Study of systemic fungal infections in autopsy material

A retrospective study of 2526 autopsy cases was done in order to find out the pattern of systemic fungal infections. The autopsy records were reviewed for case histories, gross and histological findings. The histological sections from cases showing evidence of fungalo infections were reviewed. The fungal infections were found in 28 cases. Of these 11 (93.29 percent) were aspergillosis, 8 (28.27 percent) were mucormyosis, 6 (21.43 percent) were monilial infections and 3 (10.71 percent) were monilial infections and 3 (10.71 percent) were cryptococcosis. The incidence of systemic fungal infection was 1.11 percent. The most common type of fungal infection was aspergillosis. The maximum number of fungal infection was seen in the respiratory system. The fungal infections presented as opportunistic infections in all but one case. The metabolic disturbance was the most frequent predisposing condition for systemic fungal infections.     

Controversial points in the treatment of patients with haematologic malignancies complicated with systemic fungal infections]

Prophylaxis and treatments for fungal infections differ with the infection type. However, the eradication of risk factors for outbreak of fungal infections, and the usage of appropriate antifungal agents are universally important to prevent these infections. For infections due to intrinsic fungi such as Candida spp., risk factors such as changes in normal flora by aggressive and prolonged broad-spectrum antibiotics therapy should not be permitted to emerge. On the other hand, infections due to extrinsic fungi such as Cryptococcus neoformans and Aspergillus spp. can be prevented by eradication of the colonized fungi using antifungal prophylaxis and the use of air-cleaning machines to combat colonization of patients and contamination in the hospital environment. The most important risk factor of fungal infections in patients suffering from haematologic malignancies is leukopenia. In these cases, it is crucial to reduce the duration of neutropenia and enhance the anti-microbial function using granulocyte-macrophage-colony stimulating factor. When a patient is complicated with a fungal infection, appropriate antifungal agents must be used at appropriate dosages for the appropriate period. However, there are still very few satisfactory antifungals with minimal adverse effects and good potential efficacy for systemic fungal infections. Therefore, combination therapy with amphotericin B and azole antifungals is necessary for patients with severe fungal infections. In patients complicated with fungal infections, the underlying disease is often resistant to aggressive antifungal therapy. Control of this underlying disease is thus a most important therapeutic factor.     

Oral infections and septicemia in immunocompromised patients with hematologic malignancies.

To estimate the role of oral infections during septicemic episodes in immunocompromised patients with hematologic malignancies, 78 febrile episodes in 46 patients were monitored with daily clinical and microbiological investigations. The 19 septicemic episodes did not differ from the 59 other febrile episodes in the qualitative composition of the aerobic and facultatively anaerobic oral microflora or in the presence of teeth or acute oral infections on day 1. The oral prevalence rates of members of the family Enterobacteriaceae were higher on days 10, 11, and 12 in the febrile episodes with septicemia when compared with those of febrile episodes without septicemia. The prevalence of a probable oral focus in septicemia was 10.5%, and the prevalence of a probable or possible oral origin in septicemia was 31.6%. The results suggest that prevention and elimination of oral infections may reduce the morbidity and perhaps even the mortality in these patients.     

Solid and hematologic malignancies in 60 patients with systemic mast cell disease

Although the association of malignancies and systemic mast cell disease (SMCD) is well established, the nature of this relationship is poorly understood. The observation of 19 malignancies in 17 of 60 patients with SMCD raised several questions regarding the chronological relationship of onset of SMCD and the malignancies, whether these patients are at increased risk for developing malignancy, and whether the distribution of solid vs hematologic malignancies indicates a relationship between SMCD and a particular tumor. The following malignancies were observed: eight solid tumors, seven acute nonlymphocytic leukemias, three malignant lymphomas, and one refractory anemia with excess blasts in transformation. The majority (13/17) of patients were found to have malignancies before, or within 12 months of, SMCD diagnosis. Statistical analysis suggested that patients with SMCD are not at increased risk for malignancies subsequent to the diagnosis of SMCD. The varied types of solid malignancies observed indicated a random distribution, in contrast to the hematologic malignancies that appeared to primarily affect the myeloid cells.     

