Mycopathologia DOI 10.1007/s11046-015-9917-y
An Unusual Presentation of Disseminated Histoplasmosis: Case Report and Review of Pediatric Immunocompetent Patients from India Poojan Agarwal . Malini R. Capoor . Mukul Singh . Arpita Gupta . Arini Chhakchhuak . Pradeep Debatta
Received: 6 May 2015 / Accepted: 13 June 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Histoplasmosis is a progressive disease caused by dimorphic intracellular fungi and can prove fatal. Usually, it is present in immunocompromised individuals and immunocompetent individuals in the endemic zones. We report an unusual presentation of progressive disseminated histoplasmosis. The patient in the present case report was immunocompetent child and had fever, bone pains, gradual weight loss, lymphadenopathy and hepatosplenomegaly. Disseminated histoplasmosis (DH) was diagnosed on microscopic examination and fungal culture of bone marrow, blood, skin biopsy and lymph node aspirate. The patient died on seventh day of amphotericin B. In the absence of predisposing factors and classical clinical presentation of febrile neutropenia, lung, adrenal and oropharyngeal lesions, the disease posed a diagnostic challenge. Progressive disseminated
P. Agarwal M. Singh Department of Pathology, Safadarjung Hospital, Vardhmaan Mahavir Medical College, Delhi, India M. R. Capoor (&) Department of Microbiology, Safadarjung Hospital, Vardhmaan Mahavir Medical College, C – 99, Neelambar Apartments, Opposite Sainik Vihar, Pitampura, Delhi 110034, India e-mail: [email protected]; [email protected] A. Gupta A. Chhakchhuak P. Debatta Department of Pediatrics, Safadarjung Hospital, Vardhmaan Mahavir Medical College, Delhi, India
histoplasmosis in children can be fatal despite timely diagnosis and therapy. In India, disseminated histoplasmosis is seen in immunocompetent hosts. All the pediatrics immunocompetent cases from India are also reviewed. Keywords Disseminated histoplasmosis (DH) Immunocompetent hosts Children Complications
Introduction Histoplasmosis is a fungal infection caused by endemic dimorphic fungus Histoplasma capsulatum. It has a worldwide distribution including North America, Central America, South America and Southeast Asia [1]. In India, individual cases have been reported from various states, mostly from West Bengal and Uttar Pradesh. Disseminated histoplasmosis (DH) may result from a high organism burden and is more common in very young or very old persons [2]. Worldwide, there are few cases of pediatric histoplasmosis in immunocompetent patients [3, 4]. In India, until now five cases of pediatric histoplasmosis cases in immunocompetent patients have been documented [5–9]. Furthermore, disseminated disease in India is predominantly seen in HIV-negative patients [5–11], unlike North and South America [1]. We report a case of progressive disseminated histoplasmosis in an immunocompetent pediatric patient, presenting with pyrexia of unknown origin, bone and joint pains and
123
Mycopathologia
gradual weight loss. This case merits discussion due to the rarity of the presentation mimicking acute leukemia, in a child with no underlying risk factor for progressive disseminated histoplasmosis.
