Familiarity with emerging forms of candidosis and continual surveillance for their presence in compromised patients is necessary for success in increasing the anteraortem diagnostic rate.
Cryptococcosis Extensive study has revealed clear evidence of heterogeneity within the species Cryptococcus neoformans. It is now accepted that the four serotypes, A, B, C, and D are varieties of one parent species. Thus serotypes A & D are now classified as C. neoformans var. neoformans while B and C are classified as C. neoformans var. gattii. Infections may be acquired by inhalation of non-encapsulated cells that usually originate from areas where there are old accumulations of pigeon droppings in nests and under roosting sites. Cryptococcosis is one of the most prevalent of the systemic mycoses (Patterson & Andriole, 1989; Smith, 1989; Hay, 1991). Throughout the world, it is being recognised much more frequently as a disease of debilitated and immunologically compromised subjects. Epidcmiologica] and clinical data on cryptococcosis in AIDS patients suggest a number of conclusions. First, exposure of man to C. neoformans is much higher than previously assumed. Secondly, the immunodeficiencies that develop in AIDS patients favour C. neoformans more than any other opportunistic or truly pathogenic fungus. Thirdly, although C. neoformans has a predilection for the central nervous system, dissemination to other organs occurs more frequently in AIDS patients, reflecting their increased susceptibility to infection. Until recently, most AIDS patients with cryptococcosis were homosexuals, but increasingly cases are appearing in intravenous drug abusers, recipients of blood transfusions and the heterosexual population. The prognosis for AIDS patients with cryptococcosis is very bleak with an average survival time of six months. Relapse occurs in more than 50% of the cases following cessation of antifungal treatment and continuing maintenance treatment is usually required. Pulmonary involvement may precede or accompany cryptococcal meningitis in AIDS patients. Cryptococcaemia is observed in up to 50% of patients. The urine frequently harbours cryptococci, reflecting an infectious focus in the kidneys or more probably the prostate. Prostatic infection appears to be a significant reservoir for systemic relapse after successful treatment for meningitis. Disease of other extrancural sites has been described in patients with AIDS, alone or in association with meningitis. These include myocarditis, pericarditis, lymphadenopathies, pleuritis and arthritis. Skin lesions are frequent and biopsy and culture may provide early clues to a diagnosis of cryptococcosis. The prevalence of cryptococcosis in AIDS patients has affected the laboratory methods used to diagnose this disease. Cerebrospinal fluid examination provides valuable information. In AIDS patients, pleocytosis, elevated protein concentrations, and low glucose are less frequent than in non-AIDS patients. Conversely, the numbers of yeasts are higher. Microscopy, culture and tests for capsular antigen are more often positive than in other immunocompromised subjects. Whenever available, other clinical specimens should be examined for cryptococci: blood, skin biopsies, urine sediment (possible after prostatic massage), lymph node aspirates, and respiratory secretions.
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Muconnycosis This is an opportunistic fungal disease caused by fungi of the order Mucorales which may affect any organ of the body. Alternative terms used to describe the various diseases caused by these fungi include zygomycosis and phycomycosis. The pathogenesis of the disease is unclear and, while the source is undoubtedly exogenous, definite sources of infection have not been identified. Rhinocerebral infection is still the most common form of muconnycosis in individuals in whom the major risk factor is diabetes mellitus. This is the predominant clinical form in most of the major reviews on the subject (Smith, 1989; Skahan, Wong & Armstrong, 1991). In recent years, rhinocerebral infection has been reported in two groups of patients who were often unrepresented in series compiled before 1970. Infection in patients with leukaemia and lymphoma has become increasingly common since that time and it is now clear that these diseases constitute an important risk factor. Rhinocerebral muconnycosis has also become more common in organ transplant recipients. Pulmonary mucormycosis is primarily a complication of leukaemia, lymphoma and severe granulocytopenia. Other less frequently seen manifestations of the disease include endobronchial mucormycosis, gastrointestinal mucormycosis and cutaneous muconnycosis secondary to significant trauma.
Infections due to truly pathogenic fungi In addition to their well recognised manifestations in immunocompetent individuals, histoplasmosis and coccidioidomycosis have emerged as significant infectious complications in AIDS patients and have been recognised as two of the defining opportunistic infections for this syndrome. At least 50% of AIDS patients with these infections have acquired them as their first AIDS-associated opportunistic infection. Consequently, new diagnostic tests, including antigen detection and lymphocyte studies, have been devised, and further indications for new antifungal agents have emerged. In AIDS patients, these infections are often severe and refractory to currently available antifungal chemotherapy, and frequently relapse following treatment resulting in death. Less frequently encountered infections due to truly pathogenic fungi include blastomycosis, paracoccidioidomycosis and sporotrichosis.
Other infections In addition to the increase in opportunistic infections caused by Candida spp., Aspergillus spp., C. neoformans and the agents of mucormycosis among immunocompromised patients, infections with other weakly pathogenic fungi are being encountered with increasing frequency. An ever escalating number of mycoses are being caused by saprophytic fungi previously considered as harmless. These fungi have caused lethal disseminated infections in patients compromised as a result of immunosuppression or by medical procedures that cause the physiochemical barrier of the skin to be broken. Many of these emerging pathogens are resistant to available antifungal agents.