Iron metabolism and fungal infections in patients with haematological malignancies.

AIM--To determine whether iron metabolism influences the incidence of systemic fungal infection in patients with haematological malignancies. METHODS--The study population comprised 74 patients who had undergone myeloablative chemotherapy. Systemic fungal infections were classified as confirmed (histological confirmation or characteristic septate hyphae) or possible (antibiotic resistant fever which resolved following administration of intravenous amphotericin B, together with either typical radiographic lesions or massive oropharyngeal candidiasis). Parameters of iron metabolism included serum iron concentrations, total iron binding capacity, serum transferrin, and ferritin concentrations and transferrin saturation values. RESULTS--Patients who developed a fungal infection had substantially increased transferrin saturation values and ferritin concentrations at diagnosis together with low serum transferrin and high serum iron concentrations. This profile was present in patients with a fungal infection regardless of the underlying haematological disorder. CONCLUSION--Increased transferrin saturation values and high ferritin concentrations may be additional risk factors for the development of systemic fungal infection in patients with haematological malignancies.     

Acquired hemophilia in patients with hematologic malignancies

OBJECTIVES: To evaluate the occurrence of acquired hemophilia in patients with hematologic malignancies and to assess their response to treatment. DESIGN: Data on 8 patients with hematologic neoplastic disorders and inhibitor against factor VIII were analyzed retrospectively. SETTING: Three large tertiary-care centers. RESULTS: All 8 patients presented with spontaneous or posttraumatic hemorrhages. The mean inhibitor titer at the time of diagnosis was 79 Bethesda units (BU), and residual factor VIII activity was detectable in 3 patients. The inhibitor disappeared in 5 patients after a mean of 92 days, but persisted in the 3 other patients. The patients who achieved complete resolution of their circulating anticoagulant had lower mean inhibitor titers at the time of diagnosis than those who had persistent inhibitor (27 BU vs. 167 BU, respectively). Two patients died as a result of major hemorrhages that did not respond to treatment. CONCLUSIONS: Antibodies against factor VIII may be responsible for some bleeding episodes in patients with lymphoid or myeloid malignancies. Acquired hemophilia in this setting should be differentiated from other causes of bleeding because the approach to treatment is different. No conclusion can be drawn regarding the association between the activity of the underlying illness and the inhibitor titer, although it appears that at least in some patients such a relationship may exist. The underlying pathogenetic mechanisms responsible for the production of autoantibodies against factor VIII remain unclear, but we provide a few explanations in this article.     

Cardiac fungal infections: review of autopsy findings in 60 patients

An autopsy study of 60 patients with fungal infections of the heart was undertaken. The patients ranged in age from 2 months to 79 years. Fifteen of the patients had undergone cardiac surgery; neoplasms were found in 13, renal failure in eight, bacterial infections in five, liver disease in five, gastrointestinal disorders in five, and immune disease in four; two had been intravenous drug abusers; other miscellaneous disorders were observed in three. The fungal infection was limited to the myocardium in 27 patients and to the endocardium in 17 patients. Myocardium and endocardium were involved in nine patients and pericardium and myocardium in five; two patients had pericarditis alone. The most frequent organism was Candida (62 per cent). Aspergillus (12 per cent) and Phycomycetes (12 per cent) were also found frequently. In 51 patients (85 per cent) other deep organs, usually lung, kidney, brain, or spleen were involved. Cultures for fungus had been positive in 26 patients prior to death, and postmortem cultures were positive in 29 patients. Patients who had undergone cardiac surgery had a higher incidence of endocarditis (93 per cent), with Candida (53 per cent) being the most frequent cause. Patients who had received antineoplastic drugs, antibiotics, or corticosteroids had a higher incidence of myocarditis (79 per cent), again most often due to Candida (60 per cent).     

Reduction of systemic fungal infections in patients with hematological malignancies,neutropenia, and prolonged fever by early amphotericin B therapy

Summary A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48–72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973–1981) to 4% (6 of 153 patients; 1982–1986,P<0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973–1981) to 4% (2 of 50 patients; 1982–1986,P<0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.     