Case Report A 7-year-old female, child resident of Mathura, Uttar Pradesh, North India, presented with intermittent highgrade fever along with chills and rigor for 6 months, severe multiple bone pains for 4 months and significant weight loss for the past 2 months. Patient had sought treatment from private clinic before coming to our hospital and had a history of blood transfusion 20 days back. There was no history of trauma, swelling or redness of joints, purpuric rash or bleeding from any site, and there was no history of travel. There was no history of exposure to contaminated sites like chicken coops, bird roosting areas or old buildings. She gave history of playing in her parent’s agricultural land. On general examination the patient was thin built, pale and had small pink to pearly white papules of 1–2.5 mm over both eyelids (Fig. 1). On systemic examination, moderate, firm non-tender hepatosplenomegaly was present. On bone and joint examination, tenderness over all the long bones was present (grade 4); however, all joints were free from any swelling, stiffness or effusion. Systemic examination revealed pleural and pericardial rub. A provisional clinical diagnosis of acute leukemia was made. Her investigations showed Hb of 5 gm %, TLC 3000/mm3 with differentials as polymorphs 54 %, lymphocytes 42 % and monocytes 04 %. Absolute neutrophil count was 1620/mm3, and platelet count was 50,000/mm3. Peripheral smear
Fig. 1 Tiny cutaneous pearly white to umbilicated nodule over eyelid
123
showed pancytopenia with normocytic normochromic blood picture. Monocytes in the peripheral blood film stained with Leishman stain had distorted nuclei with numerous intracellular yeast-like organisms 2–4 lm in diameter with eccentric nuclear chromatin. The organisms were surrounded by an artifactual pseudocapsule caused by cytoplasmic shrinkage (Fig. 2). These features were suggestive of intracellular yeast infection. Kidney function tests and liver function tests were essentially normal. Bone marrow was aspirated. Periodic acid–Schiff’s (PAS) stain revealed numerous extracellular as well as intracellular budding yeast cells which were PAS positive (Fig. 3, inset) and budding yeast cells on Giemsa stain (Fig. 3). Maturation was normal and M/ E ratio was 2.5:1. Bone marrow culture revealed a white growth of mold on yeast phosphate agar and brain-heart infusion agar slant at 25 °C after 19 days of incubation. The lactophenol cotton blue mount (LCB) of mold revealed tuberculate macroconidia with thin hyphae (Fig. 4). For dimorphism, the growth was subcultured on brain-heart infusion-based blood agar at 37 °C. After 16 days of incubation, yeastlike growth appeared. LCB revealed budding yeast cells around 2–4 lm in size with narrow-based budding. Skin biopsy of lid lesions was simultaneously performed, and it showed a pan-dermal infiltrate of yeast forms (Fig. 5) and its culture also yielded H. capsulatum. The isolate was sent to Post Graduate Institute of Medical Education and Research (PGIMER), National Culture Collection of Pathogenic Fungi (NCCPF), Chandigarh, India, for reconfirmation. The sequencing of the isolate using ITS 1 and ITS
Fig. 2 Peripheral blood monocyte with intracytoplasmic organisms (Leishman stain, 9400)
Mycopathologia
Fig. 5 Skin biopsy—pan-dermal infiltrate by budding yeasts cells (H&E, 9400) Fig. 3 Bone marrow aspirate with a swollen histiocyte with intracytoplasmic budding yeast cells. Scattered extracellular forms are also seen (arrow) (Giemsa stain, 9400). These were PAS positive (inset)
aspirate also yielded H. capsulatum. The liver and spleen were moderately enlarged with firm echotexture. No adrenal involvement was noted. Radiographs of long bones did not reveal any abnormality. Based on peripheral blood, bone marrow, lymph node aspirate, skin biopsy and culture findings, disseminated histoplasmosis was diagnosed. The patient was started on intravenous amphotericin B 1 mg/kg/day (cumulative dose of 30 mg/day). However, her condition deteriorated, respiratory distress aggravated, and pleuritis and pericarditis exaggerated on day three of antifungal therapy (AFT). The patient succumbed to her disseminated illness and its complications on day seven of AFT. Due to the development of complications, hepatic biopsy and pericardial fluid examination could not be performed.
Discussion Fig. 4 Lactophenol cotton blue stain showing thin hyphae with tuberculate macroconidia (9400)
2 gene primers confirmed it to be H. capsulatum. These organisms were PAS positive. Fungal blood culture revealed yeast-like growth consistent with H. capsulatum. The patient tested negative for HIV, HBsAg, ANA and ASLO. Her immunoglobulin profile (Ig G, Ig A, Ig E) was within normal limits, and CD4, CD8 and their ratio were normal. On CT scan, multiple subcentimetric nodes were present in the mediastinum as well as in the mesentery. The mediastinal lymph node
The patient in this study was a 7-year-old school girl without any predisposing factor for progressive disseminated histoplasmosis, apart from being a resident of endemic state in India. In India, histoplasmosis is not considered endemic, but areas of high prevalence are along Gangetic plains, mainly West Bengal and Uttar Pradesh. Isolated cases have been reported from Chandigarh, Bihar, Rajasthan, Madhya Pradesh and Delhi [5–11]. On the basis of histoplasmin skin sensitivity testing, prevalence of histoplasmosis in India varies from 0 to 12.3 %, with high prevalence in Delhi riverside area [12]. It has been observed that even in highly endemic
