Mycopathologia DOI 10.1007/s11046-015-9892-3
Cutaneous Manifestation of Underlying Disseminated Histoplasmosis in an Immunocompetent Host of Nonendemic Area with Reversible CD4 Cell Depletion and its Recovery on Antifungal Therapy Praveen Bharti . Kiran Bala . Naresh Gupta
Received: 13 February 2015 / Accepted: 6 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract We present the case of an 18-year-old male patient admitted with complaints of fever and rapid weight loss since 3 months. Patient had multiple umbilicated papular to nodular lesions over chin and forehead region. Complete blood count revealed bicytopenia. An excisional biopsy of the skin lesions had revealed cutaneous histoplasmosis. On further investigations for bicytopenia, histoplasmosis had been diagnosed on bone marrow trephine biopsy. For the immune status, patient’s serology against HIV was negative and his CD4 lymphocyte counts were low at 161. Patient received antifungal therapy including amphotericin B and itraconazole. He showed remarkable improvement in his general condition and blood counts. A repeat CD4 count showed normal counts, and idiopathic CD4 lymphocytopenia was excluded. Disseminated histoplasmosis presenting as cutaneous lesions in an immunocompetent host is very rare, and we are not aware of any case report in the literature where there is reversible depletion of CD4 counts following antifungal treatment in an immunocompetent host of nonendemic area. P. Bharti (&) N. Gupta Department of General Medicine, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi 110002, India e-mail: [email protected] K. Bala Department of Microbiology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
Keywords Disseminated histoplasmosis CD4 count Cutaneous Amphotericin B
Introduction Histoplasmosis is an endemic mycosis and a disease of worldwide occurrence which is most prevalent in the Ohio and Mississippi river valleys of North America, though there are rare reports of these mycoses from nonendemic regions too [1–3]. In India, endemic cases of histoplasmosis have been reported in West Bengal (eastern India) [4, 5] and sporadic cases have been reported in southern India [6, 7]. Further reports of histoplasmosis in nonendemic regions are very rare [3]. Although histoplasmosis occurs most commonly in immunosuppressed patients [8], there are a few case reports of this disease in immunocompetent hosts [9, 10]. Disseminated histoplasmosis is also associated with a condition called idiopathic CD4 cell lymphocytopenia, but has never been reported in a patient with transient CD4 cell depletion. We hereby report a case where disseminated histoplasmosis occurred in a patient with low CD4 count but completely recovered following antifungal therapy.
Case Report An 18-year-old male patient presented to our hospital with complaints of low-grade fever, loss of appetite
123
Mycopathologia
and significant weight loss in past 3 months. He also had a past history of recurrent oral ulcers and skin lesions which he did not notice much and was saying to have since a long duration. There was no history of tuberculosis, diabetes or any other chronic systemic illness. He was a nonsmoker with no history of any addictions, high-risk behaviour, promiscuous sexual activities and blood transfusion. On examination, the patient was of thin built male with stable vitals. There were multiple umbilicated papular to nodular lesions over forehead and chin, without any erythema or tenderness (Fig. 1). There was mild splenomegaly on abdominal examination. Rest of the systemic examination revealed no abnormality. On further investigations, the complete blood count revealed bicytopenia Hb 7.2 gm %; TLC 3200/mm3; DLC-Polymorphonuclear cells 75, lymphocytes 20, eosinophils 2, monocytes 3; platelet count 2.5 lakh; ESR 38; total protein 7.5 gm, with albumin levels of 2.5 mg. Other biochemical tests were normal. Sputum examination was negative for bacteria on Gram and acid fast staining. Chest X-ray was normal; however, the CECT chest revealed left hilar and pre-tracheal lymphadenopathy with the foci of calcification. Ultrasound of whole abdomen confirmed splenomegaly. Skin biopsy showed ill-defined noncaseating granulomas with macrophages and numerous oval, 2–4 mm, intracellular, narrow-based budding yeast-like cells; yeast forms of Histoplasma capsulatum (Fig. 2). Bone marrow aspiration and biopsy showed normal haematopoiesis with the presence of similar yeast forms of Histoplasma capsulatum (Fig. 3). The potassium hydroxide wet mount and Gram’s stain of biopsy sample also showed the morphologically similar yeast cells.
