Fungal infections in the immunocompromised host

Invasive fungal infections cause significant morbidity and mortality in patients with impaired immune defences. Defects in neutrophil function and neutropenia predispose to disseminated Candida, Aspergillus and Mucoraceae infections while altered T-lymphocyte mononuclear phagocyte function predisposes to infection with C. neoformans, Histoplasma and Coccidioides. Fungal infections in the immunocompromised host are difficult to diagnose and difficult to treat successfully. The diagnosis is often missed or delayed because of the non-specific clinical features, the failure to isolate or difficulty in interpreting the presence of the fungus from routine microbiological cultures, and the limited usefulness of available serological tests. The assay for cryptococcal antigen is the only currently available reliable serological test used to diagnose an invasive fungal infection. Definitive diagnosis is made by histopathological demonstration of the fungus in tissue or a positive culture from a sterile body site. Invasive procedures are often necessary to obtain adequate tissue for histology and culture. The treatment of invasive fungal infection in the immunocompromised host is amphotericin B with or without 5FC. The usual recommended dose is 1.5 to 3 g total amphotericin B over 6 to 12 weeks. The optimal dose and duration of therapy for each infection is not known. Treatment failures and relapses are common in patients who do not achieve remission of their underlying disease. Ketoconazole, a new broad-spectrum oral antifungal medication, does not appear to be effective therapy for invasive fungal infection in the immunocompromised patient based on results of small clinical trials. New diagnostic methods and therapeutic approaches are necessary to improve the outcome of these infections. Areas of current research include serological assays for fungal antigens and metabolites which may allow earlier diagnosis, treatment with combinations of antifungal agents, and the development of new antifungal agents.     

Fungal and bacterial infections in the immunocompromised host

As the number of immunocompromised patients increases due to the spread of the AIDS epidemic and the successes being achieved with transplantation, cancer chemotherapy and immunosuppressive therapy, increased attention is being turned to the prevention and treatment of the infections that afflict these individuals. The risk of infection in these patients is determined by the interaction between the epidemiologic exposures that the patient experiences and the net state of immunosuppression (the greater the exposure, the greater the chances of infection even in an immunologically competent individual; the greater the net state of immunosuppression, the greater the chances of infection even with minimal exposures). The bacterial and fungal infections that affect these patients are reviewed and strategies of antimicrobial management defined, recognizing that there are three modes of use of antimicrobial agents in these patients: therapeutic administration to treat clinical infection, and prophylactic and pre-emptive administration to prevent or abort clinical infection. These last two are of particular importance in this patient population because the prime aim of the infectious disease clinician in dealing with these problems is the prevention of clinical disease.     

Fungal infections in immunocompromised patients]

The number of immunocompromised patients is increasing due to the intensive therapy being administered those with cancer, organ transplant, and HIV infection. Fungal infections are one of the important opportunistic infections in immunocompromised patients. Early diagnosis is difficult, and the prognosis of these patinas is usually poor. Several methods of diagnosis for fungal infections have been developed: detection of antigens of the infected fungi from the sera is useful for early diagnosis; polymerase chain reaction (PCR) technology may be the most valuable method for the diagnosis of fungal infection in immunocompromised patients, and antifungal agents are the drugs used to the fungal infections in those patients. However, there are only five drugs available to fungal infections in Japan. Although amphotericin B is the recommended first choice for treatment of invasive aspergillosis, its use for immunocompromised patients is limited because of its adverse effects. Novel antifungal agents (azoles, amphotericin B drug deliver system, and 1,3-beta-D-glucan synthetase inhibitors) have been developed and some of these compounds undergoing clinical trials.     

Treatment of adenovirus infections in the immunocompromised host

Adenovirus infections are increasing as causes of morbidity and mortality in severely immunocompromised patients. The currently available antiviral agents, ribavirin and cidofovir, have yielded mixed results in case reports and small case series. Similar to cytomegalovirus disease, established adenovirus disease is often difficult to treat. Therapy may yield poor results, even when effective antiviral drugs are used. New strategies, including pre-emptive therapy, should be tested in prospective, clinical trials. New agents and adoptive transfer of specific T-cells to adenovirus might improve the current situation.     