123
Mycopathologia
areas for histoplasmosis, fungal recovery from soil can be very difficult. H. capsulatum infection is not transmissible through person-to-person contact. Infections in endemic areas are typically caused by windborne spores emanating from point sources such as bird roosts, old houses or barns, or activities involving disruption of the soil such as farming and excavation [1]. The patient in this case report resided in the endemic state (Uttar Pradesh) and is likely to have acquired the infection while playing in the fields of her parents. After review of the pertinent literature, until now five pediatric immunocompetent disseminated histoplasmosis cases have been published from India from 1966 to 2010 (Table 1). In these patients, following conditions were ruled out: HIV, malignancy, immunosuppressive or immunomodulating therapy or any other contributory immunosuppressive conditions. Age of presentations varied from 3 years to 10 years (median 5 years). In these five patients, the clinical characteristics of the patients ranged from fever (n = 4), malaise (n = 4) and pallor (n = 2). Liver and lymph nodes were the commonest organs (4) involved, followed by spleen (3), lungs (2), skin and mucocutaneous region (2). Adrenal involvement was seen in none. It is well documented that histoplasmosis is rare below 2 years of age due to immaturity of T cell immunity [13]. It has been reported previously that pediatric histoplasmosis in immune normal children has a high rate of asymptomatic and mild infections [1]. Immune normal children with symptomatic acute histoplasmosis present with fever, malaise, mild cough and non-pleuritic chest pain. In fewer than 5–10 % children, the symptoms persist and pericarditis, arthritis, arthralgia, mediastinal lymphadenopathy and maculopapular rash are seen as complication as was observed in this patient. Granulomatous inflammation in mediastinal lymph nodes induces pericarditis in 6 % of patients with acute pulmonary histoplasmosis [1, 14]. The possibility of progressive disseminated histoplasmosis leading to death of patient cannot be ruled out, as the patient in this case report was a child and had gradual weight loss, fever, fatigue, skin lesions, lymphadenopathy and hepatosplenomegaly with pancytopenia. Disseminated histoplasmosis is a rare disease that occurs primarily in immunocompromised persons, especially in patients with HIV infection and a CD4 lymphocyte count that is below 150–200/mm3
123
(150–200 9 106/L) [14]. However, disseminated disease in India is predominantly seen in HIV-negative patients who are often misdiagnosed and are inappropriately treated [9–11]. The spectrum of illness in disseminated disease ranges from a chronic, intermittent course in immunocompetent persons to an acute and rapidly fatal infection that usually occurs in infants and severely immunosuppressed persons [15]. The usual symptoms are fever, chills, non-productive cough, anterior chest discomfort, myalgias, arthralgias and fatigue [14]. Physical examination may reveal hepatosplenomegaly and lymphadenopathy or, less frequently, mucocutaneous lesions such as oropharyngeal ulceration. Laboratory evaluation frequently reveals pancytopenia caused by bone marrow involvement and abnormal results on hepatic function tests, indicating that the disease has spread to the liver [16–18]. The patient in this case report had a rare presentation of severe generalized bone pain with pyrexia mimicking acute leukemia of childhood. No significant predisposing factor for DH could be seen and it was only on the screening of peripheral blood (followed by bone marrow, LN aspirate and skin biopsy for fungal culture) where occasional but definitive presence of intracytoplasmic yeasts forms was noted which were similar in size with platelets but with a peripheral halo and a crescent-shaped peripheral chromatin. Elin et al. [19] have pointed that a number of organisms in peripheral blood may mimic H. capsulatum like P. marneffei, Balstomyces dermatitidis, Candida glabrata, Pneumocystis carinii, Leshmania species and Toxoplasma gondii. Furthermore, culture of H. capsulatum is of paramount importance as it clinches the diagnosis of histoplasmosis, thereby ensuring specific antifungal therapy. Despite diagnosis and institution of appropriate antifungal (amphotericin B), patient in this case died due to severity and complications of infection. Out of five pediatric immunocompetent cases reported in India till date, two were fatal [6–9]. This is probably associated with the lack of awareness, misdiagnosis and unwarranted anti-tubercular therapy in a tuberculosis endemic country like India. In a recent case from Delhi, a pediatric immunocompetent patient had a relapse with histoplasmosis despite appropriate therapy of induction with amphotericin B (3 weeks) followed by itraconazole (6 months). However, the patient was successfully treated by voriconazole [9]. There is a paucity of
Kaliranjan et al. [5]
Chakravarty et al. [6]
Mukherjee et al. [7]
Mukherjee et al. [8]
Dhawan et al. [9]
Current case, 2014
1
2
3
4
5
6
Author, year
7 year/F
3 year/M
3 year 10 m/ M
8 year/M
10 year/F
5 year/M
Age/sex
Mathura, Uttar Pradesh
Delhi
–
?