The fungal culture was sterile after 6–8 weeks of incubation. The ELISA for Histoplasma capsulatum (Focus diagnostics HistoplasmaTM Dx select, EL 1700) was performed. The ELISA was reactive for Histoplasma antibodies with index value of 2.20 (sensitivity— 86.3 %; specificity—83.9 %). The patient was thus diagnosed as a case of disseminated histoplasmosis and then underwent further series of investigations to look for any underlying immune dysfunction. Serology against HIV 1 and 2 was negative on two occasions. The immune status of the patient was studied in terms of lymphocyte subclasses, with the following results: CD4 counts were low, 161 cells/L (normal range 400–2100) and CD8, 848 cells/L (normal value, 200–1200); the ratio of CD4 and CD8 was low 0.2 (normal value, 0.9 to 3.4). Immunoglobulin levels were normal, IgG 803.4 mg/dl (normal range 789–2630), IgA 179.9 mg/ dl (normal value, 111–403) and IgM 50.4 mg/dl (normal value, 48–265); IgE 34.8 lI/ml (normal range 1.3–165.3). Likewise, when assessing complement fractions, C3 32.7 mg/dl and C4 43.9 mg/dl, levels were within normal limits. Patient was started on amphotericin B at a dose of 0.5 mg/kg/day with gradual escalation up to 1 mg/ kg/day for 4 weeks, and then, itraconazole was given daily per oral at dose of 200 mg for 3 weeks. After 3 weeks, CD4 count was also repeated to exclude the possibility of idiopathic CD4 cell lymphocytopenia which was normal (CD4 584 cells/mm3). There was a marked improvement of his symptoms, and he was discharged on oral itraconazole. He visited again 3 weeks later with fading skin lesions and is on regular follow-up.
Discussion
Fig. 1 Photograph of patient having multiple papular to nodular skin lesions over chin
123
Histoplasmosis is an uncommon fungal disease caused by Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var duboisii [11, 12]. Yeast forms of this fungus replicate within the reticuloendothelial system and disseminate in the absence of a good immune status. Histoplasmosis presents clinically as acute or chronic pulmonary infection, disseminated histoplasmosis and mediastinal fibrosis. Histoplasmosis is rare, as it is thought to be endemic only in small regions in West Bengal in western India [4, 5]. However, sporadic cases from southern India have been reported. Our patient was a resident of a
Mycopathologia Fig. 2 Multiple ill-defined noncaseating granulomas present with yeast forms of Histoplasma capsulatum in the skin biopsy
Numerous intracellular Periodic Acid Schiff-posive rounded yeast cells within macrophages
Fig. 3 Normal haematopoiesis and macrophages with yeast form of Histoplasma capsulatum in bone marrow aspirate
nonendemic region of India. We believe that our patient had contracted the disease via inhalation of conidia of Histoplasma capsulatum present in the soil contaminated by the excreta of bats or birds [13]. Inhalation of either fungal conidia or mycelial fragments is the primary mode of infection for histoplasmosis. Immunocompetent hosts are able to control and limit infections of Histoplasma; however, hosts with defective cell-mediated immunity and those exposed to chemotherapeutic and immunosuppressive agents are at risk of developing progressive disseminated histoplasmosis involving the reticuloendothelial system, including the liver, spleen, kidney, lymph nodes,