Immunoprophylaxis and immunotherapy of Gram-negative infections in the immunocompromised host

Gram-negative infections remain a prominent cause of serious morbidity and mortality in hospitalized patients despite skilful antibiotic therapy and supportive care. A recently developed immunological approach to this problem is based on antiserum to an E. coli mutant (J5) which elicits antibody cross-reactive with a wide range of Gram-negative pathogens. The antitoxic and protective powers of E. coli J5 antiserum have been demonstrated in animal models. In carefully conducted clinical trials, J5 antiserum or J5 plasma of human origin has been established as a potent adjunctive therapy for the severe consequences of Gram-negative bacteraemia and in the prophylaxis of such infections in surgical patients. The question remains open whether such antiserum may have a similar prophylactic power in severely neutropenic patients. Clinical trials currently underway or soon to be started should help to clarify the practical prophylactic power of J5 hyperimmune globulin against shock and death in high-risk patients.     

Adenoviruses in the immunocompromised host.

Adenoviruses are among the many pathogens and opportunistic agents that cause serious infection in the congenitally immunocompromised, in patients undergoing immunosuppressive treatment for organ and tissue transplants and for cancers, and in human immunodeficiency virus-infected patients. Adenovirus infections in these patients tend to become disseminated and severe, and the serotypes involved are clustered according to the age of the patient and the nature of the immunosuppression. Over 300 adenovirus infections in immunocompromised patients, with an overall case fatality rate of 48%, are reviewed in this paper. Children with severe combined immunodeficiency syndrome and other primary immunodeficiencies are exposed to the serotypes of subgroups B and C that commonly infect young children, and thus their infections are due to types 1 to 7 and 31 of subgenus A. Children with bone marrow and liver transplants often have lung and liver adenovirus infections that are due to an expanded set of subgenus A, B, C, and E serotypes. Adults with kidney transplants have viruses of subgenus B, mostly types 11, 34, and 35, which cause cystitis. This review indicates that 11% of transplant recipients become infected with adenoviruses, with case fatality rates from 60% for bone marrow transplant patients to 18% for renal transplant patients. Patients with AIDS become infected with a diversity of serotypes of all subgenera because their adult age and life-style expose them to many adenoviruses, possibly resulting in antigenically intermediate strains that are not found elsewhere. Interestingly, isolates from the urine of AIDS patients are generally of subgenus B and comprise types 11, 21, 34, 35, and intermediate strains of these types, whereas isolates from stool are of subgenus D and comprise many rare, new, and intermediate strains that are untypeable for practical purposes. It has been estimated that adenoviruses cause active infection in 12% of AIDS patients and that 45% of these infections terminate in death within 2 months. In all immunocompromised patients, generalized illness involving the central nervous system, respiratory system, hepatitis, and gastroenteritis usually have a fulminant course and result in death. Treatments for adenovirus infections are of little proven value, although certain purine and pyrimidine analogs have shown beneficial effects in vitro and may be promising drugs.     

Enteric infections in Perugia's area: laboratory diagnosis,clinical aspects and epidemiology during 2001

During 2001 we analyzed 523 stool specimens (330 children, 193 adults) of patients with recent diarrhoea. We processed all specimens for protozoa, rotavirus, adenovirus, toxin A of C. difficile, and usual enteropathogen bacteria. Salmonella prevailed in 12.8% of cases (16.4% among children, 6.7% among adults), Campylobacter in 9.9% (11.5% and 7.3%), C. difficile toxin A producer in 11.3% (13.7% and 8.1%); other bacteria generally prevailed in 2.4%, protozoa in 2.7%. Among children rotavirus prevailed in 41.4%, adenovirus in 3.6%. Enteritis prevailed in children between 1 and 6 years of age. All pathogens were reported during all the seasons, but salmonellosis and campylobacteriosis were more frequent during spring and summer, rotavirus infections during the winter. Non particular and/or specific correlations could be observed between clinical manifestations and pathogen agents; anyway only bacteria were identified among invasive enterites. Vomitus was more frequent in rotavirus infections. Finally the Authors suggest a rational and efficacious methodology for diagnosis of presumptive infectious diarrhoeas.     

Coryneform bacteria in infectious diseases: clinical and laboratory aspects.