Candida guilliermondii fungemia in patients with hematologic malignancies

The microbiological, clinical, and epidemiological features of most non-Candida albicans Candida species are well known, but much less is known about species such as Candida guilliermondii, an uncommon pathogen causing a variety of deep-seated infections in immunocompromised hosts. To characterize C. guilliermondii fungemia in patients with hematological malignancies and its susceptibility to antifungal drugs, all cases of C. guilliermondii fungemia diagnosed in our department between 1983 and 2005 were retrospectively analyzed and the literature was reviewed. C. guilliermondii caused 29/243 (11.7%) candidemia episodes diagnosed during the study period. Central venous catheters were the documented sources of candidemia in 19/29 episodes (65.5%), and invasive tissue infections were documented in 2 (6.9%). In the remaining eight, the catheter was not removed and the source of the fungemia remained obscure. Seven episodes ended in death, but only one could be attributed to invasive C. guilliermondii infection. Molecular typing data reveal no evidence of common infection sources. Isolates displayed high rates of in vitro susceptibility to amphotericin B (100%), voriconazole (95%), and fluconazole (90%) and lower rates of in vitro susceptibility to flucytosine (86%), itraconazole (76%), and caspofungin (33%). Our literature review confirms that C. guilliermondii is a significantly more frequent cause of candidemia among cancer patients compared with the general hospital population. It accounted for <1% of the total number of Candida bloodstream isolates reported in the articles we reviewed, with higher rates in Europe (1.4%) and Asia (1.8%) compared with North America (0.3%).     

Microbiology of systemic fungal infections

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.     

Blastomycosis and opportunistic infections in patients with acquired immunodeficiency syndrome. An autopsy study.

Patients with acquired immunodeficiency syndrome (AIDS) are subject to a host of opportunistic infections, but to our knowledge a predisposition to blastomycosis has not previously been established. Autopsies of two patients with AIDS revealed disseminated blastomycosis with massive pulmonary involvement, Blastomyces meningoencephalitis, and widespread dissemination. The massive systemic involvement and rapid terminal course in both cases may reflect the state of acquired immunodeficiency. An analysis of an autopsy series showed that the incidence of blastomycosis was increased in patients with AIDS, although some other opportunistic organisms were more common (eg, Pneumocystis carinii, Mycobacterium avium-intracellulare, and Candida species). Thus, the diagnosis and treatment of blastomycosis must be pursued in patients with AIDS. Additional data are needed to further determine the incidence of blastomycosis in the population of patients with AIDS.     

Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients

The efficacy and safety of oral fluconazole versus a polyene regimen in preventing mycoses in neutropenic patients was compared. Patients with haematological malignancy or bone marrow transplantation received as antifungal prophylaxis either fluconazole 200 mg daily or a regimen consisting of clotrimazole trouches 10 mg twice daily with mycostatin, 500,000 i.u. four times daily, benadryl and cepacol mouthwash. Ninety patients at risk for fungus infection were evaluable. Four of 42 patients (9.5 %; confidence interval 2 %–23 %) on fluconazole and 17 of 48 patients (35.4 %; confidence interval 22 %–52 %) (p<0.01) on the clotrimazole regimen developed a clinically significant fungal infection, including 3 (7.1 %) and 11 (22.9 %) patients respectively who had severe fungal infection, mainly pulmonary aspergillosis. Death directly due to a fungal infection within 100 days of the start of prophylaxis occurred in 2 of 42 patients (4.8 %) and 9 of 48 patients (18.8 %) respectively (p<0.06). Kaplan-Meier analysis showed that the chance of survival on fluconazole was statistically greater than for the clotrimazole regimen (p<0.04). A decrease of candidal colonisation of the gastrointestinal and genitourinary tracts occurred only in patients receiving fluconazole. No significant toxicity occurred. A 200 mg daily dose of fluconazole given to these patients thus appears to be well tolerated and to provide a protective effect against the development of fungal infection and death from severe fungal disease.     