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M. D. Rkfaanhon Unosoal infections caused by yeasts
An increasing number of systemic infections are being caused by yeasts belonging to the genera Rhodotonda, Saccharomyces, Geotrichum, Hansenula, Trichosporon and Malassezia (Pityrosporum) (Anaissie, Bodey & Rinaldi, 1989; Warnock & Johnson, 1991). Among the unusual Candida species isolated from clinical specimens are Candida chiropterorum from peritoneal dialysis fluid, Candida ciferii causing superficial infection, at least ten reports of Candida lusitaniae implicated in systemic infection and the isolation of Candida rugosa from blood and causing pulmonary infection (Anaissie et al., 1989). One example of an unusual yeast infection that is becoming more common in compromised patients is localized deep or disseminated infection caused by Trichosporon beigelii or Trichosporon capitation. These infections are thought to be acquired from cutaneous sites because these yeasts can be isolated from such sites in many normal and immunocompromised hosts (Walsh, 1989). The emergence of T. beigelii as an agent of disseminated disease has had important implications for therapy because it appears to be resistant to amphotericin B in vitro. Moreover, in-vitro resistance has correlated with refractory, disseminated trichosporonosis in neutropenic patients (Walsh et al., 1990). Many homosexuals have been found to harbour T. beigelii in the anal region. Colonization may imply a potential risk of developing invasive trichosporonosis of endogenous origin.
Unusual infections earned byfilamentousfungi Many of the unusual infections caused byfilamentousfungal pathogens in both normal and immunocompromised individuals belong to one or other of two groups of diseases termed phaeohyphomycosis and hyalohyphomycosis.
Phaeohyphomycosis The aetiological agents of phaeohyphomycosis are common causes of infection among the populations of many underdeveloped countries and are being recognised more frequently as causes of both superficial and disseminated disease in immunocompromised hosts (Ajello, 1986; Weitzman, 1986; Warnock & Johnson, 1991). The organisms have brown, yeast-like, pseudohypha-like filaments, or hyphae that may be regular, distorted, or swollen in shape. Primary inoculation phaeohyphomycosis is often caused by traumatic implantation of fungi such as Exophialajeanselmei, Wangiella dermatitidis and certain other dematiaceous moulds, e.g. Alternaria spp. Most disseminated infections are thought to be acquired by inhalation. However, it is conceivable that dissemination may originate from cutaneous sites. Deep infections caused by Alternaria, Bipolar is, Exserohilum and Curvularia spp. have been reported and the features of individual infections have been reviewed recently (Warnock & Johnson, 1991). Other, less common, causes of infection in immunocompromised patients include Phialophora parasitica and Xylohypha bantiana (Cladosporium bantianum or Cladosporiwn trichoides).
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Hyalohyphomycosis The term hyalohyphomycosis encompasses all infections due to nonpigmcntcd, septate filamentous moulds that appear as colourless hyphae in tissue. Hyalohyphomycosis includes infections caused by such diverse opportunistic pathogens as PsendaUescheria boydii and Fusarium, Paecilomyces, Penicillium, Scopulariopsis, Acremonhim, Chrysosporium, Sepedonium and Scedosporiwn spp. (Ajello, 1986; Weitzman, 1986; Warnock & Johnson, 1991). Correct identification of these organisms is becoming increasingly important because the outcome of therapy frequently depends on the choice of an appropriate antifungal drug. Infections caused by these fungi are rare but appear to be increasing in incidence. Common features implicated in their pathogenesis appear to be cutaneous lesions that progress to disseminated disease, or the inhalation of spores which become readily airborne when discharged from fruiting structures. Many individual cases caused by these fungi have been reviewed recently (Warnock & Johnson, 1991). Over the past 30 years some 30 cases of infection caused by Penicillium mameffei have been reported. Six cases diagnosed in the last two years occurred in HIV-positive patients who were natives of, or visitors to, rural areas of S E Asia where the fungus occurs in the environment. The infection was disseminated in all cases except where the diagnosis was made early by isolating the fungus from bronchoalveolar lavage fluid in the absence of radiological evidence of pulmonary involvement. The fungus was isolated from the lung in all cases. The differential diagnosis includes tuberculosis and other systemic fungal infections. Implications for diagnosis Laboratory procedures for diagnosis of opportunistic mycoses continue to be updated, but currently depend upon a range of microscopy techniques, culture and serological procedures. Rapid tests for detection of specific antigens in body fluids and tissues appear especially promising. The use of DNA probes for identification of fungi is attracting attention and providing useful epidemiological data. Only by careful identification and reporting will it be possible to determine the relative importance of unusual fungal pathogens. Identification of recently described opportunistic pathogens has been based upon their microscopic morphology. Because the structures used to identify fungi are at times difficult to recognise, there is a need for other approaches to identify many of these fungi. Over the past few years the exoantigen procedure has been applied to a number of groups of medically important fungi and has been shown to be an excellent and definitive technique. More recently, the exoantigen test has been extended to isolates of Bipolaris spp. and Exserohilion spp. and shown to be useful for differentiating the two genera (Pasarell, McGinnis & Standard, 1990). The development of rapid identification systems for medically important yeasts and the emergence of unusual yeasts in immunocompromised patients here highlighted the requirement for yeast identification at the routine laboratory level. An illustrative point is the increasing number of reports of in-vitro amphotericin B resistance and clinical resistance shown by Candida tropicalis, C. lusitaniae, Candida parapsilosis, Candida guilliermondii and T. beigelii. The availability of well characterized polyvalent and monoclonal antibodies to the major fungal pathogens has stimulated rapid development of diagnostic kits for the
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detection of circulating antigens in body fluids. Latex particle agglutination and double antibody liposomal-bascd formats are being marketed for systemic candidosis and invasive aspergiUosis. Monoclonal antibodies to cell wall and cytoplasmic components of C. neoformans, H. capsulation and P. brasiliensis have been described. These reagents have obvious potential in new generations of tests for diagnosis and identification of fungal isolates. Furthermore, chromosomal DNA probes have been described and applied to the detection of fungal elements in clinical specimens (Gabal, 1989).