?
?
–
?
West Bengal
?
–
?
?
–
Pallor
?
Fever
West Bengal
Mathura, Uttar Pradesh
Tamil Nadu
Place/ state
?
?
?
?
–
?
?
?
?
?
–
–
?
?
–
?
–
–
?
–
?
–
?
–
Pulmonary
Lymph node Cardiac
_
–
?
?
?
?
?
–
–
-
–
–
Peripheral blood, bone marrow, skin biopsy
Skin biopsy
Bone marrow
Lymph node
Lung biopsy
Lymph node
Histoplasma capsulatum, culture and sequencing
Histoplasma capsulatum
Not done
Histoplasma capsulatum
Sterile
Sterile
Culture
HPE
Skin, mucocutaneous
Liver
Spleen
Fungus identified in
Organ involvement
Table 1 Summary of pediatric immunocompetent histoplasmosis cases reported from India
Amphotericin B
Itraconazole, amphotericin, voriconazole
Amphotericin B
Nystatin penicillin and streptomycin, amphotericin B could not be procured
None
Not available
Treatment
Died
Survived
Died
Died
Survived
Not available
Result
Mycopathologia
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Mycopathologia
antifungal susceptibility studies from India. In a recent study depicting antifungal susceptibility profile of 21 isolates collected from northwestern India, the authors concluded that the mycelial and yeasts forms of the isolates were inhibited by itraconazole, posaconazole, voriconazole, amphotericin B and isavuconazole, respectively, and both the forms had good agreement on minimum inhibitory concentration [11]. In conclusion, progressive disseminated histoplasmosis in children can be fatal despite timely diagnosis and therapy. This case highlights a rare presentation of histoplasmosis in an immunocompetent child mimicking acute leukemia, causing diagnostic dilemma. Acknowledgments The authors acknowledge the help of Dr (Prof.) Arunaloke Chakrabarti and Dr M. R. Shivaprakash, National Culture Collection of Pathogenic Fungi, PGIMER, Chandigarh, India, for reconfirming the isolate by DNA sequencing. The authors also acknowledge the help of Late Mrs. Kamlawati, Senior Technician, Department of Microbiology, V.M.M.C and Safdarjung Hospital, Delhi, India, for her technical expertise in the case.
References 1. Reiss E, Shadomy HJ, Lyon GM III. Histoplasmosis. In: Reiss E, Shadomy HJ, Lyon III GM, editors. Fundamental medical mycology. New Jersey: Wiley-Blackwell Publication; 2012. p. 165–86. 2. Adderson EE. Histoplasmosis in a pediatric oncology center. J Pediatr. 2004;144(1):100–6. 3. Brodsky AL, Gregg MB, Lowenstein MW, Kaufman L, Mallison GF. Outbreak of histoplasmosis associated with the 1970 Earth Day activities. Am J Med. 1970;54:333–42. 4. Kleinman MB. Histoplasma capsulatum (histoplasmosis). In: Long SS, Pickering LK, Prober CG, editors. Principle and practice of infectious diseases. Philadelphia: Churchill Livingstone (Elsevier); 2003.
