Three cases of imported histoplasmosis in our hospital

Since 1999 we have observed three cases of imported histoplasmosis in our hospital. One was an immunocompetent individual and two further patients were immunosuppressed (renal transplantation and HIV infection C3). Two patients were born in endemic areas (Equatorial Guinea and Ecuador) and a third patient had a history of previous travel to the Peruvian Amazonia. The different clinical presentations and diagnostic tools of histoplasmosis are discussed.     

Histoplasmosis in Africa: Current perspectives,knowledge gaps,and research priorities

BackgroundHistoplasmosis is a chronic granulomatous disease caused by the thermally dimorphic fungus Histoplasma capsulatum. The 2 variants Histoplasma capsulatum var. capsulatum (Hcc) and Histoplasma capsulatum var. duboisii (Hcd) causes infection in humans and commonly termed classical or American histoplasmosis and African histoplasmosis, respectively. Histoplasma capsulatum var. farciminosum (Hcf) affects equines. In recent times, there have been heightened sensitization on fungal infections such as histoplasmosis in Africa, aimed at improving awareness among relevant stakeholders, particularly healthcare workers. This effort is expected to be paralleled with increased detection of both classical and African histoplasmosis, which has remained underdiagnosed over the years. In this narrative review, we describe the current perspectives of histoplasmosis in Africa, identify knowledge gaps, and suggest research priorities.MethodsA PubMed, Google Scholar, and Africa Journal Online (AJOL) literature search was conducted for studies on histoplasmosis in Africa between 2000 and 2020. Histoplasmosis essays in medical mycology textbooks were also consulted. This narrative review was prepared from the data gathered.FindingsIn the past 2 decades, histoplasmosis in general has seen a relative increase in case detection in some Africa countries, probably attributable to the gradually increasing medical mycology advocacy efforts in Africa. Histoplasmosis cases are dominated by African histoplasmosis mostly in Western and Central Africa, while classical histoplasmosis is more common in Southern and Northern Africa. Although both classical and African histoplasmosis are common in Africa, the latter is more restricted to Africa, and cases outside the continent usually have a travel history to the continent. Despite the clinical and laboratory difference between African histoplasmosis and classical histoplasmosis, it is not straightforward to distinguish them. The typical manifestation of African histoplasmosis is the appearance of lesions affecting the skin, bones, and lymph nodes and unusually linked to human immunodeficiency virus (HIV)/AIDS. By contrast, classical histoplasmosis mostly affects the lungs and is often associated with immunosuppression, mainly HIV/AIDS. The present perspectives of histoplasmosis in Africa highlight unclear details on the true burden, strain diversity, infection route and genetic basis of African histoplasmosis, availability of specie-specific diagnostic tools, and compliance with recommended antifungal therapy. These knowledge gaps represent research questions that require scientific exploration.ConclusionsDespite a subtle increase in identifying histoplasmosis cases in Africa, it remains underdiagnosed and neglected in some parts of the continent. Increasing awareness and training among healthcare workers, bridging diagnostic and therapeutic gaps, and encouraging more research in Africa are crucial to improve the current perspectives of histoplasmosis in Africa.     

Perforation of the Nasal Septum as the First Sign of Histoplasmosis Associated with AIDS and Review of Published Literature

Disseminated histoplasmosis in South America is associated with AIDS in 70–90 % of cases. It is visceral and cutaneous, compromising the oral, pharynx, and laryngeal mucous membranes. The involvement of the nasal mucosa is unusual. Two patients with perforation of the nasal septum as the only sign of their disease were clinically and histopathologically diagnosed as leishmaniasis. The revision of the biopsies and the culture of nasal discharge secretions showed that the pathogens seen were not amastigotes but Histoplasma capsulatum. Other mycotic lesions were not detected, nor there was history of cutaneous leishmaniasis. The leishmanin skin test, available only for the male patient, was negative. The PCR and immunofluorescence antibody titers for Leishmania were negative in both patients. They were HIV positive; in the male, his CD4+ T cell count was 60/mm³ and in the female 133/mm³. The nasal ulcer was the only manifestation of histoplasmosis and the first of AIDS in both patients. The male patient recovered with amphotericin B and itraconazole treatment. The female has improved with itraconazole. Both patients received antiretroviral treatment. Nasal mucous membrane ulcers should include histoplasmosis among the differential diagnosis. In conclusion, two patients had perforation of their nasal septum as the only manifestation of histoplasmosis, a diagnosis confirmed by nasal mucosa biopsy and by culture of H. capsulatum, findings which demonstrated that both patients had AIDS.     

Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil

Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.     

Disseminated histoplasmosis with lesions restricted to the larynx in a patient with AIDS. Report of a case and review of the literature

Histoplasmosis is an endemic and systemic mycosis, caused by the dimorphic fungus Histoplasma capsulatum var capsulatum. Disseminated disease in immunocompromised patients generally results from the reactivation of latent foci after a prolonged period of asymptomatic infection. We report a case of laryngeal histoplasmosis as the unique clinical manifestation of a progressive form of the disease in a patient with advanced HIV/AIDS disease. Histopathological analysis of laryngeal biopsy smears revealed granulomas containing Histoplasma-like organisms. Treatment with amphotericin B followed by itraconazole resulted in complete remission of laryngeal lesions. To our knowledge, this is the third case report of laryngeal histoplasmosis in a patient with AIDS.     

Risk Factors for Disseminated Histoplasmosis in a Cohort of HIV-Infected Patients in French Guiana

Disseminated histoplasmosis is the first AIDS-defining infection in French Guiana. A retrospective cohort study studied predictive factors of disseminated histoplasmosis in HIV-infected patients between 1996 and 2008. Cox proportional hazards models were used. The variables studied were age, sex, last CD4/CD8 count, CD4 nadir, herpes or pneumocystosis, cotrimoxazole and fluconazole use, antiretroviral treatment and the notion of recent initiation of HAART. A total of 1404 patients were followed for 6833 person-years. The variables independently associated with increased incidence of disseminated histoplasmosis were CD4 count<50 per mm3, CD4 count between 50 and 200 per mm3, a CD4 nadir <50 per mm3, CD8 count in the lowest quartile, herpes infection, and recent antiretroviral treatment initiation (less than 6 months). The variables associated with decreased incidence of histoplasmosis were antiretroviral treatment for more than 6 months, fluconazole treatment, and pneumocystosis. There were 13.5% of deaths at 1 month, 17.5% at 3 months, and 22.5% at 6 months after the date of diagnosis of histoplasmosis. The most important predictive factors for death within 6 months of diagnosis were CD4 counts and antiretroviral treatment. The present study did not study environmental/occupational factors but provides predictive factors for disseminated histoplasmosis and its outcome in HIV patients in an Amazonian environment during the HAART era.     

Gastrointestinal Histoplasmosis in a Hepatitis C-Infected Individual

Gastrointestinal histoplasmosis is a rare manifestation of this fungal infection, typically identified in immunocompromised patients, such as those with HIV/AIDS. Here, we report a case of disseminated histoplasmosis with gastrointestinal involvement in a Hepatitis C-infected patient. The fungal agent was confirmed to be Histoplasma capsulatum by a DNA probe assay performed on a bone marrow sample. We propose that this fungal disease should be kept on the differential of patients infected with the Hepatitis C virus, as it has been reported to have numerous damaging effects on the adaptive immune system.     

Histoplasmosis in a Brazilian center: clinical forms and laboratory tests

Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum, is endemic in many regions of the Americas, Asia and Africa. It has a wide spectrum of clinical manifestations, from asymptomatic infection to severe disseminated disease. A retrospective study was carried out to describe the clinical forms and assess the clinical significance of the laboratory diagnostic tests of patients with histoplasmosis during the period of July 1987 to December 2003 at Instituto de Pesquisa Clínica Evandro Chagas/ FIOCRUZ, RJ, Brazil. Seventy-four patients were included. Forty-nine percent of the cases (n = 36) occurred in HIV positive patients who presented with disseminated disease. The remaining 38 cases were classified in different clinical forms. Histoplasma capsulatum was isolated from 69.5% of the clinical specimens sent to culture. Immunodiffusion and immunoblot were positive in 72.6% and 100% of the performed tests, respectively. Histopathologic findings suggestive of H. capsulatum were found in 63.2% of the performed exams. Serology had a lower proportion of positivity amongst AIDS patients, when compared with HIV negative patients (X2 = 6.65; p lower than 0.008). Statistical differences between AIDS and non-AIDS patients were not observed with culture and histopathology. The specific role of each test varies according to the clinical form. Physicians need to know the value and limitations of the available diagnostic tests, but before that, they have to think about histoplasmosis and consider this clinical entity in their differential diagnosis.     

