|Year : 2022 | Volume
| Issue : 2 | Page : 98-102
Disseminated Histoplasmosis in HIV patients- Case series from a single tertiary care centre in India
Sumit Arora1, Kuldeep K Ashta1, Syed Asif Hashmi2, N Arun1, Sharmila Dudani2
1 Department of Medicine, ACMS and Base Hospital, New Delhi, India
2 Department of Pathology, ACMS and Base Hospital, New Delhi, India
|Date of Submission||21-Mar-2021|
|Date of Decision||06-Dec-2021|
|Date of Acceptance||20-Dec-2021|
|Date of Web Publication||02-Mar-2022|
Dr. Sharmila Dudani
Department of Pathology, ACMS and Base Hospital, Delhi Cantt, New Delhi
Source of Support: None, Conflict of Interest: None
Introduction: HIV-positive patients are at risk of developing various opportunistic infections, including disseminated histoplasmosis, the incidence of which is 29% in India. Diagnosis is usually delayed as the clinical manifestations are diverse and mimic other common diseases endemic to this region such as tuberculosis and visceral leishmaniasis. This leads to preventable morbidity and mortality. Materials and Methods: We carried out a retrospective data analysis of 1280 HIV positive patients' who were on treatment at our centre between 2016 and 2020., of which 8 cases of confirmed histoplasmosis were identified. The clinicopathological spectrum and outcomes of these patients were analyzed and presented as a case series. Results: The median age of patients was 39.5 years. In six out of eight patients, disseminated histoplasmosis was the initial presentation of HIV. Fever, weight loss, macular-papular skin lesions, bicytopenia, and respiratory system involvement were the most common clinical manifestations. Pulmonary lesions included patchy areas of consolidation, miliary nodules, and pleural effusion. Gastrointestinal symptoms were uncommon. In six out of eight patients, CD4 count was <50/mm3. The median CD4 count and median HIV RNA at presentation were 21.5 per mm3 (interquartile range [IQR]: 12–54) and 2.98 × 105 copies/ml (IQR: 1.24 × 104–5.33 × 106), respectively. Diagnosis in all cases was made by direct visualization of the fungus on biopsy. Most patients responded to L-amphotericin or itraconazole. Three out of eight patients expired due to septic shock following disseminated disease. Conclusion: A high index of clinical suspicion along with early institution of therapy is essential to reduce mortality.
Keywords: Disseminated histoplasmosis, HIV, immunodeficiency, India
|How to cite this article:|
Arora S, Ashta KK, Hashmi SA, Arun N, Dudani S. Disseminated Histoplasmosis in HIV patients- Case series from a single tertiary care centre in India. APIK J Int Med 2022;10:98-102
|How to cite this URL:|
Arora S, Ashta KK, Hashmi SA, Arun N, Dudani S. Disseminated Histoplasmosis in HIV patients- Case series from a single tertiary care centre in India. APIK J Int Med [serial online] 2022 [cited 2022 May 26];10:98-102. Available from: https://www.ajim.in/text.asp?2022/10/2/98/338900
| Introduction|| |
Histoplasmosis, a fungal disease caused by Histoplasma capsulatum, is found in soils worldwide.,,,,, It exists in a filamentous saprophytic form in the environment and a parasitic yeast form in tissue and body fluids. The filamentous form may contain both microconidia and macroconidia, which are smooth walled, infectious with a diameter of 2–4 μ. The yeast forms are small, budding seen within the macrophages.
Histoplasmosis in immunocompetent patients is usually endemic to certain parts of the world and may be asymptomatic or self-limiting with low morbidity and mortality. However, in patients with HIV, it is symptomatic, disseminated in 95% of cases, and usually fatal in the absence of appropriate treatment. Mortality from histoplasmosis in HIV ranges from 10% to 40%. Disseminated histoplasmosis (extrapulmonary form) has been included as an AIDS-defining infection.
Patients with HIV are at high risk for opportunistic infections, including disseminated histoplasmosis, with prevalence rates in the general population ranging from 2% to 27% in the USA and 29% in India., There have been 388 cases reported from India (including both immunocompetent and immunocompromised patients) from 1995 to 2016 from isolated parts of the country, especially from the Gangetic plains of West Bengal. Immunocompromised states included diabetes, HIV, adrenal insufficiency, and renal transplant associated. Most of the cases have been reported during the last two decades, reflecting increased awareness among physicians and the availability of better diagnostic modalities for diagnosing the disease. Approximately 35 cases have also been reported from Bangladesh, Nepal, Pakistan, and Sri Lanka.