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5. Histoplasmosis KR. The Madras. Clin J. 1966;3:81. 6. Chakravorty SC, Damodaran VN, Abraham S. Histoplasmosis in childhood in India (a case report with family study). Indian J Chest Dis. 1968;10:204. 7. Mukherjee AM, Khan KP, Sanyal M, Basu N. Histoplasmosis in India with report of two cases. J Indian Med Assoc. 1971;56:121–5. 8. Mukherjee AK, Mukherjee D, Mukhopadhyay M. Histoplasmosis in India: a clinicopathological review with report of a case in a child. Indian J Pathol Microbiol. 1986;29:263–70. 9. Dhawan J, Verma P, Sharma A, et al. Disseminated cutaneous histoplasmosis in an immunocompetent child, relapsed with itraconazole, successfully treated with voriconazole. Pediatr Dermatol. 2010;27:549–51. 10. Kathuria S, Capoor MR, Yadav S, Singh A, Ramesh V. Disseminated histoplasmosis in an apparently immunocompetent individual from north India: a case report and review. Med Mycol. 2013;51:774–8. 11. Kathuria S, Singh Pradeep K, Meis JF, Chowdhary A. In vitro antifungal susceptibility profile and correlation of mycelia and yeast forms of molecularly characterized Histoplasma capsulatum strains from India. Antimicrobial Agents Chemother. 2014;58:5613–6. 12. Vishwanathan R, Chakravarty SC, Randhawa HS, deMonte AJH. Pilot histoplasmosis survey in Delhi area. Br Med J. 1960;1:399–400. 13. Subramanian S, Abraham OC, Rupali P, Zachariah A, Mathews MS, Mathai D. Disseminated histoplasmosis. JAPI. 2005;53:185–9. 14. Anstead GM, Patterson TF. Endemic mycoses. In: Aaisse EJ, McGinnis MR, Pfaller MA, editors. Clinical mycology. Philadelphia: Churchill Livingstone, Elsevier; 2009. p. 355–73. 15. Gurney JW, Conces DJ. Pulmonary histoplasmosis. Radiology. 1996;199:297–306. 16. Bradsher RW. Histoplasmosis and blastomycosis. Clin Infect Dis. 1996;22(suppl 2):S102–11. 17. Kurowski R, OstapchuK. Overview of histoplasmosis. Am Fam Phys. 2002;66(12):2247–52. 18. Tan JS, File TM Jr, Salata RA, Tan MJ, editors. Expert guide to infectious diseases. Philadelphia: ACP Press; 2008. 19. Elin RJ, Whitis J, Snyder J. Infectious disease diagnosis from a peripheral blood smear. Lab Med. 2000;31:324–8.
An Unusual Presentation of Disseminated Histoplasmosis: Case Report and Review of Pediatric Immunocompetent Patients from India Poojan Agarwal . Malini R. Capoor . Mukul Singh . Arpita Gupta . Arini Chhakchhuak . Pradeep Debatta
Received: 6 May 2015 / Accepted: 13 June 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Histoplasmosis is a progressive disease caused by dimorphic intracellular fungi and can prove fatal. Usually, it is present in immunocompromised individuals and immunocompetent individuals in the endemic zones. We report an unusual presentation of progressive disseminated histoplasmosis. The patient in the present case report was immunocompetent child and had fever, bone pains, gradual weight loss, lymphadenopathy and hepatosplenomegaly. Disseminated histoplasmosis (DH) was diagnosed on microscopic examination and fungal culture of bone marrow, blood, skin biopsy and lymph node aspirate. The patient died on seventh day of amphotericin B. In the absence of predisposing factors and classical clinical presentation of febrile neutropenia, lung, adrenal and oropharyngeal lesions, the disease posed a diagnostic challenge. Progressive disseminated
P. Agarwal M. Singh Department of Pathology, Safadarjung Hospital, Vardhmaan Mahavir Medical College, Delhi, India M. R. Capoor (&) Department of Microbiology, Safadarjung Hospital, Vardhmaan Mahavir Medical College, C – 99, Neelambar Apartments, Opposite Sainik Vihar, Pitampura, Delhi 110034, India e-mail: [email protected]; [email protected] A. Gupta A. Chhakchhuak P. Debatta Department of Pediatrics, Safadarjung Hospital, Vardhmaan Mahavir Medical College, Delhi, India
histoplasmosis in children can be fatal despite timely diagnosis and therapy. In India, disseminated histoplasmosis is seen in immunocompetent hosts. All the pediatrics immunocompetent cases from India are also reviewed. Keywords Disseminated histoplasmosis (DH) Immunocompetent hosts Children Complications
Introduction Histoplasmosis is a fungal infection caused by endemic dimorphic fungus Histoplasma capsulatum. It has a worldwide distribution including North America, Central America, South America and Southeast Asia [1]. In India, individual cases have been reported from various states, mostly from West Bengal and Uttar Pradesh. Disseminated histoplasmosis (DH) may result from a high organism burden and is more common in very young or very old persons [2]. Worldwide, there are few cases of pediatric histoplasmosis in immunocompetent patients [3, 4]. In India, until now five cases of pediatric histoplasmosis cases in immunocompetent patients have been documented [5–9]. Furthermore, disseminated disease in India is predominantly seen in HIV-negative patients [5–11], unlike North and South America [1]. We report a case of progressive disseminated histoplasmosis in an immunocompetent pediatric patient, presenting with pyrexia of unknown origin, bone and joint pains and
123
Mycopathologia
gradual weight loss. This case merits discussion due to the rarity of the presentation mimicking acute leukemia, in a child with no underlying risk factor for progressive disseminated histoplasmosis.