Cerebrospinal fluid miRNA profile in HIV‐encephalitis

MicroRNAs are short non‐coding RNAs that modulate gene expression by translational repression. Because of their high stability in intracellular as well as extracellular environments, miRNAs have recently emerged as important biomarkers in several human diseases. However, they have not been tested in the cerebrospinal fluid (CSF) of HIV‐1 positive individuals. Here, we present results of a study aimed at determining the feasibility of detecting miRNAs in the CSF of HIV‐infected individuals with and without encephalitis (HIVE). We also evaluated similarities and differences between CSF and brain tissue miRNAs in the same clinical setting. We utilized a high throughput approach of miRNA detection arrays and identified differentially expressed miRNAs in the frontal cortex of three cases each of HIV+, HIVE, and HIV? controls, and CSF of 10 HIV‐positive and 10 HIV‐negative individuals. For the CSF samples, the group of HIV+ individuals contained nine cases of HIV‐associated neurological disorders (HAND) and, among those, four had HIVE. All the HIV‐negative samples had non‐viral acute disseminate encephalomyelitis. A total of 66 miRNAs were found differentially regulated in HIV+ compared to HIV? groups. The greatest difference in miRNA expression was observed when four cases of HIVE were compared to five non‐HIVE cases, previously normalized with the HIV‐negative group. After statistical analyses, 11 miRNAs were fund significantly up‐regulated in HIVE. Although more clinical samples should be examined, this work represents the first report of CSF miRNAs in HIV‐infection and offers the basis for future investigation. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.     

Gastrointestinal disseminated histoplasmosis in HIV-infected patients: A descriptive and comparative study

Disseminated histoplasmosis is one the main AIDS-defining opportunistic infections in HIV-infected patients, notably in Latin America. The non-specific and proteiform clinical presentation leads to diagnostic delays that may lead to fatal outcomes. This retrospective multicentric study aimed to describe the frequency and manifestations of gastrointestinal histoplasmosis in French Guiana, and to compare patients with disseminated histoplasmosis with or without gastrointestinal involvement.Between January 1, 1981 and October 1, 2014 co-infections with HIV and histoplasmosis were enrolled. Inclusion criteria were: age >18 years, confirmed HIV infection; first proven episode of histoplasmosis.Among 349 cases of disseminated histoplasmosis, 245 (70%) had a gastrointestinal presentation. Half of patients with gastrointestinal signs had abdominal pain or diarrhea, mostly watery. Half of patients with abdominal pain had diarrhea (63/124) and half of those with diarrhea (63/123) had abdominal pain. A significant proportion of patients also had hepatomegaly and, to a lesser degree, splenomegaly. After adjusting for potential confounding, the presence of lymphadenopathies >2cm (AOR = 0.2, IC95 = 0.04–0.7, P = 0.01), Haitian origin (AOR = 0.04, IC95 = 0.004–0.4, P = 0.006) were associated with a lower prevalence of gastrointestinal signs and positive gastrointestinal presence of H. capsulatum. Persons with a gastrointestinal H. capsulatum were more likely to have a decreased prothrombin time, lower ferritin, lower liver enzymes, and lower concentrations of LDH than those without gastrointestinal signs and symptoms. They also had a shorter interval between symptoms onset and diagnosis. Patients with a positive gastrointestinal identification of H. capsulatum were less likely to die at 1 month than those without a gastrointestinal presentation (respectively, 4.6% vs 18.5%, P = 0.01).Subacute or chronic gastrointestinal presentations are very frequent during disseminated histoplasmosis, they seem less severe, and should lead to suspect the diagnosis in endemic areas. There were populational or geographic differences in the frequency of gastrointestinal manifestations that could not be explained.     