bone marrow and mucocutaneous tissues [14]. It is also recognized as an AIDS-defining illness [1]. Histoplasmosis infection is often categorized as being present in an HIV-positive or HIV-negative individual, as there are differences in presentation and response to therapy. Histoplasmosis has also been described in patients with a condition called idiopathic CD4 lymphocytopenia. In our patient, we suspected this condition but the repeat count after 3 weeks came out to be normal; hence, this condition was ruled out. Very few articles have been published on disseminated histoplasmosis in immunocompetent from nonendemic regions of India such as Delhi [15, 16], Haryana [17, 18], Chandigarh [19], Uttarpradesh [20]. Twelve cases of disseminated histoplasmosis from north-western India had been diagnosed, and their antifungal susceptibilities were performed [21]. Cutaneous manifestation of deep mycosis is uncommon and fairly limited to few fungi species [22]. However, a number of dimorphic fungi are known in the causation of deep mycoses in immunocompromised persons [23]. These fungi may exist as moulds/hyphae or yeasts and are morphologically distinct for various species, while the clinical course of disease is usually indolent. Localized cutaneous presentation is variable and may take the form of circumscribed nodules, ulcers, abscesses or papules, thus a common cause of delayed or misdiagnosis with other cutaneous lesions [24]. Cutaneous deep mycosis in immunocompetent hosts will
123
Mycopathologia
often elicit distinct histologic inflammatory response characterized by granuloma formation, and diagnosis can be achieved with tissue or fluid culture, tissue histology stained with H&E, PAS and GMS, immunohistochemistry and serology [25]. Histoplasmosis accounted for 37 % of these cases with a higher frequency in males [22]. Idiopathic CD4 lymphopenia (ICL) is a rare syndrome characterised by depleted CD4T lymphocytes to a level less than 300 cells/ml or \20 % of total lymphocytes over a period of minimum 6 weeks in patients without evidence of HIV infection, history of primary immunodeficiency or therapy-induced immunosuppression [26]. ICL patients had at least one opportunistic infection, with the most common being cryptococcus, mycobacteria, Candida and varicella zoster virus (VZV) [27]. Malignancies were found in 18 % of patients, with the most common being lymphoma, squamous cell carcinoma of the skin and Kaposi’s sarcoma. Autoimmune diseases were seen in 14 %, with Sjogren’s syndrome, sarcoidosis and psoriasis being the most common [28]. Low CD4? T lymphocyte counts (CD4 counts) are associated with a variety of conditions, including many viral infections such as HIV, human T cell lymphotrophic virus, various bacterial infections, parasitic infections such as toxoplasma, cryptosporidium, sepsis, tuberculosis, coccidioidomycosis, burns, trauma, intravenous injections of foreign proteins, malnutrition, over-exercising, pregnancy, corticosteroid use, normal daily variation, psychological stress. In some of these conditions, low CD4 count falls even below 200, but Histoplasma infection itself can cause low CD4 count that was not studied earlier. Human immunodeficiency virus is the most common causative agent responsible for CD4 lymphocytopenia. Our case highlights two important issues: firstly, the occurrence of disseminated histoplasmosis in immunocompetent host and secondly, the association of low CD4 count with deep fungal infections as in our case Histoplasma capsulatum which is reversible on antifungal therapy.
References 1. O’Hara CD, Allegretto MW, Taylor GD, et al. Epiglottic histoplasmosis presenting in a nonendemic region. Arch Pathol Lab Med. 2004;128:574–7. 2. Minamoto GY, Rosenberg AS. Fungal infections in patients with acquired immune deficiency syndrome. Med Clin North Am. 1997;81:381–409.