High diversity is seen to exist in infectivity, pathogenesis, virulence, and clinical spectrum of different strains of histoplasmosis worldwide coupled with the host's immune status, which gives rise to protean manifestations. The actual burden of histoplasmosis in HIV patients in India is not completely understood both due to inadequate knowledge and lack of disease recognition by physicians since it is frequently misdiagnosed for common endemic infections such as tuberculosis or leishmaniasis, which are prevalent in the country, as well as malignancy. Although isolated case reports of histoplasmosis in HIV from India are available, this case series is a retrospective analysis of the clinicopathological spectrum and outcomes of disseminated histoplasmosis exclusively in HIV patients treated at our center.
| Materials and Methods|| |
Approval from the Institutional Ethics Committee was obtained, and an observational, retrospective single-center study in accordance with the tenets of the Declaration of Helsinki was undertaken wherein we analyzed the clinical [Figure 1]a, radiological [Figure 1d]] laboratory, immunovirological, therapeutic, and survival data of 1280 HIV-positive patients who were on treatment between 2016 and 2020, of which eight patients were diagnosed with disseminated histoplasmosis. Archived materials (X-rays and slides) of these patients were also reviewed.
|Figure 1: a) Papular skin eruptions over face. b) BM aspirate. Histiocyte showing numerous smooth walled intracellular yeast forms of Histoplasma. MGG stain 1000 X. c) Transbronchial lung biopsy - Interstial thickening with lympho histiocytic infiltrate and yeast forms of Histoplasma. H&E stain. 400 X. d) CT abdomen. Hepatosplenomegaly with multiple splenic nodules|
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Diagnosis in all cases was made by visualization of the organisms by pathological examination of various biopsy materials from skin, transbronchial lung tissue, palatal ulcer, and bone marrow [Figure 1]b and [Figure 1]c. Only proven incident cases of histoplasmosis were included. Patients who responded with empirical antifungal treatment after a suspected diagnosis were excluded from this study. CD4 counts were determined by using BD FACSCanto II flow cytometry (BD Biosciences, USA) and HIV viral load (reverse transcription-polymerase chain reaction [PCR]) by GeneXpert system (CBNAAT), Cepheid India Pvt. Ltd.
Direct examination of pathological tissue smears by staining with May–Grunwald–Giemsa was done in all patients. In the case of tissue sections staining by hematoxylin and eosin (H and E), periodic acid–Schiff and Gomori's methenamine silver were used. Histoplasma was identified by visual detection of the yeast forms as 2–4 μ round-to-oval macroconidia with clear halo within macrophages.
Culture could not be done in all patients. Histoplasma antigen detection assays, Polymerase chain reaction (PCR). Serologic studies and skin testing (histoplasmin test) were not employed. Consent for the use of anonymized data for publication and educational purposes was obtained from all HIV patients at the time of the first enrollment at the clinic.
| Results|| |
Among the 1280 HIV patients whose data were reviewed, 8 patients presented with disseminated histoplasmosis. The clinical case summary of all the patients is outlined in [Table 1]. Histoplasmosis was the first presentation of HIV seen in six out of eight patients, and one patient presented with Histoplasma IRIS manifesting within 6 months of starting ART. The median age of patients was 39.5 years (interquartile range [IQR]: 30–56). Seven patients were males.
|Table 1: Clinicopathological summary of HIV patients' with Histoplasmosis|
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All patients had multisystem involvement at the time of presentation, with some constitutional symptoms such as fever, weight loss, or anorexia present in all cases. Hematological (six patients), mucocutaneous (four), and respiratory system (four) involvement were the most common systemic manifestations.
The median CD4 count was 21.5 per mm3 (IQR: 12–54), and the median HIV RNA at presentation was 2.98 × 105 (IQR: 1.24 × 104–5.33 × 106).