Histoplasmosis as cause of penile ulcer in acquired immune deficiency syndrome (AIDS): three case reports

Background Histoplasma capsulatum is the causative agent of American histoplasmosis. The relationship between disseminated histoplasmosis and AIDS has been well established. Widespread hematogenous dissemination of Histoplasma capsulatum in HIV positive patients can cause a plethora of clinical manifestations; virtually any organic system can be affected. However, genital ulceration by H. capsulatum in patients with AIDS is a real challenge during investigation of the infection due to the great variety of differential diagnoses that are involved. Method The diagnosis was performed by histopathologic study; H. capsulatum was detected by silver staining (Grocott staining) and confirmed by immunocytochemistry. Results We report three cases of histoplasmosis in patients with AIDS, in which we observed genital ulcers, an unusual form of presentation of this disease. In one of these cases, the treatment resulted in total cure. Conclusion The cases reported herein are to illustrate the plurality of pathologies and clinical manifestations, which may affect immunocompromised patients. The correct diagnosis of fungal diseases in these patients following well established treatment will improve the prognosis.     

Histoplasmosis: cytodiagnosis and review of literature with special emphasis on differential diagnosis on cytomorphology

N. Gupta, S. K. Arora, A. Rajwanshi, R. Nijhawan and R. Srinivasan
Histoplasmosis: cytodiagnosis and review of literature with special emphasis on differential diagnosis on cytomorphology Background: Human infection with Histoplasma capsulatum runs the gamut from asymptomatic to disseminated disease. In immunocompromised patients, a tiny inoculum can lead to widespread disseminated infection. Early diagnosis and initiation of treatment is therefore important. Objective: To review the cases of histoplasmosis diagnosed on fine needle aspiration cytology (FNAC) and to discuss the clinical presentation, associated inflammatory response, load of organisms and differential diagnosis on cytomorphology in these cases. Methods: Retrospective review of seven cases of histoplasmosis at a tertiary‐care centre during the period from 1998 to 2009 was performed. Clinical presentation along with cytomorphological features were studied and discussed in detail. Results: The mean age of patients was 48.6 years and six out of seven were male. History of immunodeficiency (HIV) was available in five cases. Six patients presented with peripheral and/or abdominal lymphadenopathy. One patient had nodular shadows in both lungs and two also had skin lesions. On cytological smears, a variable load of uniform round to oval, about 2–4 μm in diameter, budding yeasts were seen intracellularly (within histiocytes) as well as extracellularly. In one case (HIV positive), these organisms were also seen within neutrophil polymorphonuclear leucocytes. In two cases, an inflammatory response in the form of epithelioid cell granulomas along with multinucleated giant cells was seen. Conclusions: FNAC is a reliable tool to recognize infection with H. capsulatum in tissues. This infection can cause a variable inflammatory response, which should be considered while reporting on such cases.     

Diagnosis and management of histoplasmosis

Histoplasmosis occurs sporadically or during outbreaks in endemic areas. The risk for severe forms of histoplasmosis is substantially higher among the growing population of immunocompromised patients. Recent research efforts have focused on analyzing epidemics, identifying risk factors for the disease, developing improved noninvasive diagnostic assays, and assessing the roles of newer antifungal drugs. Guidelines have been published for the prevention of occupationally acquired histoplasmosis and for reducing the risk of disease in patients with HIV infection. A third-generation Histoplasma antigen assay has been developed, which has superior performance characteristics compared to other noninvasive diagnostic tests. Treatment guidelines for the various clinical forms of histoplasmosis have been formulated and updated. Two newer azoles with activity against Histoplasma capsulatum, voriconazole and posaconazole, have been released; in vitro susceptibility data and animal model results have been reported, and treatment experience with these drugs has accumulated.     

Histoplasmosis in HIV-Infected Patients: Epidemiological,Clinical and Necropsy Data from a Brazilian Teaching Hospital

Histoplasmosis occurs in 5–10% of HIV-infected patients in endemic areas and evolves to severe and disseminated infection with mortality rates over 50% in some regions. This report presents epidemiological, clinical and outcome data from HIV-infected patients with histoplasmosis confirmed by culture and/or at necropsy who were admitted to a Brazilian teaching hospital. Data from 65 patients were obtained from their respective medical and necropsy records. From 2005 to 2018, 36 HIV-infected patients were diagnosed with histoplasmosis confirmed by culture. At admission, most of these patients presented disseminated fungal infection, whereas 15 (41.7%) were simultaneously diagnosed with both HIV infection and histoplasmosis. Fever, weight loss, hepatosplenomegaly, respiratory and digestive symptoms were present in 86.2%, 50%, 44.4% and 41.7% of the patients, respectively. At admission, 24 patients had low CD4 T-cell count and high viral load values. Among the 30 patients who received antifungals, 16 (53.3%) were cured, 13 (43.3%) died, and one was lost to follow-up. Six patients died prior to therapy. From 1990 to 2018, 63 necropsies of patients with Histoplasma capsulatum infection were performed. Of these patients, 29 (46.0%) were HIV-infected individuals, including 21 (72.4%) who presented disseminated histoplasmosis and 21 (72.4%) who were diagnosed with histoplasmosis at necropsy. The epidemiological, clinical and outcome profiles presented herein are similar to those described elsewhere and reinforce the difficulties that are still present in limited-resource settings where advanced immunodeficiency, combined with severe fungal infection and late patient admissions, is related to poor outcomes.