References Ajcllo, L. (1986). Hyalohyphomycosis and phaeohyphomycosis: two global disease entities of pubb'c health importance. European Journal of Epidemiology 2, 243-51. Anaissie, E. J., Bodey, G. P. & Rinaldi, M. G. (1989). Emerging fungal pathogens. European Journal of Clinical Microbiology and Infectious Diseases 8, 323-30. Bodey, G. P. & Anaissie, E. J. (1989). Chronic systemic candidiasis. European Journal of Clinical Microbiology and Infectious Diseases 8, 855-7. Bodey, G. P. & Vartivarian, S. (1989). Aspergillosis. European Journal of Clinical Microbiology and Infectious Diseases 8, 413-37. Cohen, J. (1991). Clinical manifestations and management of aspergillosis in the compromised patient. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 117-52. John Wiley, Chichester. Dei Cas, E. & Vernes, A. (1986). Parasitic adaptation of pathogenic fungi to mammalian hosts. CRC Critical Reviews in Microbiology 13, 173-218. Douglas, L. J. (1987). Adhesion of Candida species to epithelial surfaces. CRC Critical Reviews in Microbiology 15, 27^*3. Dupont, B (1991). Clinical manifestations and management of candidosis in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 55-83. John Wiley, Chichester. Gabal, M. A. (1989). Development of a chromosomal DNA probe for the laboratory diagnosis of aspergillosis. Mycopathologia 106, 121-9. Hay, R. J. (1991). Clinical manifestations and management of cryptococcosis in the compromised patient. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 85-115. John Wiley, Chichester. Kennedy, M. J. (1988). Adhesion and association mechanisms of Candida albicans. In Current Topics in Medical Mycology, Vol. 2 (McGinnis, M. R., Ed.), pp. 73-169. Springer-Verlag, New York. Knox, W. F., Hooton, V. N. & Barson, A. J. (1987). Pulmonary vascular candidiasis and use of central venous catheters in neonates. Journal of Clinical Pathology 40, 559-65. Meunier, F. (1989). Candidiasis. European Journal of Clinical Microbiology and Infectious Diseases 8, 438-47. Odds, F. C. (1988). Candida and Candidosis, 2nd edn. Bailliere Tindall, London. Pasarell, L., McGinnis, M. R. & Standard, P. G. (1990). Differentiation of medically important isolates of Bipolaris and Exserohilum with exoantigens. Journal of Clinical Microbiology 28, 1655-7. Patterson, T. F. & Andriole, V. T. (1989). Current concepts in cryptococcosis. European Journal of Clinical Microbiology and Infectious Diseases 8, 457-65. Peterson, D. E. & Schimpff, S. C. (1989). Aspergillus sinusitis in neutropenic patients with cancer, a review. Biomedidne and Pharmacotherapy 43, 307-12. Richardson, M. D. & Shankland, G. S. (1991). Pathogenesis of fungal infection in the noncompromised host. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D , Eds), pp. 1-22. John Wiley, Chichester. Samaranayake, L. P. & MacFarlane, T. W. (1990). Oral Candidosis. Wright, London. Skahan, K. J., Wong, B. & Armstrong, D. (1991). Clinical manifestations and management of mucormycosis in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 153-90. John Wiley, Chichester.
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Smith, J. M. B. (1989). Opportunistic Mycoses of Man and Other Animals. C. A. B. International MycologjcaJ Institute, Wallingford. VioUier, A. F., Peterson, D. E., De Jongh, C. A., Newman, K. A. Gray, W. C, Sutherland, J. C. et al. (1986). Aspergillus sinusitis in cancer patients. Cancer 58, 366-71. Walsh, T. J. (1989). Trichosporonosis. Infectious Disease Clinics of North America 3, 43-52. Walsh, T. J., Melcher, G. P., Rinaldi, M. G., Lecciones, J., McGough, D. A., Kelly, P. et al. (1990). Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. Journal of Clinical Microbiology 28, 1616-22. Walsh, T. J. & Pizzo, P. A. (1988). Nosocomial fungal infections: a classification for hospitalacquired fungal infections and mycoses arising from endogenous flora or reactivation. Annual Review of Microbiology 42, 517-45. Warnock, D. W. & Johnson, E. M. (1991). Clinical manifestations and management of hyalohyphomycosis, phaeohyphomycosis and other uncommon forms of fungal infection in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 247-310. John Wiley, Chichester. Weitzman, I. (1986). Saprophytic molds as agents of cutaneous and subcutaneous infection in the immunocompromised host. Archives of Dermatology 122, 1161-8.