Case Report A 7-year-old female, child resident of Mathura, Uttar Pradesh, North India, presented with intermittent highgrade fever along with chills and rigor for 6 months, severe multiple bone pains for 4 months and significant weight loss for the past 2 months. Patient had sought treatment from private clinic before coming to our hospital and had a history of blood transfusion 20 days back. There was no history of trauma, swelling or redness of joints, purpuric rash or bleeding from any site, and there was no history of travel. There was no history of exposure to contaminated sites like chicken coops, bird roosting areas or old buildings. She gave history of playing in her parent’s agricultural land. On general examination the patient was thin built, pale and had small pink to pearly white papules of 1–2.5 mm over both eyelids (Fig. 1). On systemic examination, moderate, firm non-tender hepatosplenomegaly was present. On bone and joint examination, tenderness over all the long bones was present (grade 4); however, all joints were free from any swelling, stiffness or effusion. Systemic examination revealed pleural and pericardial rub. A provisional clinical diagnosis of acute leukemia was made. Her investigations showed Hb of 5 gm %, TLC 3000/mm3 with differentials as polymorphs 54 %, lymphocytes 42 % and monocytes 04 %. Absolute neutrophil count was 1620/mm3, and platelet count was 50,000/mm3. Peripheral smear
Fig. 1 Tiny cutaneous pearly white to umbilicated nodule over eyelid
123
showed pancytopenia with normocytic normochromic blood picture. Monocytes in the peripheral blood film stained with Leishman stain had distorted nuclei with numerous intracellular yeast-like organisms 2–4 lm in diameter with eccentric nuclear chromatin. The organisms were surrounded by an artifactual pseudocapsule caused by cytoplasmic shrinkage (Fig. 2). These features were suggestive of intracellular yeast infection. Kidney function tests and liver function tests were essentially normal. Bone marrow was aspirated. Periodic acid–Schiff’s (PAS) stain revealed numerous extracellular as well as intracellular budding yeast cells which were PAS positive (Fig. 3, inset) and budding yeast cells on Giemsa stain (Fig. 3). Maturation was normal and M/ E ratio was 2.5:1. Bone marrow culture revealed a white growth of mold on yeast phosphate agar and brain-heart infusion agar slant at 25 °C after 19 days of incubation. The lactophenol cotton blue mount (LCB) of mold revealed tuberculate macroconidia with thin hyphae (Fig. 4). For dimorphism, the growth was subcultured on brain-heart infusion-based blood agar at 37 °C. After 16 days of incubation, yeastlike growth appeared. LCB revealed budding yeast cells around 2–4 lm in size with narrow-based budding. Skin biopsy of lid lesions was simultaneously performed, and it showed a pan-dermal infiltrate of yeast forms (Fig. 5) and its culture also yielded H. capsulatum. The isolate was sent to Post Graduate Institute of Medical Education and Research (PGIMER), National Culture Collection of Pathogenic Fungi (NCCPF), Chandigarh, India, for reconfirmation. The sequencing of the isolate using ITS 1 and ITS
Fig. 2 Peripheral blood monocyte with intracytoplasmic organisms (Leishman stain, 9400)
Mycopathologia
Fig. 5 Skin biopsy—pan-dermal infiltrate by budding yeasts cells (H&E, 9400) Fig. 3 Bone marrow aspirate with a swollen histiocyte with intracytoplasmic budding yeast cells. Scattered extracellular forms are also seen (arrow) (Giemsa stain, 9400). These were PAS positive (inset)
aspirate also yielded H. capsulatum. The liver and spleen were moderately enlarged with firm echotexture. No adrenal involvement was noted. Radiographs of long bones did not reveal any abnormality. Based on peripheral blood, bone marrow, lymph node aspirate, skin biopsy and culture findings, disseminated histoplasmosis was diagnosed. The patient was started on intravenous amphotericin B 1 mg/kg/day (cumulative dose of 30 mg/day). However, her condition deteriorated, respiratory distress aggravated, and pleuritis and pericarditis exaggerated on day three of antifungal therapy (AFT). The patient succumbed to her disseminated illness and its complications on day seven of AFT. Due to the development of complications, hepatic biopsy and pericardial fluid examination could not be performed.