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3. Taylor GD, Fanning EA, Ferguson JP, et al. Disseminated histoplasmosis in a non-endemic area. Can Med Assoc J. 1985;133:763–5. 4. Sanyal M, Thammaya A. Skin sensitivity to histoplasmin in Calcutta and its neighborhood. Indian J Dermatol Venereol Leprol. 1980;46:94–8. 5. Mukherjee AM, Khan KP, Sanyal M, Basu N. Histoplasmosis in India with report of two cases. J Ind Med Assoc. 1971;56:121–5. 6. Saoji AM, Grover S, Mene AR, Patoria NK, Sharma KD. Histoplasmosis. J Indian Med Assoc. 1976;66:37–8. 7. Nair SP, Vijayadharan M, Vincent M. Primaty cutaneous histoplasmosis. Indian J Dermatol Venereol Leprol. 2000; 66:151–3. 8. Sayal SK, Prasad PS, Sanghi S. Disseminated histoplasmosis: cutaneous presentation. Indian J Dermatol Venereol Leprol. 2003;69:90–1. 9. Sharma S, Kumari N, Ghosh P, Aggarwal A. Disseminated histoplasmosis in an immune competent individual-a case report. Indian J Pathol Microbiol. 2005;48:204–6. 10. Alcure ML, Di Hipo´lito Ju´nior O, Almeida OP, Bonilha H, Lopes MA. Oral histoplasmosis in an HIV-negative patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006; 101:33–6. 11. Mendell GL, Bennet JE, Dolin R. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone Inc; 1995. 12. Tewari RP, Wheat LJ, Ajello L. Agents of histoplasmosis. In: Ajello L, Hay J, editors. Topley and Wilson’s Microbiology and Microbial Infections, vol. 4. 9th ed. London: Arnold; 1998. p. 373–93. 13. Nyga˚rd K, Brantsaeter A, Feruglio S, Ravn J, Dotevall L, Hasle G, et al. Histoplasmosis among travellers to Central America. Tidsskr Nor Laegeforen. 2006;126:2838–42. 14. Harnalikar M, Kharkar V, Khopkar U. Disseminated cutaneous histoplasmosis in an immunocompetent adult. Indian J Dermatol. 2012;57(3):205–6. 15. Kumar N, Jain S, Singh ZN. Disseminated histoplasmosis with reactive hemophagocytosis: aspiration cytology findings in two cases. Diagn Cytopathol. 2000;23(6):422–4. 16. Grover SB, Midha N, Gupta M, Sharma U, Talib VH. Imaging spectrum in disseminated histoplasmosis: case report and brief review. Australas Radiol. 2005;49(2):175–8. 17. Singh S, Chhabra S, Goyal R, Garg S. Cytodiagnosis of histoplasmosis: case reports from two patients with variable clinical presentation. Diagn Cytopathol. 2012;40(12): 1090–2. 18. Kathuria S, Capoor MR, Yadav S, Singh A, Ramesh V. Disseminated histoplasmosis in an immunocompetent adult from non-endemic area: case report and review. Med Mycol. 2013;51(7):774–8. 19. Gupta N, Arora SK, Rajwanshi A, Nijhawan R, Srinivasan R. Histoplasmosis: cytodiagnosis and review of literature with special emphasis on differential diagnosis on cytomorphology. Cytopathology. 2010;21(4):240–4. 20. Mukherjee A, Tangri R, Verma N, Gautam D. Chronic disseminated histoplasmosis bone marrow involvement in an immunocompetent patient. Indian J Hematol Blood Transfus. 2010;26(2):65–7. 21. Kathuria S, Singh PK, Meis JF, Chowdhary A. In vitro antifungal susceptibility profile and correlation of mycelial
Mycopathologia and yeast forms of molecularly characterized Histoplasma capsulatum strains from India. Antimicrob Agents Chemother. 2014;58(9):5613–6. 22. Samaila O, Abdullahi K. Cutaneous manifestations of deep mycosis: an experience in a tropical pathology laboratory. Ind J Dermatol. 2011;56(3):282–6. 23. Hinshaw M, Longley JB. Fungal Diseases. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF, editors. Lever’s histopathology of the skin. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. p. 601–34. 24. Sanchez LR, Raimer SS. Panniculitis, Inclusions, Fungi and Parasites. In: Sanchez LR, Raimer SS, editors. Landes Bioscience vademecum Dermatopathology Georgetown Texas. USA: Landes Bioscience; 2001. p. 179–84.
25. Wheat LJ. Laboratory diagnosis of histoplasmosis: update 2000. Semin Respir Infect. 2001;16:131–40. 26. Zonio DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, et al. Idiopathic CD4? lymphocytopenia: natural history and prognostic factors. Blood. 2008;112(2):287–94. 27. Ahmad DS, Esmadi M, Steinmann WC. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med. 2013;3(2):37–47. 28. Denu RA, Rush PS, Ahrens SE, Westergaard RP. Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis. Med Mycol Case Rep. 2014;6: 73–5.