All patients were given amphotericin B or itraconazole, or both. Four patients recovered. One patient (Case 6) was lost to follow-up. Mortality was seen in three patients due to multiorgan failure following septic shock. One of these patients died of disseminated histoplasmosis with superimposed SARS-COV-2 pneumonia.
| Discussion|| |
H. capsulatum, a fungus found in moist, fertile soil contaminated by bat/bird droppings, was first described by Darling in 1906, wherein he referred to it as a parasitic disease similar to kala-azar reported from India. The first case of Histoplasma from India was reported by Panja and Sen in 1954.
Disseminated histoplasmosis may affect multiple organs,, and the clinical manifestations vary depending on the patients' immune status and chronicity of infection. As per some studies, male HIV patients appear to have a greater risk of histoplasmosis and suffer higher mortality. However, this was not corroborated in a similar study from the USA. All our patients had multisystem involvement at the time of presentation.
The median age of our cohort was higher at 39.5 years as compared to 29 years, as reported by Bonifaz et al., reflecting that possibly the infection was acquired at an older age. Patients commonly present with nonspecific symptoms such as fever, anorexia, fatigue, and weight loss, making clinical diagnosis challenging and delayed. All our patients had at least two constitutional symptoms at the time of presentation.
H. capsulatum is believed to have a predilection for the reticuloendothelial system, and thus, hepatosplenomegaly is a prominent feature, as was observed in three of our patients (Cases 2, 4, and 8) [Figure 1]d. Hematologic abnormalities in the form of anemia, bicytopenia, or pancytopenia were found to be the most common systemic findings seen in six of our patients. Three out of 8 patients were diagnosed on bone marrow evaluation [Figure 1]b.
Pulmonary manifestations were the second most common systemic involvement present in four out of eight cases (Cases 1, 2, 7, and 8), though only one patient was symptomatic with cough and dyspnea. Miliary lung opacities were the most common finding seen in three out of these four patients. Other studies have also reported similar findings, with 50% of histoplasmosis patients with HIV infection presenting with respiratory system involvement. Isolated pulmonary involvement has been described in patients with CD4 count <200/mm3, wherein it may need to be differentiated from Pneumocystis jirovecii infection. One of our patient presented with miliary pattern of lung involvement on Chest X-ray, and diagnosis could only be confirmed by lung biopsy. [Figure 1]c.
Mucocutaneous lesions have been studied extensively and frequently reported from South America but are very uncommon in North America., This raises the possibility of differing virulence of Histoplasma strains among different continents., It is believed that strains from S. America are more dermotrophic than those prevalent in N.America. Mucocutaneous lesions have been described to appear late in the disease, reflecting an advanced stage of immunosuppression, and also to considerably vary in their morphologic appearance and distribution. Skin lesions have been classically described as molluscum-like lesions. Dermatological presentation of histoplasmosis also includes papules, nodules, vesicles, erosions, ulcers, or ulcero-cutaneous lesions of the oral or nasal mucosa. Crusting plaques have also been described. Lesions may be isolated or multiple, localized, or diffuse., The polymorphism seen in skin lesions makes the clinical diagnosis of histoplasmosis difficult based on dermatological examination alone; it nevertheless represents an easily accessible site for tissue biopsy and diagnosis. In our study, three patients (Cases 2, 5, and 7) [Figure 1]a presented with a papular skin rash, of which one was typically molluscum like and the diagnosis was confirmed by skin biopsy. One patient (Case 6) had a palatal ulcer, and diagnosis of histoplasmosis was made by biopsy of the ulcer. We did not observe any other erosions or nodular/vesicular lesions.
Mucocutaneous lesions were more likely to be diagnosed by direct examination rather than fungal culture, as observed in the present case series as well. They were likely to be associated with more profound immunosuppression and risk of early death.
It has been reported that patients with mucocutaneous lesions were less likely to develop gastrointestinal (GI) symptoms. This was also observed by us. Patients with GI symptoms (Case 1 and 4) did not manifest with any skin lesions though statistical conclusions cannot be derived from such small numbers.
Neurological manifestations have been uncommonly described in only 10%–20% of patients. These include chronic meningitis, cerebral vasculitis with stroke, encephalitis, and isolated spinal cord involvement., We observed delirium, urinary incontinence, and neck rigidity in Case 7 only, whereas altered sensorium was a late manifestation seen in patients with multiorgan failure due to septic shock.