Opportunistic and pathogenic fungi Makobn D. Richardson
Medical Mycology Unit, Anderson College Building, University of Glasgow, 56 Dumbarton Road, Glasgow Gil 6NU, UK The number of fungal species reported to cause disease in man is increasing rapidly. Very few of these fungi are capable of infecting a normal host. Important progress has been achieved in an understanding of fungal pathogenicity including the mechanisms of adherence to host tissues, penetration of tissues, multiplication within the host, and the interaction of fungal cells with host effector cells. In addition to the increase in infections by opportunistic and pathogenic fungi in compromised patients, caused by Candida spp., Aspergillus spp., Cryptococcus neoformans, Histoplasma capsulation and Coccidioides immitis, many fungi that occur as saprophytes in the environment and which had previously been considered to be nonpathogenic are now being encountered as causes of human infection. The advent of these unusual infections has led to reappraisal of the diagnostic tests involved in the investigation of fungal infections and has had important implications for the choice of treatment. Many of these fungi have a similar tissue appearance and the organisms must be isolated and identified to ensure that the most appropriate treatment is given. Introduction
Fungi have a major influence on the health and livelihood of mankind. Diseases caused by fungi are termed mycoses, and range from very common mild chronic infections affecting the skin, via deep cutaneous or subcutaneous infections, to acute or chronic infections of deep tissues, many of which are potentially lethal. Fungi are eukaryotic organisms with a denned nucleus enclosed by a nuclear membrane, a plasma membrane that contains lipids, glycoproteins and sterols, mitochondria, Golgi apparatus, ribosomes bound to an endoplasmic reticulum, and a cytoskeleton with microtubules, microfilaments and intermediate filaments. The structure and function of fungal cells are very similar to those of mammalian cells. These similarities present major problems when developing antifungal compounds specific for an invading fungus. Although there are about 300,000 species of fungi, only 200 or so species have become well adapted to a parasitic mode of existence. Very few of these can infect man. Mammalian hosts may acquire a fungal infection in three ways. Firstly, they may be exposed to truly pathogenic organisms that normally occur as saprophytes in the environment. Some of these fungi have a limited natural distribution. For instance, Coccidioides immitis is found in certain semi-arid areas of the southwestern United States and similar geographic sites in Central and South America where there are hot summers, few cold periods in the winter, and alkaline soils. Paracoccidioides brasilien1 0305-7453/91/28A001 + 11 $0100/0
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sis, the causal agent of paracoccidioidomycosis, is geographically restricted to South and Central America. By contrast, Sporothrix schenckii has been isolated frequently from decaying vegetation in many different parts of the world. Secondly, individuals who are immunosuppressed may acquire a fungal infection following exposure to weakly pathogenic organisms that occur as saprophytes in the environment. Such organisms are termed opportunistic pathogens. Infections such as aspergillosis and candidosis are being seen increasingly in immunocompromised patients, particularly those with haematological malignancies or the acquired immune deficiency syndrome (AIDS). Thirdly, individuals may be exposed to infective propagules of the dermatophyte fungi, organisms which are very well adapted to parasitism and quite capable of invading the healthy host. Occasionally, dermatophyte fungi are found on the skin and scalp of individuals in the absence of symptoms: this is thought to represent transient colonization or a carrier state. Causal agents of mycoses The aetiological agents of mycoses can be classified according to their degree of parasitic adaptation (Dei Cas & Vcrnes, 1986). (1) Fungi that are able to invade and develop in the tissues of a healthy host, with no recognisable predisposition. The principal infections in this group are histoplasmosis, blastomycosis, coccidioidomycosis and paracoccidioidomycosis. The causal organisms are found in the environment and the majority of human infections are acquired by inhalation. (2) Fungi that give rise to infection following traumatic implantation into healthy tissue, e.g. those that cause chromoblastomycosis and mycetoma. (3) Environmental fungi that are able to invade the tissues of an immunocompromised host. The causal organisms of diseases such as aspergillosis, cryptococcosis and mucormycosis are widespread in the environment and commonly give rise to infection following inhalation. (4) Commensal yeasts, such as Candida spp., that cause endogenous infection. Apart from infections caused by dermatophytes, Candida infections outnumber all other mycoses. Members of the genus Candida are regarded as endogenous pathogens and can cause both superficial and deep-seated diseases which are worldwide in distribution. Of relatively low virulence by comparison with bacteria and viruses, Candida spp. are generally classified as opportunistic pathogens that cause disease only in hosts with some underlying pathological process or deficiency state. These fungi tend to cause infection in the newborn, or in debilitated, pregnant, or immunosuppressed individuals, particularly those with leukaemia. Candida spp. also cause endocarditis, pyelonephritis and other forms of visceral infection. Other yeasts cause various superficial diseases; for instance, pityriasis versicolor and white piedra. Many of the yeasts that cause disease are commensals, exerting pathogenic effects only when the balance between the host and its indigenous flora is deranged. Opportunity for yeasts to invade tissues is afforded by many of the procedures of modern medicine, such as organ transplantation, open-heart surgery, prolonged parenteral nutrition, and the use of cytotoxic and
Opportnnistk and patbogeok fungi
3
immunosuppressive drugs, as well as by antibiotics that suppress the normal bacterial flora. Deep-seated infections caused by these fungi are serious and life-threatening, for all have an extremely grave prognosis if not diagnosed or predicted promptly. It is also important to note, however, that certain species of Candida possess morphological and biochemical attributes that may enhance the ability to invade susceptible hosts. For instance, the high incidence of Candida albicans isolated from cases of systemic infection, compared with other species of Candida, may be due to a number of virulence determinants not possessed or expressed by these other species. (5) The dermatophytes, which cause cutaneous infections that primarily involve keratinized tissues of the epidermis, pilosebaceous follicles and nail. Fungal infections can be classified according to the sites of the body that are primarily affected. Superficial mycoses are infections limited to the keratinized layers of the skin, nail and hair. Many are mild and readily diagnosed, and respond well to therapy. The subcutaneous mycoses are caused by a distinctive group of fungi which are virtually confined to the tropics; although these infections are not common they are difficult to diagnose and treat adequately. Systemic mycoses are infections of the internal organs of the body. It is convenient to differentiate between the systemic mycoses caused by primary pathogens, such as Histoplasma capsulation or C. immitis, which can occur in healthy individuals, and those caused by opportunistic fungi, such as C. albicans, which generally tend to occur in debilitated hosts. Most individuals affected by the truly pathogenic fungi have mild signs or subclinical manifestations. In contrast, opportunistic fungal infections by definition almost always produce significant disease. Patbogenesb of fungal disease A pathogenic fungus has to complete a number of steps in order to initiate an infection and has to counteract a range of non-specific and specific host defence mechanisms (Richardson & Shankland, 1991). Few fungi that fail to accomplish these steps are successful pathogens. There are many ways in which fungi can express determinants of virulence which enable the host to be invaded and the fungus to survive in the host's internal environment, e.g. by perturbing or avoiding host defences. The basis of the pathogenicity of medically important fungi is multifactorial, but the following components are contributory in many cases. (1) Adherence to the stratum corneum or mucous surfaces of the host is a necessary step for colonization and is a prelude to tissue penetration. Intensive study has been carried out on the adhesion of Candida cells to epithelial cells of the oral cavity, the gut lining and the vagina. Experiments in animals have shown that Candida cells adhere to the basement membrane of endothelial cells of blood vessels (Douglas, 1987; Kennedy, 1988). (2) Penetration of host tissues is necessary to facilitate access to target organs or body fluids. Structures that penetrate host tissues are rarely formed by zooparasitic fungi, unlike the numerous examples seen in species pathogenic to plants. However, a few human pathogens undergo transition from a filamentous growth form to a yeast form when they invade tissues. The truly pathogenic fungi such as C. immitis and H.