Coryneform isolates from clinical specimens frequently cannot be identified by either reference laboratories or research laboratories. Many of these organisms are skin flora that belong to a large number of taxonomic groups, only 40% of which are in the genus Corynebacterium. This review provides an update on clinical presentations, microbiological features, and pathogenic mechanisms of infections with nondiphtheria Corynebacterium species and other pleomorphic gram-positive rods. The early literature is also reviewed for a few coryneforms, especially those whose roles as pathogens are controversial. Recognition of newly emerging opportunistic coryneforms is dependent on sound identification schemes which cannot be developed until cell wall analyses and nucleic acid studies have defined the taxonomic groups and all of the reference strains within each taxon have been shown by molecular methods to be authentic members. Only then can reliable batteries of biochemical tests be selected for distinguishing each taxon.     

EDTA-dependent pseudothrombocytopenia: clinical aspects and laboratory tests

EDTA-dependent pseudothrombocytopenia (EDTA-PTCP) is a phenomenon caused by EDTA-dependent anti-platelet antibody. This antibody induces platelet agglutination in vitro, resulting in a decrease in platelet counts. It is necessary for clinicians to consider the possible presence of PTCP in cases of patients having low platelet counts without any hemorrhagic tendency. In this article, we describe some aspects of EDTA-PTCP including, (1) characteristics of platelet agglutination, (2)possible mechanisms for antibody production, (3) several methods to determine the true platelet number, and also (4) a few similar phenomena induced by antibodies independent of EDTA.     

Herpes virus infections: clinical manifestations and therapeutic strategies in immunocompromised patients

Herpesvirus infections are a major cause of morbidity and mortality in immunosuppressed patients. Bone marrow and organ transplant recipients are model patient populations for studying the natural history of herpesvirus infections because the infections occur predictably after transplantation. Herpes simplex virus infections occur within the first month after transplantation and may cause severe mucocutaneous disease. Cytomegalovirus infections occur one to three months after transplantation and are the major viral cause of morbidity and mortality. Varicella-zoster virus infections occur four to five months after transplantation and rarely cause life-threatening infection. Further studies of Epstein-Barr virus are necessary to determine its significance as a pathogen. The development of new antiviral agents has introduced effective therapeutic approaches for herpes simplex virus infections and varicella-zoster virus infections. Efforts to treat or prevent cytomegalovirus infections in transplant recipients have had limited success. However, new therapeutic strategies may lead to therapies which may reduce the severity of these infections and lead to increased survival in bone marrow transplant and organ transplant recipients.     

Nocardia infections: clinical and biological aspects]

The nocardiosis is an infection caused by a bacterial pathogen agent, Nocardia, belonging to the Actinomycetales order. They are Gram-positive, strictly aerobic bacteria. Members of the genus Nocardia are ubiquitous. They are frequently isolated from soil, water, air dusts. The mode of contamination occurs by inhalation or by cutaneous or ocular traumatic lesion. Clinically, nocardiosis is essentially characterized by pulmonary diseases. Others secondary localizations are described, such as in the central nervous system. Nocardia can be responsible for important cutaneous, subcutaneous and lymphocutaneous manifestations. In the same way, some extrapulmonary diseases and spread nocardiosis are more rarely observed. Several factors seem to favour the development of Nocardia. The immunocompromised patients, particularly those with organ transplant and the patients treated with immunosuppressor treatments, offer strong predispositions to this opportunistic disease. The nocardiosis is nevertheless observed in healthy persons. In front of polymorphic and specific-less clinical manifestations, large phenotypic heterogeneity, and resistance profiles to specific antibiotics, a correct diagnosis for Nocardia species is necessary to apply an adequate treatment. The techniques of identification based on the chemotaxonomic analysis and the susceptibility to different inhibitors are efficient for the identification of genus and species. However, because of the slow growth rate of Nocardia, the reading of these tests can require several weeks of incubation. With the intention of the rapid identification of genus and species, the molecular techniques (PCR-RFLP) seem to be efficient. The technique of RAPD allows an efficient molecular typing, which will give a better knowledge concerning transmission, ecological niches and epidemic reservoirs.     