Endocardial involvement and adrenal insufficiency may also be seen, the latter being more common in immunocompetent patients. None of our patients developed adrenal or cardiac involvement. Approximately 10%–20% of patients with disseminated histoplasmosis may present with septic shock, DIC, and multiorgan failure with high mortality. Three of our eight patients developed septic shock, and all three succumbed to it (Cases 3, 5, and 8).
An independently increased incidence of disseminated histoplasmosis is observed when CD4 counts <50 per mm3,, which may be responsible for the disseminated manifestations. Our study also revealed similar findings. The median CD4 count of all our patients was 21.5 per mm3 (IQR: 12–54), and 6/8 patients had a CD4 count <50 per mm3. The median CD4 counts of patients who died following severe disseminated sepsis were 17 per mm3 (IQR: 12–24).
In the era of availability of HAART, early diagnosis and institution of treatment by amphotericin B and itraconazole have provided promising results and helped in recovery; studies have shown that a low CD4 count (<50/mm3), CD8 count (<650/mm3), male gender, and history of herpes simplex infections are independent host risk factors for developing histoplasmosis. These may be helpful pointers of disseminated histoplasmosis when an HIV-positive patient presents with multisystemic clinical manifestations, leading to early diagnosis and institution of appropriate treatment.
| Conclusion|| |
A high index of clinical suspicion needs to be maintained to diagnose histoplasmosis in HIV due to its nonspecific spectrum of manifestations and their resemblance to tuberculosis and kala-azar. Patients' living with HIV and AIDS (PLHA) with CD4 <100 cells / mm3 and presenting with a multisystem involvement should always be evaluated and the diagnosis confirmed by histopathology or other confirmatory methods to look for histoplasmosis among other differential diagnoses. Newer, faster, and simpler modalities of diagnosis like urinary Histoplasma antigen are urgently needed to prevent delay in diagnosis.
The study is limited by the small number of cases and the retrospective nature of data. Occupation of these patients involving activities with soil, or poultry, if any, was not available. The travel history of this cohort to any endemic histoplasmosis region was not available. CD8 counts and history of herpes simplex infection also were not available.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, Eads ME, Israel KS, et al.
Disseminated histoplasmosis in the acquired immune deficiency syndrome: Clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-74.
Huber F, Nacher M, Aznar C, Pierre-Demar M, El Guedj M, Vaz T, et al.
AIDS-related Histoplasma capsulatum
var. capsulatum infection: 25 years experience of French Guiana. AIDS 2008;22:1047-53.
Arango M, Castañeda E, Agudelo CI, De Bedout C, Agudelo CA, Tobón A, et al.
Histoplasmosis: Results of the Colombian national survey, 1992-2008. Biomedica 2011;31:344-56.
Pan B, Chen M, Pan W, Liao W. Histoplasmosis: A new endemic fungal infection in China? Review and analysis of cases. Mycoses 2013;56:212-21.
Peigne V, Dromer F, Elie C, Lidove O, Lortholary O; French Mycosis Study Group. Imported acquired immunodeficiency syndrome-related histoplasmosis in metropolitan France: A comparison of pre-highly active anti-retroviral therapy and highly active anti-retroviral therapy eras. Am J Trop Med Hyg 2011;85:934-41.
Ashbee HR, Evans EG, Viviani MA, Dupont B, Chryssanthou E, Surmont I, et al.
Histoplasmosis in Europe: Report on an epidemiological survey from the European Confederation of Medical Mycology Working Group. Med Mycol 2008;46:57-65.
Kauffman CA. Histoplasmosis: A clinical and laboratory update. Clin Microbiol Rev 2007;20:115-32.
Couppié P, Aznar C, Carme B, Nacher M. American histoplasmosis in developing countries with a special focus on patients with HIV: Diagnosis, treatment, and prognosis. Curr Opin Infect Dis 2006;19:443-9.
Centers for Disease Control (CDC). Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR Suppl 1987;36 Suppl I:1S-15S.
Randhawa HS, Khan ZU. Histoplasmosis in India: Current status. Indian J Chest Dis Allied Sci 1994;36:193-213.
Randhawa HS, Gugnani HC. Occurrence of histoplasmosis in the Indian sub-continent: An overview and update. J Med Res Pract 2018; 7: 71-83. [doi: 10.20936/jm].
Gupta A, Ghosh A, Singh G, Xess I. A twenty-first-century perspective of disseminated histoplasmosis in India: Literature review and retrospective analysis of published and unpublished cases at a tertiary care hospital in North India. Mycopathologia 2017;182:1077-93.