4
M. D. Rkfaanfaoo
capsulation exhibit this type of dimorphism; it probably results from a metabolic alteration of the fungal cells following contact with the tissues of the host. The acquisition of a yeast-like morphology is not, however, always associated with enhanced pathogenicity. The pathogenic potential of C. albicans appears to be linked to the formation of germ tubes and the development of pseudohyphae and true mycelium. All the various growth forms of C. albicans are usually seen in host tissues. (3) To multiply in vivo the fungus must be thermotolerant, able to adapt to the physicochemical conditions of the host, able to utilize available nutrients, and able to compete with other microorganisms for essential food materials. However, to penetrate host tissues and multiply, pathogenic fungi also require mechanisms that enable them to resist a wide variety of host defences. Fungi appear to exploit and acquire a number of mechanisms that enable them to do this once they have become established. These attributes are directly connected with the morphological form assumed in tissue, growth rate, and cell wall structure. (4) Fungi appear to be quite adept at avoiding or perturbing host defences. Examples include: the secretion of cytotoxins against immunocompetent cells; and the secretion of cortisone-like substances that stabilize biological membranes therefore allowing the growth of H. capsulation within pulmonary macrophages, for example. (5) The successful completion of the pathogenic process includes damage to tissue. As far as is known fungi that cause invasive disease do not secrete toxins that harm the host. Tissue damage most probably results from direct invasion with displacement or destruction of vital structures, and toxic effects of the inflammatory response. Fungi may also grow as masses of cells (fungal balls) that occlude bronchi in the lungs or tubules and ureters in the kidneys, leading to obstruction, secondary infection and tissue damage. Aspergillus and Rhizopus spp. have a propensity to grow in the walls of arteries or veins, leading to occlusion and ischaemic tissue necrosis. Fungal vegetations are formed on heart valves in fungal endocarditis. Detached pieces of fungal growth may localize in any organ and cause arterial occlusion with resultant tissue necrosis.
Changes in the incidence and spectrum of mycoses and emerging opportunists The number of infections due to pathogenic and opportunistic fungi has increased over the past few years. This increase is mainly attributable to modern techniques in the management of seriously ill and debilitated patients, i.e. iatrogenic causes. Numerous reviews have documented this rising incidence among cancer patients, transplant recipients, intravenous drug abusers, patients receiving antibiotics or parenteral nutrition, those with chronic obstructive or destructive lung diseases, and individuals with impairment of phagocytic or lymphocytic cell function. Estimates of these infections are likely to be quite conservative in comparison with the true magnitude of disease, because many infections are not notifiable or are not recorded and many infections are only diagnosed post mortem.
Opportunistic and pathogenic fungi
5
Nosocomial infections
Nosocomial fungal infections have emerged as a frequent cause of morbidity and mortality in recent years. Both candidosis and aspergillosis have increased in incidence by some 300% over the ten year period from 1980 to 1990. Many other fungi have also been reported to cause infection in hospitalized patients. Walsh & Pizzo (1988) have defined a nosocomial fungal infection as any superficial, locally invasive, or disseminated mycosis acquired from the hospital environment (Type I, hospital-acquired) or developing during the course of a patient's hospitalization from a fungus previously colonizing or latently infecting a patient (Type n, hospital-associated). Walsh & Pizzo (1988) further subdivided Type II infections into those developing from endogenous colonizing fungi (Subtype IIA) and those developing from reactivation of latently infecting fungi (Subtype IIB). Significant risk factors for nosocomial fungal infections include increasing age, T-cell depletion, the use of prednisone as prophylaxis for graftversus-host disease, and profound and prolonged neutropenia. For instance, a group of cancer patients who developed aspergillus sinusitis had been granulocytopenic for a mean period of 42 days (Viollier et al., 1986). Aspergillosis The frequency of aspergillosis has increased substantially in recent years, primarily as a consequence of the use of more intensive therapeutic regimens in patients with acute leukaemia or other haematologjcal malignancies and in organ transplant recipients (Bodey & Vartivarian, 1989; Smith, 1989; Cohen, 1991). Spores of Aspergillus species are ubiquitous in the environment and may reach very high numbers in enclosed areas particularly adjacent to hospital construction work. Several point source outbreaks of invasive aspergillosis in immunocompromised patients have demonstrated the need for filtered air and efficient ventilation systems in hospital environments. Invasive aspergillosis typically occurs in patients with suppressed host defences, such as those receiving bone marrow transplants and leukaemic patients undergoing induction treatment. Such infections in the neutropenic patient are most commonly caused by Aspergillus fumigatus, the commonest sites of infection being the lungs and upper respiratory tract. Less frequently described sites of infection include the sinuses (Peterson & Schimpff, 1989). Cutaneous aspergillosis may be associated with intravenous catheters. Ctndidosis
The incidence of candidosis has increased dramatically in the last few decades. New clinical manifestations have appeared, new approaches to diagnosis have been described and a number of new species have been associated with clinical disease (Odds, 1988; Meunier, 1989; Smith, 1989; Samaranayake & MacFarlane, 1990; Dupont, 1991). New clinical entities include the chronic candidosis syndrome (hepatosplenic candidosis) in leukaemic patients (Bodey & Anaissie, 1989) and pulmonary vascular candidosis in infants receiving prolonged parenteral feeding and multiple antibiotics (Knox, Hooton & Barson, 1987). Oral Candida infection has emerged as a major problem in AIDS patients; it is frequently followed by other, more serious, opportunistic infections. A high proportion of AIDS patients with oral candidosis also develop oesophageal candidosis, although this rarely leads to systemic infection.