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Cutaneous Manifestation of Underlying Disseminated Histoplasmosis in an Immunocompetent Host of Nonendemic Area with Reversible CD4 Cell Depletion and its Recovery on Antifungal Therapy Praveen Bharti . Kiran Bala . Naresh Gupta
Received: 13 February 2015 / Accepted: 6 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract We present the case of an 18-year-old male patient admitted with complaints of fever and rapid weight loss since 3 months. Patient had multiple umbilicated papular to nodular lesions over chin and forehead region. Complete blood count revealed bicytopenia. An excisional biopsy of the skin lesions had revealed cutaneous histoplasmosis. On further investigations for bicytopenia, histoplasmosis had been diagnosed on bone marrow trephine biopsy. For the immune status, patient’s serology against HIV was negative and his CD4 lymphocyte counts were low at 161. Patient received antifungal therapy including amphotericin B and itraconazole. He showed remarkable improvement in his general condition and blood counts. A repeat CD4 count showed normal counts, and idiopathic CD4 lymphocytopenia was excluded. Disseminated histoplasmosis presenting as cutaneous lesions in an immunocompetent host is very rare, and we are not aware of any case report in the literature where there is reversible depletion of CD4 counts following antifungal treatment in an immunocompetent host of nonendemic area. P. Bharti (&) N. Gupta Department of General Medicine, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi 110002, India e-mail: [email protected] K. Bala Department of Microbiology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
Keywords Disseminated histoplasmosis CD4 count Cutaneous Amphotericin B
Introduction Histoplasmosis is an endemic mycosis and a disease of worldwide occurrence which is most prevalent in the Ohio and Mississippi river valleys of North America, though there are rare reports of these mycoses from nonendemic regions too [1–3]. In India, endemic cases of histoplasmosis have been reported in West Bengal (eastern India) [4, 5] and sporadic cases have been reported in southern India [6, 7]. Further reports of histoplasmosis in nonendemic regions are very rare [3]. Although histoplasmosis occurs most commonly in immunosuppressed patients [8], there are a few case reports of this disease in immunocompetent hosts [9, 10]. Disseminated histoplasmosis is also associated with a condition called idiopathic CD4 cell lymphocytopenia, but has never been reported in a patient with transient CD4 cell depletion. We hereby report a case where disseminated histoplasmosis occurred in a patient with low CD4 count but completely recovered following antifungal therapy.
Case Report An 18-year-old male patient presented to our hospital with complaints of low-grade fever, loss of appetite
123
Mycopathologia
and significant weight loss in past 3 months. He also had a past history of recurrent oral ulcers and skin lesions which he did not notice much and was saying to have since a long duration. There was no history of tuberculosis, diabetes or any other chronic systemic illness. He was a nonsmoker with no history of any addictions, high-risk behaviour, promiscuous sexual activities and blood transfusion. On examination, the patient was of thin built male with stable vitals. There were multiple umbilicated papular to nodular lesions over forehead and chin, without any erythema or tenderness (Fig. 1). There was mild splenomegaly on abdominal examination. Rest of the systemic examination revealed no abnormality. On further investigations, the complete blood count revealed bicytopenia Hb 7.2 gm %; TLC 3200/mm3; DLC-Polymorphonuclear cells 75, lymphocytes 20, eosinophils 2, monocytes 3; platelet count 2.5 lakh; ESR 38; total protein 7.5 gm, with albumin levels of 2.5 mg. Other biochemical tests were normal. Sputum examination was negative for bacteria on Gram and acid fast staining. Chest X-ray was normal; however, the CECT chest revealed left hilar and pre-tracheal lymphadenopathy with the foci of calcification. Ultrasound of whole abdomen confirmed splenomegaly. Skin biopsy showed ill-defined noncaseating granulomas with macrophages and numerous oval, 2–4 mm, intracellular, narrow-based budding yeast-like cells; yeast forms of Histoplasma capsulatum (Fig. 2). Bone marrow aspiration and biopsy showed normal haematopoiesis with the presence of similar yeast forms of Histoplasma capsulatum (Fig. 3). The potassium hydroxide wet mount and Gram’s stain of biopsy sample also showed the morphologically similar yeast cells.