     

Opportunistic invasive mycoses in AIDS. An autopsy study of 211 cases.

The opportunistic mycoses are an important cause of morbidity-mortality among patients with severe immunosuppression provoked by HIV. We present a study of 211 serial autopsies of patients with HIV/AIDS infection carried out by our service in a period of 10 years, observing frequency of invasive mycoses of the 44.1%. Pneumocystis carinii infection was the most frequent (32%) with a prevalence of lung affection. Candidiasis follows it in order of frequency with 31.1%, predominantly the oropharyngeal manifestation. Systemic or cerebromeningeal cryptococcosis were serious and common disorder (29%). Diseminated histoplasmosis occurred in 9.6% and in three cases (3.2%) pulmonary aspergillosis was diagnosed as a postmortem discovery in cavity lesions. In our series, other less common HIV-associated were not identified.     

不同人类免疫缺陷病毒感染途径群体中戊型肝炎病毒的流行情况

本研究旨在了解不同人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染途径群体中戊型肝炎病毒(hepatitis E virus,HEV)抗体情况,探讨HEV疫苗接种的必要性。采集HIV感染者的血清或血浆,利用酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)检测HEV IgG抗体、IgM抗体及抗原,荧光定量聚合酶链反应(polymerase chain reaction,PCR)检测HEV核酸,Roche高纯化HIV-1核酸定量检测试剂盒(PCR荧光法)检测HIV感染者的HIV载量。比较分析不同HIV感染途径群体中HEV流行率的差别。结果显示,HIV感染者中HEV IgG抗体的阳性率为37.4%,静脉吸毒、成分献血和传播途径不明HIV感染群体的HEV IgG抗体阳性率分别为49.3%、39.5%和30.4%。HEV核酸荧光PCR检测结果均为阴性。3种HIV感染群体之间HEV IgG抗体阳性率差异无统计学意义(χ~2=2.978,P0.05)。HEV IgG阳性与阴性感染者之间HIV载量差异无统计学意义(P0.05)。结果提示,为保护HIV感染者免受HEV感染,应考虑接种HEV疫苗。     

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study

BackgroundHistoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions.MethodologyWe conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation.Principal findingsEvidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections.ConclusionsThe high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon.     

Beneficial effect of GB virus C co-infection in Human Immunodeficiency Virus type 1-infected individuals

Several reports have documented a better prognosis for HIV‐1‐infected patients co‐infected with GBV‐C, while other reports have contradicted such findings with the result that this issue remains controversial. We attempted to clarify the complicated status of the effect of GBV‐C co‐infection on HIV‐1‐infected patients. GBV‐C RNA was detected in 37 samples in 182 HIV‐1‐infected patients (20.3%) using RT/nested PCR. Of these, 3 were determined to be GBV‐C genotype 1, 12 were genotype 2, and the remaining 22 were genotype 3. The GBV‐C viral load quantified by real‐time PCR ranged from 7.8 × 10³ to 3.3 × 10⁶ copies/ml. Weakly negative correlation was observed between GBV‐C viral load and HIV‐1 viral load in 19 HAART‐naïve patients, indicating that a higher GBV‐C viral load is associated with a greater suppression of HIV‐1 replication. A previously published in vitro study suggested that GBV‐C infection would induce up‐regulation of RANTES, leading to suppression of HIV‐1 replication. However, in our present study, the blood RANTES level was significantly lower in the GBV‐C co‐infected group than in the uninfected group (190–9,959 vs. 264–31,038 pg/ml, P=0.004). Our results suggested that a suppression of HIV‐1 replication by GBV‐C co‐infection is not mediated by up‐regulated RANTES, and thus call for another as yet unknown factor.