Discussion Fig. 4 Lactophenol cotton blue stain showing thin hyphae with tuberculate macroconidia (9400)
2 gene primers confirmed it to be H. capsulatum. These organisms were PAS positive. Fungal blood culture revealed yeast-like growth consistent with H. capsulatum. The patient tested negative for HIV, HBsAg, ANA and ASLO. Her immunoglobulin profile (Ig G, Ig A, Ig E) was within normal limits, and CD4, CD8 and their ratio were normal. On CT scan, multiple subcentimetric nodes were present in the mediastinum as well as in the mesentery. The mediastinal lymph node
The patient in this study was a 7-year-old school girl without any predisposing factor for progressive disseminated histoplasmosis, apart from being a resident of endemic state in India. In India, histoplasmosis is not considered endemic, but areas of high prevalence are along Gangetic plains, mainly West Bengal and Uttar Pradesh. Isolated cases have been reported from Chandigarh, Bihar, Rajasthan, Madhya Pradesh and Delhi [5–11]. On the basis of histoplasmin skin sensitivity testing, prevalence of histoplasmosis in India varies from 0 to 12.3 %, with high prevalence in Delhi riverside area [12]. It has been observed that even in highly endemic
123
Mycopathologia
areas for histoplasmosis, fungal recovery from soil can be very difficult. H. capsulatum infection is not transmissible through person-to-person contact. Infections in endemic areas are typically caused by windborne spores emanating from point sources such as bird roosts, old houses or barns, or activities involving disruption of the soil such as farming and excavation [1]. The patient in this case report resided in the endemic state (Uttar Pradesh) and is likely to have acquired the infection while playing in the fields of her parents. After review of the pertinent literature, until now five pediatric immunocompetent disseminated histoplasmosis cases have been published from India from 1966 to 2010 (Table 1). In these patients, following conditions were ruled out: HIV, malignancy, immunosuppressive or immunomodulating therapy or any other contributory immunosuppressive conditions. Age of presentations varied from 3 years to 10 years (median 5 years). In these five patients, the clinical characteristics of the patients ranged from fever (n = 4), malaise (n = 4) and pallor (n = 2). Liver and lymph nodes were the commonest organs (4) involved, followed by spleen (3), lungs (2), skin and mucocutaneous region (2). Adrenal involvement was seen in none. It is well documented that histoplasmosis is rare below 2 years of age due to immaturity of T cell immunity [13]. It has been reported previously that pediatric histoplasmosis in immune normal children has a high rate of asymptomatic and mild infections [1]. Immune normal children with symptomatic acute histoplasmosis present with fever, malaise, mild cough and non-pleuritic chest pain. In fewer than 5–10 % children, the symptoms persist and pericarditis, arthritis, arthralgia, mediastinal lymphadenopathy and maculopapular rash are seen as complication as was observed in this patient. Granulomatous inflammation in mediastinal lymph nodes induces pericarditis in 6 % of patients with acute pulmonary histoplasmosis [1, 14]. The possibility of progressive disseminated histoplasmosis leading to death of patient cannot be ruled out, as the patient in this case report was a child and had gradual weight loss, fever, fatigue, skin lesions, lymphadenopathy and hepatosplenomegaly with pancytopenia. Disseminated histoplasmosis is a rare disease that occurs primarily in immunocompromised persons, especially in patients with HIV infection and a CD4 lymphocyte count that is below 150–200/mm3
123