The fungal culture was sterile after 6–8 weeks of incubation. The ELISA for Histoplasma capsulatum (Focus diagnostics HistoplasmaTM Dx select, EL 1700) was performed. The ELISA was reactive for Histoplasma antibodies with index value of 2.20 (sensitivity— 86.3 %; specificity—83.9 %). The patient was thus diagnosed as a case of disseminated histoplasmosis and then underwent further series of investigations to look for any underlying immune dysfunction. Serology against HIV 1 and 2 was negative on two occasions. The immune status of the patient was studied in terms of lymphocyte subclasses, with the following results: CD4 counts were low, 161 cells/L (normal range 400–2100) and CD8, 848 cells/L (normal value, 200–1200); the ratio of CD4 and CD8 was low 0.2 (normal value, 0.9 to 3.4). Immunoglobulin levels were normal, IgG 803.4 mg/dl (normal range 789–2630), IgA 179.9 mg/ dl (normal value, 111–403) and IgM 50.4 mg/dl (normal value, 48–265); IgE 34.8 lI/ml (normal range 1.3–165.3). Likewise, when assessing complement fractions, C3 32.7 mg/dl and C4 43.9 mg/dl, levels were within normal limits. Patient was started on amphotericin B at a dose of 0.5 mg/kg/day with gradual escalation up to 1 mg/ kg/day for 4 weeks, and then, itraconazole was given daily per oral at dose of 200 mg for 3 weeks. After 3 weeks, CD4 count was also repeated to exclude the possibility of idiopathic CD4 cell lymphocytopenia which was normal (CD4 584 cells/mm3). There was a marked improvement of his symptoms, and he was discharged on oral itraconazole. He visited again 3 weeks later with fading skin lesions and is on regular follow-up.
Discussion
Fig. 1 Photograph of patient having multiple papular to nodular skin lesions over chin
123
Histoplasmosis is an uncommon fungal disease caused by Histoplasma capsulatum var capsulatum and Histoplasma capsulatum var duboisii [11, 12]. Yeast forms of this fungus replicate within the reticuloendothelial system and disseminate in the absence of a good immune status. Histoplasmosis presents clinically as acute or chronic pulmonary infection, disseminated histoplasmosis and mediastinal fibrosis. Histoplasmosis is rare, as it is thought to be endemic only in small regions in West Bengal in western India [4, 5]. However, sporadic cases from southern India have been reported. Our patient was a resident of a
Mycopathologia Fig. 2 Multiple ill-defined noncaseating granulomas present with yeast forms of Histoplasma capsulatum in the skin biopsy
Numerous intracellular Periodic Acid Schiff-posive rounded yeast cells within macrophages
Fig. 3 Normal haematopoiesis and macrophages with yeast form of Histoplasma capsulatum in bone marrow aspirate
nonendemic region of India. We believe that our patient had contracted the disease via inhalation of conidia of Histoplasma capsulatum present in the soil contaminated by the excreta of bats or birds [13]. Inhalation of either fungal conidia or mycelial fragments is the primary mode of infection for histoplasmosis. Immunocompetent hosts are able to control and limit infections of Histoplasma; however, hosts with defective cell-mediated immunity and those exposed to chemotherapeutic and immunosuppressive agents are at risk of developing progressive disseminated histoplasmosis involving the reticuloendothelial system, including the liver, spleen, kidney, lymph nodes,