Weekly liposomal amphotericin B as secondary prophylaxis for invasive fungal infections in patients with hematological malignancies

There have been no published studies evaluating the efficacy and safety of weekly liposomal amphotericin B as secondary prophylaxis in leukemic patients with invasive fungal infections (IFIs). We found in a retrospective review of our experience with 14 such patients admitted from 2003-2009 that the use of this approach was associated with frequent relapse of IFIs (36%) and kidney injury (36%).     

Fungal infections in cancer patients: An international autopsy survey

In an attempt to estimate the frequency of fungal infections among cancer patients, a survey of autopsy examinations was conducted in multiple institutions in Europe, Japan and Canada. Fungal infections were identified most often in leukemic patients and transplant recipients (25 % each). Fifty-eight percent of fungal infections were caused byCandida spp. and 30 % byAspergillus spp. There was considerable variability in the frequency of fungal infections in different countries. Nevertheless, this study clearly demonstrates that fungal infections represent a common complication in cancer patients, especially in patients with leukemia.     

Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies

We hypothesize that coordination between the two DNA parental sets in somatic cells is essential for the stability of the diploid genome, and that its disruption is associated with the many alterations observed in the various cancerous phenotypes. As coordination between two allelic counterparts is well exemplified by synchrony in replication timing, we examined, in blood cells of patients suffering from various hematologic malignancies, replication patterns of five loci. These loci were three cancer-implicated genes (TP53, AML1, and RB1) and two nontranscribed sequences engaged in chromosome segregation. All five loci normally display synchrony in allelic replication timing. In addition, in order to exemplify an asynchronous mode of allelic replication, we followed the replication of allelic counterparts of an imprinted gene (SNRPN), which is distinguished by its asynchronous mode of allelic replication (allele-specific replication). Allelic replication patterns were studied by fluorescence in situ hybridization (FISH), which has been shown to distinguish between nonreplicated and replicated regions of the genome in interphase cells, based on the structure of the specific hybridization signals that are being detected. Using the FISH replication assay we observed, for all loci which normally exhibit synchrony in allelic replication, loss of synchrony when present in blood cells of patients with hematologic malignancies. The loss of synchrony in allelic replication in patients' cells was accompanied by aneuploidy (chromosome losses and gains), the hallmark of cancer. We were able to reinstate the normal pattern of replication in the patients' cells by introducing an inhibitor of DNA methylation. It thus appears loss of allelic coordination is an epigenetic alteration characterizing cancer, which is easily identified by simple cytogenetic means and has a potential use in both cancer investigation and detection.     

Clinical significance of post-treatment viral load of cytomegalovirus in patients with hematologic malignancies

ObjectivesPatients with hematologic diseases were at high risk for cytomegalovirus (CMV) diseases. In the present study, we compare various prognostic factors during CMV viremia, with specific emphasis on the relationship between viremia eradication and the long-term prognosis of patients after each episode.MethodsAdult patients with hematologic diseases who had a detectable CMV viral load (VL) (equal to or above 150 copies/mL) were included in the study. Medical records were reviewed for demographic data including age, sex, hematologic and other underlying diseases, status of stem cell transplantation, antiviral medication, serum CMV viral load before and after antiviral treatment.ResultsA total of 101 episodes of CMV viremia occurred in patients with hematologic diseases. Comparison of various prognostic factors revealed non-survivors more frequently suffered from pneumonia and concomitant bacterial or fungal infections, had less frequently undergone hematopoietic stem cell transplantation (HSCT), and had higher peak VLs during viremic episodes. After antiviral therapy, eradication of viremia was much less frequently achieved in non-survivors. The Kaplan–Meier curves revealed that patients with detectable end-treatment VL had lower survival rates even if the antivirals were administered for more than 21 days. In a multivariate Cox proportional-hazard model, a detectable VL at the end of antiviral therapy independently predicted mortality within 180 days.ConclusionsIn patients with hematologic diseases suffering CMV viremia, failure to eradicate viremia after antiviral therapy indicates a higher chance of mortality and can be regarded as a useful indicator in evaluating the patient's long-term prognosis.