(150–200 9 106/L) [14]. However, disseminated disease in India is predominantly seen in HIV-negative patients who are often misdiagnosed and are inappropriately treated [9–11]. The spectrum of illness in disseminated disease ranges from a chronic, intermittent course in immunocompetent persons to an acute and rapidly fatal infection that usually occurs in infants and severely immunosuppressed persons [15]. The usual symptoms are fever, chills, non-productive cough, anterior chest discomfort, myalgias, arthralgias and fatigue [14]. Physical examination may reveal hepatosplenomegaly and lymphadenopathy or, less frequently, mucocutaneous lesions such as oropharyngeal ulceration. Laboratory evaluation frequently reveals pancytopenia caused by bone marrow involvement and abnormal results on hepatic function tests, indicating that the disease has spread to the liver [16–18]. The patient in this case report had a rare presentation of severe generalized bone pain with pyrexia mimicking acute leukemia of childhood. No significant predisposing factor for DH could be seen and it was only on the screening of peripheral blood (followed by bone marrow, LN aspirate and skin biopsy for fungal culture) where occasional but definitive presence of intracytoplasmic yeasts forms was noted which were similar in size with platelets but with a peripheral halo and a crescent-shaped peripheral chromatin. Elin et al. [19] have pointed that a number of organisms in peripheral blood may mimic H. capsulatum like P. marneffei, Balstomyces dermatitidis, Candida glabrata, Pneumocystis carinii, Leshmania species and Toxoplasma gondii. Furthermore, culture of H. capsulatum is of paramount importance as it clinches the diagnosis of histoplasmosis, thereby ensuring specific antifungal therapy. Despite diagnosis and institution of appropriate antifungal (amphotericin B), patient in this case died due to severity and complications of infection. Out of five pediatric immunocompetent cases reported in India till date, two were fatal [6–9]. This is probably associated with the lack of awareness, misdiagnosis and unwarranted anti-tubercular therapy in a tuberculosis endemic country like India. In a recent case from Delhi, a pediatric immunocompetent patient had a relapse with histoplasmosis despite appropriate therapy of induction with amphotericin B (3 weeks) followed by itraconazole (6 months). However, the patient was successfully treated by voriconazole [9]. There is a paucity of
Kaliranjan et al. [5]
Chakravarty et al. [6]
Mukherjee et al. [7]
Mukherjee et al. [8]
Dhawan et al. [9]
Current case, 2014
1
2
3
4
5
6
Author, year
7 year/F
3 year/M
3 year 10 m/ M
8 year/M
10 year/F
5 year/M
Age/sex
Mathura, Uttar Pradesh
Delhi
–
?
?
?
–
?
West Bengal
?
–
?
?
–
Pallor
?
Fever
West Bengal
Mathura, Uttar Pradesh
Tamil Nadu
Place/ state
?
?
?
?
–
?
?
?
?
?
–
–
?
?
–
?
–
–
?
–
?
–
?
–
Pulmonary
Lymph node Cardiac
_
–
?
?
?
?
?
–
–
-
–
–
Peripheral blood, bone marrow, skin biopsy
Skin biopsy
Bone marrow
Lymph node
Lung biopsy
Lymph node
Histoplasma capsulatum, culture and sequencing
Histoplasma capsulatum
Not done
Histoplasma capsulatum
Sterile
Sterile
Culture
HPE
Skin, mucocutaneous
Liver
Spleen
Fungus identified in
Organ involvement
Table 1 Summary of pediatric immunocompetent histoplasmosis cases reported from India
Amphotericin B
Itraconazole, amphotericin, voriconazole
Amphotericin B
Nystatin penicillin and streptomycin, amphotericin B could not be procured
None
Not available
Treatment
Died
Survived
Died
Died
Survived
Not available
Result
Mycopathologia
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Mycopathologia
antifungal susceptibility studies from India. In a recent study depicting antifungal susceptibility profile of 21 isolates collected from northwestern India, the authors concluded that the mycelial and yeasts forms of the isolates were inhibited by itraconazole, posaconazole, voriconazole, amphotericin B and isavuconazole, respectively, and both the forms had good agreement on minimum inhibitory concentration [11]. In conclusion, progressive disseminated histoplasmosis in children can be fatal despite timely diagnosis and therapy. This case highlights a rare presentation of histoplasmosis in an immunocompetent child mimicking acute leukemia, causing diagnostic dilemma. Acknowledgments The authors acknowledge the help of Dr (Prof.) Arunaloke Chakrabarti and Dr M. R. Shivaprakash, National Culture Collection of Pathogenic Fungi, PGIMER, Chandigarh, India, for reconfirming the isolate by DNA sequencing. The authors also acknowledge the help of Late Mrs. Kamlawati, Senior Technician, Department of Microbiology, V.M.M.C and Safdarjung Hospital, Delhi, India, for her technical expertise in the case.
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