bone marrow and mucocutaneous tissues [14]. It is also recognized as an AIDS-defining illness [1]. Histoplasmosis infection is often categorized as being present in an HIV-positive or HIV-negative individual, as there are differences in presentation and response to therapy. Histoplasmosis has also been described in patients with a condition called idiopathic CD4 lymphocytopenia. In our patient, we suspected this condition but the repeat count after 3 weeks came out to be normal; hence, this condition was ruled out. Very few articles have been published on disseminated histoplasmosis in immunocompetent from nonendemic regions of India such as Delhi [15, 16], Haryana [17, 18], Chandigarh [19], Uttarpradesh [20]. Twelve cases of disseminated histoplasmosis from north-western India had been diagnosed, and their antifungal susceptibilities were performed [21]. Cutaneous manifestation of deep mycosis is uncommon and fairly limited to few fungi species [22]. However, a number of dimorphic fungi are known in the causation of deep mycoses in immunocompromised persons [23]. These fungi may exist as moulds/hyphae or yeasts and are morphologically distinct for various species, while the clinical course of disease is usually indolent. Localized cutaneous presentation is variable and may take the form of circumscribed nodules, ulcers, abscesses or papules, thus a common cause of delayed or misdiagnosis with other cutaneous lesions [24]. Cutaneous deep mycosis in immunocompetent hosts will
123
Mycopathologia
often elicit distinct histologic inflammatory response characterized by granuloma formation, and diagnosis can be achieved with tissue or fluid culture, tissue histology stained with H&E, PAS and GMS, immunohistochemistry and serology [25]. Histoplasmosis accounted for 37 % of these cases with a higher frequency in males [22]. Idiopathic CD4 lymphopenia (ICL) is a rare syndrome characterised by depleted CD4T lymphocytes to a level less than 300 cells/ml or \20 % of total lymphocytes over a period of minimum 6 weeks in patients without evidence of HIV infection, history of primary immunodeficiency or therapy-induced immunosuppression [26]. ICL patients had at least one opportunistic infection, with the most common being cryptococcus, mycobacteria, Candida and varicella zoster virus (VZV) [27]. Malignancies were found in 18 % of patients, with the most common being lymphoma, squamous cell carcinoma of the skin and Kaposi’s sarcoma. Autoimmune diseases were seen in 14 %, with Sjogren’s syndrome, sarcoidosis and psoriasis being the most common [28]. Low CD4? T lymphocyte counts (CD4 counts) are associated with a variety of conditions, including many viral infections such as HIV, human T cell lymphotrophic virus, various bacterial infections, parasitic infections such as toxoplasma, cryptosporidium, sepsis, tuberculosis, coccidioidomycosis, burns, trauma, intravenous injections of foreign proteins, malnutrition, over-exercising, pregnancy, corticosteroid use, normal daily variation, psychological stress. In some of these conditions, low CD4 count falls even below 200, but Histoplasma infection itself can cause low CD4 count that was not studied earlier. Human immunodeficiency virus is the most common causative agent responsible for CD4 lymphocytopenia. Our case highlights two important issues: firstly, the occurrence of disseminated histoplasmosis in immunocompetent host and secondly, the association of low CD4 count with deep fungal infections as in our case Histoplasma capsulatum which is reversible on antifungal therapy.
References 1. O’Hara CD, Allegretto MW, Taylor GD, et al. Epiglottic histoplasmosis presenting in a nonendemic region. Arch Pathol Lab Med. 2004;128:574–7. 2. Minamoto GY, Rosenberg AS. Fungal infections in patients with acquired immune deficiency syndrome. Med Clin North Am. 1997;81:381–409.