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M. D. Rkhmrdsoo
Familiarity with emerging forms of candidosis and continual surveillance for their presence in compromised patients is necessary for success in increasing the anteraortem diagnostic rate.
Cryptococcosis Extensive study has revealed clear evidence of heterogeneity within the species Cryptococcus neoformans. It is now accepted that the four serotypes, A, B, C, and D are varieties of one parent species. Thus serotypes A & D are now classified as C. neoformans var. neoformans while B and C are classified as C. neoformans var. gattii. Infections may be acquired by inhalation of non-encapsulated cells that usually originate from areas where there are old accumulations of pigeon droppings in nests and under roosting sites. Cryptococcosis is one of the most prevalent of the systemic mycoses (Patterson & Andriole, 1989; Smith, 1989; Hay, 1991). Throughout the world, it is being recognised much more frequently as a disease of debilitated and immunologically compromised subjects. Epidcmiologica] and clinical data on cryptococcosis in AIDS patients suggest a number of conclusions. First, exposure of man to C. neoformans is much higher than previously assumed. Secondly, the immunodeficiencies that develop in AIDS patients favour C. neoformans more than any other opportunistic or truly pathogenic fungus. Thirdly, although C. neoformans has a predilection for the central nervous system, dissemination to other organs occurs more frequently in AIDS patients, reflecting their increased susceptibility to infection. Until recently, most AIDS patients with cryptococcosis were homosexuals, but increasingly cases are appearing in intravenous drug abusers, recipients of blood transfusions and the heterosexual population. The prognosis for AIDS patients with cryptococcosis is very bleak with an average survival time of six months. Relapse occurs in more than 50% of the cases following cessation of antifungal treatment and continuing maintenance treatment is usually required. Pulmonary involvement may precede or accompany cryptococcal meningitis in AIDS patients. Cryptococcaemia is observed in up to 50% of patients. The urine frequently harbours cryptococci, reflecting an infectious focus in the kidneys or more probably the prostate. Prostatic infection appears to be a significant reservoir for systemic relapse after successful treatment for meningitis. Disease of other extrancural sites has been described in patients with AIDS, alone or in association with meningitis. These include myocarditis, pericarditis, lymphadenopathies, pleuritis and arthritis. Skin lesions are frequent and biopsy and culture may provide early clues to a diagnosis of cryptococcosis. The prevalence of cryptococcosis in AIDS patients has affected the laboratory methods used to diagnose this disease. Cerebrospinal fluid examination provides valuable information. In AIDS patients, pleocytosis, elevated protein concentrations, and low glucose are less frequent than in non-AIDS patients. Conversely, the numbers of yeasts are higher. Microscopy, culture and tests for capsular antigen are more often positive than in other immunocompromised subjects. Whenever available, other clinical specimens should be examined for cryptococci: blood, skin biopsies, urine sediment (possible after prostatic massage), lymph node aspirates, and respiratory secretions.
Opportunistic and pathogenic fungi
7
Muconnycosis This is an opportunistic fungal disease caused by fungi of the order Mucorales which may affect any organ of the body. Alternative terms used to describe the various diseases caused by these fungi include zygomycosis and phycomycosis. The pathogenesis of the disease is unclear and, while the source is undoubtedly exogenous, definite sources of infection have not been identified. Rhinocerebral infection is still the most common form of muconnycosis in individuals in whom the major risk factor is diabetes mellitus. This is the predominant clinical form in most of the major reviews on the subject (Smith, 1989; Skahan, Wong & Armstrong, 1991). In recent years, rhinocerebral infection has been reported in two groups of patients who were often unrepresented in series compiled before 1970. Infection in patients with leukaemia and lymphoma has become increasingly common since that time and it is now clear that these diseases constitute an important risk factor. Rhinocerebral muconnycosis has also become more common in organ transplant recipients. Pulmonary mucormycosis is primarily a complication of leukaemia, lymphoma and severe granulocytopenia. Other less frequently seen manifestations of the disease include endobronchial mucormycosis, gastrointestinal mucormycosis and cutaneous muconnycosis secondary to significant trauma.
Infections due to truly pathogenic fungi In addition to their well recognised manifestations in immunocompetent individuals, histoplasmosis and coccidioidomycosis have emerged as significant infectious complications in AIDS patients and have been recognised as two of the defining opportunistic infections for this syndrome. At least 50% of AIDS patients with these infections have acquired them as their first AIDS-associated opportunistic infection. Consequently, new diagnostic tests, including antigen detection and lymphocyte studies, have been devised, and further indications for new antifungal agents have emerged. In AIDS patients, these infections are often severe and refractory to currently available antifungal chemotherapy, and frequently relapse following treatment resulting in death. Less frequently encountered infections due to truly pathogenic fungi include blastomycosis, paracoccidioidomycosis and sporotrichosis.