Alternaria infections: laboratory diagnosis and relevant clinical features

The genus Alternaria contains several species of melanized hyphomycetes that cause opportunistic human infections. The published literature contains 210 reported cases of human alternarioses between 1933 and the present day. The most frequent clinical manifestations are cutaneous and subcutaneous infections (74.3%), followed by oculomycosis (9.5%), invasive and non-invasive rhinosinusitis (8.1%) and onychomycosis (8.1%). Immunosuppression is frequently associated with cutaneous and subcutaneous infections and rhinosinusitis. The most important risk factors for cutaneous and subcutaneous infections are solid organ transplantation and Cushing's syndrome, and those for rhinosinusitis are bone marrow transplants. Having been exposed to soil and garbage is common in all cases of oculomycosis, with corticotherapy being a risk factor in 50% of these cases. Previous contact with soil and/or trauma to the nails is associated with most cases of onychomycosis. In general, alternariosis shows a good response to conventional antifungal drugs. On some occasions, steroid suppression or reduction is sufficient to resolve an infection. Itraconazole is the antifungal drug used most frequently to successfully treat onychomycosis and cutaneous and subcutaneous infections. Posaconazole and voriconazole are promising therapeutic options, with the latter being especially so for oculomycosis.     

Immunization in the adult immunocompromised host

The number of patients with impaired immune response has been steadily increasing within the last years, not only with the onset of the AIDS epidemic, but also due to increasing numbers of subjects on immunosuppressive therapies. These patients are at an increased risk for infections, many of which are preventable by immunization. Inactivated vaccines are generally safe in subjects with underlying immunosuppression. However, immune response and protection may be hampered, depending on the extent of immunosuppression. In contrast, live vaccines such as yellow fever, measles, rubella, herpes zoster, and cholera may lead to severe reactions in immunocompromised patients and have been shown to deteriorate some immune-mediated diseases such as multiple sclerosis. Data on the efficacy of vaccines in biological therapies is scarce. Where necessary vaccines should be updated before immunosuppressive therapies are started. To improve the vaccination status several guidelines exist for immunosuppressed patients at risk such as those with rheumatic diseases, asplenia or solid organ and hematopoietic stem cell transplantation.     

Fungal infections of the small and large intestine.

AIMS: To study the pathological features of fungal infections affecting the lower intestinal tract (duodenum, small and large bowels). METHODS: Between mid-1981 and mid-1991, 14 cases of deep mycotic infections affecting the lower intestinal tract were found among 890 consecutive necropsies on patients with malignant disease treated in a regional cancer centre (incidence 1.6%). These 14 cases accounted for 54% of all gastrointestinal fungal infection detected. The relevant clinical, necropsy, histological and microbiological data were reviewed. RESULTS: Candida spp and Aspergillus spp accounted for all infections. The macroscopic appearances included ulcers of varying configuration, mucosal flecks, sloughed mucous membranes, polypoid masses and segmental lesions. Either organism could produce this range of lesions, but Candida tended to have a mucosal location and Aspergillus was associated with transmural invasion. Combined infections showed Candida in the surface mucosa and Aspergillus hyphae in submucosal vessels with spread into the bowel wall in a radiating pattern. During the final illness, gastrointestinal symptoms and signs were often slight and microbiological investigations were unhelpful. CONCLUSIONS: Variable gross appearances are relevant for endoscopists, particularly lesions which resemble pseudomembranous colitis. Endoscopic biopsy specimens may have a role in antemortem diagnosis. Failure to diagnose these infections during life emphasises the importance of necropsy in the clinicopathological audit of deaths in this group of patients.     

Sensitization to the fish parasite Anisakis simplex: clinical and laboratory aspects

Hypersensitivity to Anisakis simplex is a worldwide medical problem. The parasite larvae die after freezing or cooking, but the tolerance of sensitized subjects to eating frozen fish remains a matter of controversy with contradictory findings. The aim of this study was to test if intolerance to properly cooked/frozen fish was due to the recognition of a particular allergen. Sixty-four patients with Anisakis simplex sensitization were studied by an IgE multiblot using simultaneously five different antigenic extracts. The antigens tested were a crude extract, excretory/secretory allergens, a heated extract, and two gradient ethanol precipitates of the crude extract. Intolerance was reported by 20% of the patients and was not related to the detection of any special allergen, nor to total or specific IgE levels. Intolerant patients only reported a higher frequency of digestive symptoms than the patients who tolerated fish ingestion. The most sensitive immunoblot antigen source was the 50–66% ethanol fraction of a crude extract (10× concentrated) that was found to be positive in 100% of the samples. Interestingly, 95% sensitivity in the IgE-immunoblot assay could be achieved using only two allergens, Ani s 1 and Ani s 4. Allergens from the dead larvae remain a problem for 20% of the sensitized subjects. The use of a fractionated and concentrated crude extract improved the sensitivity of the immunoblot assay.