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3. Taylor GD, Fanning EA, Ferguson JP, et al. Disseminated histoplasmosis in a non-endemic area. Can Med Assoc J. 1985;133:763–5. 4. Sanyal M, Thammaya A. Skin sensitivity to histoplasmin in Calcutta and its neighborhood. Indian J Dermatol Venereol Leprol. 1980;46:94–8. 5. Mukherjee AM, Khan KP, Sanyal M, Basu N. Histoplasmosis in India with report of two cases. J Ind Med Assoc. 1971;56:121–5. 6. Saoji AM, Grover S, Mene AR, Patoria NK, Sharma KD. Histoplasmosis. J Indian Med Assoc. 1976;66:37–8. 7. Nair SP, Vijayadharan M, Vincent M. Primaty cutaneous histoplasmosis. Indian J Dermatol Venereol Leprol. 2000; 66:151–3. 8. Sayal SK, Prasad PS, Sanghi S. Disseminated histoplasmosis: cutaneous presentation. Indian J Dermatol Venereol Leprol. 2003;69:90–1. 9. Sharma S, Kumari N, Ghosh P, Aggarwal A. Disseminated histoplasmosis in an immune competent individual-a case report. Indian J Pathol Microbiol. 2005;48:204–6. 10. Alcure ML, Di Hipo´lito Ju´nior O, Almeida OP, Bonilha H, Lopes MA. Oral histoplasmosis in an HIV-negative patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006; 101:33–6. 11. Mendell GL, Bennet JE, Dolin R. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone Inc; 1995. 12. Tewari RP, Wheat LJ, Ajello L. Agents of histoplasmosis. In: Ajello L, Hay J, editors. Topley and Wilson’s Microbiology and Microbial Infections, vol. 4. 9th ed. London: Arnold; 1998. p. 373–93. 13. Nyga˚rd K, Brantsaeter A, Feruglio S, Ravn J, Dotevall L, Hasle G, et al. Histoplasmosis among travellers to Central America. Tidsskr Nor Laegeforen. 2006;126:2838–42. 14. Harnalikar M, Kharkar V, Khopkar U. Disseminated cutaneous histoplasmosis in an immunocompetent adult. Indian J Dermatol. 2012;57(3):205–6. 15. Kumar N, Jain S, Singh ZN. Disseminated histoplasmosis with reactive hemophagocytosis: aspiration cytology findings in two cases. Diagn Cytopathol. 2000;23(6):422–4. 16. Grover SB, Midha N, Gupta M, Sharma U, Talib VH. Imaging spectrum in disseminated histoplasmosis: case report and brief review. Australas Radiol. 2005;49(2):175–8. 17. Singh S, Chhabra S, Goyal R, Garg S. Cytodiagnosis of histoplasmosis: case reports from two patients with variable clinical presentation. Diagn Cytopathol. 2012;40(12): 1090–2. 18. Kathuria S, Capoor MR, Yadav S, Singh A, Ramesh V. Disseminated histoplasmosis in an immunocompetent adult from non-endemic area: case report and review. Med Mycol. 2013;51(7):774–8. 19. Gupta N, Arora SK, Rajwanshi A, Nijhawan R, Srinivasan R. Histoplasmosis: cytodiagnosis and review of literature with special emphasis on differential diagnosis on cytomorphology. Cytopathology. 2010;21(4):240–4. 20. Mukherjee A, Tangri R, Verma N, Gautam D. Chronic disseminated histoplasmosis bone marrow involvement in an immunocompetent patient. Indian J Hematol Blood Transfus. 2010;26(2):65–7. 21. Kathuria S, Singh PK, Meis JF, Chowdhary A. In vitro antifungal susceptibility profile and correlation of mycelial
Mycopathologia and yeast forms of molecularly characterized Histoplasma capsulatum strains from India. Antimicrob Agents Chemother. 2014;58(9):5613–6. 22. Samaila O, Abdullahi K. Cutaneous manifestations of deep mycosis: an experience in a tropical pathology laboratory. Ind J Dermatol. 2011;56(3):282–6. 23. Hinshaw M, Longley JB. Fungal Diseases. In: Elder DE, Elenitsas R, Johnson BL, Murphy GF, editors. Lever’s histopathology of the skin. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. p. 601–34. 24. Sanchez LR, Raimer SS. Panniculitis, Inclusions, Fungi and Parasites. In: Sanchez LR, Raimer SS, editors. Landes Bioscience vademecum Dermatopathology Georgetown Texas. USA: Landes Bioscience; 2001. p. 179–84.
25. Wheat LJ. Laboratory diagnosis of histoplasmosis: update 2000. Semin Respir Infect. 2001;16:131–40. 26. Zonio DI, Falloon J, Bennett JE, Shaw PA, Chaitt D, Baseler MW, et al. Idiopathic CD4? lymphocytopenia: natural history and prognostic factors. Blood. 2008;112(2):287–94. 27. Ahmad DS, Esmadi M, Steinmann WC. Idiopathic CD4 lymphocytopenia: spectrum of opportunistic infections, malignancies, and autoimmune diseases. Avicenna J Med. 2013;3(2):37–47. 28. Denu RA, Rush PS, Ahrens SE, Westergaard RP. Idiopathic CD4 lymphocytopenia with giant cell arteritis and pulmonary mucormycosis. Med Mycol Case Rep. 2014;6: 73–5.
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