Other infections In addition to the increase in opportunistic infections caused by Candida spp., Aspergillus spp., C. neoformans and the agents of mucormycosis among immunocompromised patients, infections with other weakly pathogenic fungi are being encountered with increasing frequency. An ever escalating number of mycoses are being caused by saprophytic fungi previously considered as harmless. These fungi have caused lethal disseminated infections in patients compromised as a result of immunosuppression or by medical procedures that cause the physiochemical barrier of the skin to be broken. Many of these emerging pathogens are resistant to available antifungal agents.
8
M. D. Rkfaanhon Unosoal infections caused by yeasts
An increasing number of systemic infections are being caused by yeasts belonging to the genera Rhodotonda, Saccharomyces, Geotrichum, Hansenula, Trichosporon and Malassezia (Pityrosporum) (Anaissie, Bodey & Rinaldi, 1989; Warnock & Johnson, 1991). Among the unusual Candida species isolated from clinical specimens are Candida chiropterorum from peritoneal dialysis fluid, Candida ciferii causing superficial infection, at least ten reports of Candida lusitaniae implicated in systemic infection and the isolation of Candida rugosa from blood and causing pulmonary infection (Anaissie et al., 1989). One example of an unusual yeast infection that is becoming more common in compromised patients is localized deep or disseminated infection caused by Trichosporon beigelii or Trichosporon capitation. These infections are thought to be acquired from cutaneous sites because these yeasts can be isolated from such sites in many normal and immunocompromised hosts (Walsh, 1989). The emergence of T. beigelii as an agent of disseminated disease has had important implications for therapy because it appears to be resistant to amphotericin B in vitro. Moreover, in-vitro resistance has correlated with refractory, disseminated trichosporonosis in neutropenic patients (Walsh et al., 1990). Many homosexuals have been found to harbour T. beigelii in the anal region. Colonization may imply a potential risk of developing invasive trichosporonosis of endogenous origin.
Unusual infections earned byfilamentousfungi Many of the unusual infections caused byfilamentousfungal pathogens in both normal and immunocompromised individuals belong to one or other of two groups of diseases termed phaeohyphomycosis and hyalohyphomycosis.
Phaeohyphomycosis The aetiological agents of phaeohyphomycosis are common causes of infection among the populations of many underdeveloped countries and are being recognised more frequently as causes of both superficial and disseminated disease in immunocompromised hosts (Ajello, 1986; Weitzman, 1986; Warnock & Johnson, 1991). The organisms have brown, yeast-like, pseudohypha-like filaments, or hyphae that may be regular, distorted, or swollen in shape. Primary inoculation phaeohyphomycosis is often caused by traumatic implantation of fungi such as Exophialajeanselmei, Wangiella dermatitidis and certain other dematiaceous moulds, e.g. Alternaria spp. Most disseminated infections are thought to be acquired by inhalation. However, it is conceivable that dissemination may originate from cutaneous sites. Deep infections caused by Alternaria, Bipolar is, Exserohilum and Curvularia spp. have been reported and the features of individual infections have been reviewed recently (Warnock & Johnson, 1991). Other, less common, causes of infection in immunocompromised patients include Phialophora parasitica and Xylohypha bantiana (Cladosporium bantianum or Cladosporiwn trichoides).
Opportunistic and pathogenic
ftmgi
9
Hyalohyphomycosis The term hyalohyphomycosis encompasses all infections due to nonpigmcntcd, septate filamentous moulds that appear as colourless hyphae in tissue. Hyalohyphomycosis includes infections caused by such diverse opportunistic pathogens as PsendaUescheria boydii and Fusarium, Paecilomyces, Penicillium, Scopulariopsis, Acremonhim, Chrysosporium, Sepedonium and Scedosporiwn spp. (Ajello, 1986; Weitzman, 1986; Warnock & Johnson, 1991). Correct identification of these organisms is becoming increasingly important because the outcome of therapy frequently depends on the choice of an appropriate antifungal drug. Infections caused by these fungi are rare but appear to be increasing in incidence. Common features implicated in their pathogenesis appear to be cutaneous lesions that progress to disseminated disease, or the inhalation of spores which become readily airborne when discharged from fruiting structures. Many individual cases caused by these fungi have been reviewed recently (Warnock & Johnson, 1991). Over the past 30 years some 30 cases of infection caused by Penicillium mameffei have been reported. Six cases diagnosed in the last two years occurred in HIV-positive patients who were natives of, or visitors to, rural areas of S E Asia where the fungus occurs in the environment. The infection was disseminated in all cases except where the diagnosis was made early by isolating the fungus from bronchoalveolar lavage fluid in the absence of radiological evidence of pulmonary involvement. The fungus was isolated from the lung in all cases. The differential diagnosis includes tuberculosis and other systemic fungal infections. Implications for diagnosis Laboratory procedures for diagnosis of opportunistic mycoses continue to be updated, but currently depend upon a range of microscopy techniques, culture and serological procedures. Rapid tests for detection of specific antigens in body fluids and tissues appear especially promising. The use of DNA probes for identification of fungi is attracting attention and providing useful epidemiological data. Only by careful identification and reporting will it be possible to determine the relative importance of unusual fungal pathogens. Identification of recently described opportunistic pathogens has been based upon their microscopic morphology. Because the structures used to identify fungi are at times difficult to recognise, there is a need for other approaches to identify many of these fungi. Over the past few years the exoantigen procedure has been applied to a number of groups of medically important fungi and has been shown to be an excellent and definitive technique. More recently, the exoantigen test has been extended to isolates of Bipolaris spp. and Exserohilion spp. and shown to be useful for differentiating the two genera (Pasarell, McGinnis & Standard, 1990). The development of rapid identification systems for medically important yeasts and the emergence of unusual yeasts in immunocompromised patients here highlighted the requirement for yeast identification at the routine laboratory level. An illustrative point is the increasing number of reports of in-vitro amphotericin B resistance and clinical resistance shown by Candida tropicalis, C. lusitaniae, Candida parapsilosis, Candida guilliermondii and T. beigelii. The availability of well characterized polyvalent and monoclonal antibodies to the major fungal pathogens has stimulated rapid development of diagnostic kits for the
10
M. D. Richardson
detection of circulating antigens in body fluids. Latex particle agglutination and double antibody liposomal-bascd formats are being marketed for systemic candidosis and invasive aspergiUosis. Monoclonal antibodies to cell wall and cytoplasmic components of C. neoformans, H. capsulation and P. brasiliensis have been described. These reagents have obvious potential in new generations of tests for diagnosis and identification of fungal isolates. Furthermore, chromosomal DNA probes have been described and applied to the detection of fungal elements in clinical specimens (Gabal, 1989).