Edwards JA, Rappleye CA. Histoplasma mechanisms of pathogenesis – One portfolio doesn't fit all. FEMS Microbiol Lett 2011;324:1-9.
Mahajan VK, Raina RK, Singh S, Rashpa RS, Sood A, Chauhan PS, et al.
Case report: Histoplasmosis in Himachal Pradesh (India): An emerging endemic focus. Am J Trop Med Hyg 2017;97:1749-56.
Darling ST. The morphology of the parasite (Histoplasma capsulatum
) and the lesions of histoplasmosis, a fatal disease of tropical America. J Exp Med 1909;11:515-31.
Panja G, Sen S. A unique case of histoplasmosis. J Indian Med Assoc 1954;23:257-8.
Assi MA, Sandid MS, Baddour LM, Roberts GD, Walker RC. Systemic histoplasmosis: A 15-year retrospective institutional review of 111 patients. Medicine (Baltimore) 2007;86:162-9.
Goodwin RA Jr., Shapiro JL, Thurman GH, Thurman SS, Des Prez RM. Disseminated histoplasmosis: Clinical and pathologic correlations. Medicine (Baltimore) 1980;59:1-33.
Nacher M, Adenis A, Adriouch L, Dufour J, Papot E, Hanf M, et al.
What is AIDS in the amazon and the guineas? Establishing the burden of disseminated histoplasmosis. Am J Trop Med Hyg 2011;84:239-40.
McKinsey DS, Spiegel RA, Hutwagner L, Stanford J, Driks MR, Brewer J, et al.
Prospective study of histoplasmosis in patients infected with human immunodeficiency virus: Incidence, risk factors, and pathophysiology. Clin Infect Dis 1997;24:1195-203.
Bonifaz A, Chang P, Moreno K, Fernández-Fernández V, Montes de Oca G, Araiza J, et al.
Disseminated cutaneous histoplasmosis in acquired immunodeficiency syndrome: Report of 23 cases. Clin Exp Dermatol 2009;34:481-6.
Adenis AA, Aznar C, Couppié P. Histoplasmosis in HIV-infected patients: A review of new developments and remaining gaps. Curr Trop Med Rep 2014;1:119-28.
Wheat J. Endemic mycoses in AIDS: A clinical review. Clin Microbiol Rev 1995;8:146-59.
Hajjeh RA, Pappas PG, Henderson H, Lancaster D, Bamberger DM, Skahan KJ, et al.
Multicenter case-control study of risk factors for histoplasmosis in human immunodeficiency virus-infected persons. Clin Infect Dis 2001;32:1215-20.
Gutierrez ME, Canton A, Sosa N, Puga E, Talavera L. Disseminated histoplasmosis in patients with AIDS in panama: A review of 104 cases. Clin Infect Dis 2005;40:1199-202.
Durkin MM, Connolly PA, Karimi K, Wheat E, Schnizlein-Bick C, Allen SD, et al.
Pathogenic differences between North American and Latin American strains of Histoplasma capsulatum
var. capsulatum in experimentally infected mice. J Clin Microbiol 2004;42:4370-3.
Cunha VS, Zampese MS, Aquino VR, Cestari TF, Goldani LZ. Mucocutaneous manifestations of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome: Particular aspects in a Latin-American population. Clin Exp Dermatol 2007;32:250-5.
Karimi K, Wheat LJ, Connolly P, Cloud G, Hajjeh R, Wheat E, et al.
Differences in histoplasmosis in patients with acquired immunodeficiency syndrome in the United States and Brazil. J Infect Dis 2002;186:1655-60.
Morote S, Nacher M, Blaizot R, Ntab B, Blanchet D, Drak Alsibai K, et al
. Comparison of disseminated histoplasmosis with and without cutaneo-mucous lesions in persons living with HIV in French Guiana. J Fungi (Basel) 2020;6:133.
Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40:844-52.
Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum
infections of the central nervous system. A clinical review. Medicine (Baltimore) 1990;69:244-60.
Wheat LJ, Chetchotisakd P, Williams B, Connolly P, Shutt K, Hajjeh R. Factors associated with severe manifestations of histoplasmosis in AIDS. Clin Infect Dis 2000;30:877-81.