References Ajcllo, L. (1986). Hyalohyphomycosis and phaeohyphomycosis: two global disease entities of pubb'c health importance. European Journal of Epidemiology 2, 243-51. Anaissie, E. J., Bodey, G. P. & Rinaldi, M. G. (1989). Emerging fungal pathogens. European Journal of Clinical Microbiology and Infectious Diseases 8, 323-30. Bodey, G. P. & Anaissie, E. J. (1989). Chronic systemic candidiasis. European Journal of Clinical Microbiology and Infectious Diseases 8, 855-7. Bodey, G. P. & Vartivarian, S. (1989). Aspergillosis. European Journal of Clinical Microbiology and Infectious Diseases 8, 413-37. Cohen, J. (1991). Clinical manifestations and management of aspergillosis in the compromised patient. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 117-52. John Wiley, Chichester. Dei Cas, E. & Vernes, A. (1986). Parasitic adaptation of pathogenic fungi to mammalian hosts. CRC Critical Reviews in Microbiology 13, 173-218. Douglas, L. J. (1987). Adhesion of Candida species to epithelial surfaces. CRC Critical Reviews in Microbiology 15, 27^*3. Dupont, B (1991). Clinical manifestations and management of candidosis in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 55-83. John Wiley, Chichester. Gabal, M. A. (1989). Development of a chromosomal DNA probe for the laboratory diagnosis of aspergillosis. Mycopathologia 106, 121-9. Hay, R. J. (1991). Clinical manifestations and management of cryptococcosis in the compromised patient. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 85-115. John Wiley, Chichester. Kennedy, M. J. (1988). Adhesion and association mechanisms of Candida albicans. In Current Topics in Medical Mycology, Vol. 2 (McGinnis, M. R., Ed.), pp. 73-169. Springer-Verlag, New York. Knox, W. F., Hooton, V. N. & Barson, A. J. (1987). Pulmonary vascular candidiasis and use of central venous catheters in neonates. Journal of Clinical Pathology 40, 559-65. Meunier, F. (1989). Candidiasis. European Journal of Clinical Microbiology and Infectious Diseases 8, 438-47. Odds, F. C. (1988). Candida and Candidosis, 2nd edn. Bailliere Tindall, London. Pasarell, L., McGinnis, M. R. & Standard, P. G. (1990). Differentiation of medically important isolates of Bipolaris and Exserohilum with exoantigens. Journal of Clinical Microbiology 28, 1655-7. Patterson, T. F. & Andriole, V. T. (1989). Current concepts in cryptococcosis. European Journal of Clinical Microbiology and Infectious Diseases 8, 457-65. Peterson, D. E. & Schimpff, S. C. (1989). Aspergillus sinusitis in neutropenic patients with cancer, a review. Biomedidne and Pharmacotherapy 43, 307-12. Richardson, M. D. & Shankland, G. S. (1991). Pathogenesis of fungal infection in the noncompromised host. In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D , Eds), pp. 1-22. John Wiley, Chichester. Samaranayake, L. P. & MacFarlane, T. W. (1990). Oral Candidosis. Wright, London. Skahan, K. J., Wong, B. & Armstrong, D. (1991). Clinical manifestations and management of mucormycosis in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 153-90. John Wiley, Chichester.
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Smith, J. M. B. (1989). Opportunistic Mycoses of Man and Other Animals. C. A. B. International MycologjcaJ Institute, Wallingford. VioUier, A. F., Peterson, D. E., De Jongh, C. A., Newman, K. A. Gray, W. C, Sutherland, J. C. et al. (1986). Aspergillus sinusitis in cancer patients. Cancer 58, 366-71. Walsh, T. J. (1989). Trichosporonosis. Infectious Disease Clinics of North America 3, 43-52. Walsh, T. J., Melcher, G. P., Rinaldi, M. G., Lecciones, J., McGough, D. A., Kelly, P. et al. (1990). Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. Journal of Clinical Microbiology 28, 1616-22. Walsh, T. J. & Pizzo, P. A. (1988). Nosocomial fungal infections: a classification for hospitalacquired fungal infections and mycoses arising from endogenous flora or reactivation. Annual Review of Microbiology 42, 517-45. Warnock, D. W. & Johnson, E. M. (1991). Clinical manifestations and management of hyalohyphomycosis, phaeohyphomycosis and other uncommon forms of fungal infection in the compromised patient In Fungal Infection in the Compromised Patient, 2nd edn (Warnock, D. W. & Richardson, M. D., Eds), pp. 247-310. John Wiley, Chichester. Weitzman, I. (1986). Saprophytic molds as agents of cutaneous and subcutaneous infection in the immunocompromised host. Archives of Dermatology 122, 1161-8.
