Histoplasmosis, heart failure, hemolysis and haemophagocytic lymphohistiocytosis
Nitin Gupta1, Kutty Sharada Vinod1, Ankit Mittal1, Aswin Pius Ajay Kumar1, Arvind Kumar1, Naveet Wig1,&
1Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
Naveet Wig, Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
Histoplasmosis is an endemic mycosis with global distribution, primarily reported in immunocompromised individuals. A 29-year old immunocompetent male presented with fever, hepatosplenomegaly and pancytopenia. His peripheral blood showed features suggestive of intravascular hemolysis and echocardiography showed features suggestive of pulmonary arterial hypertension. Bone marrow showed yeast with morphology suggestive of Histoplasma capsulatum. Further investigations revealed hyperferritinemia, hypofibrinogenemia and increased triglycerides. With a diagnosis of progressive disseminated histoplasmosis with secondary Haemophagocytic lymphohistiocytosis, he was successfully treated with amphotericin B followed by itraconazole. We report this case to highlight the atypical and rare manifestations of histoplasmosis.
Histoplasmosis is an endemic mycosis caused by the dimorphic fungi, Histoplasma capsulatum. The mode of infection is by inhalation of microconidia that are usually found in bird or bat guano containing soil. In immunocompetent individuals, such acute infection resolves on its own while the disease may be limited to lungs or disseminate to liver, spleen and bone marrow in immunocompromised . Definite diagnosis of histoplasmosis is made by demonstrating fungi on microscopy or cultures. Cultures may take up to six weeks to become positive and can lead to a significant delay in diagnosis. The treatment of choice is amphotericin B followed by oral itraconazole or itraconazole alone depending upon severity and extent of disease . We report a case of histoplasmosis in a young immunocompetent male with atypical presentations.
Patient and observation
A 29-year old male patient from Delhi with no known prior comorbidities
presented with fever and dry cough for 40 days and progressively worsening
dyspnea for 15 days. This was associated with loss of appetite and loss
of weight (5kg in 40 days). On general physical examination, patient was
febrile, pulse rate was 134/min, SpO2 on room air was 92%, respiratory
rate was 36/min and blood pressure was 110/70 mm of Hg. Pallor was present
but there was no icterus, cyanosis, pedal edema or lymphadenopathy. On systemic
examination, moderate hepatosplenomegaly was present. Chest was bilaterally
clear. On initial laboratory investigation, he was found to have pancytopenia
(Haemoglobin-8.4/dl, Platelet count-79,000/µl, total leucocyte count-3900/µl).
Malarial parasites were not seen on peripheral smear and quantitative buffy
coat examination. Blood and urine cultures were sterile. Serology for HIV
1 &2 was non-reactive. Antibodies against rk-39 were negative. Widal titre
was < 1:40 for typhoidal O, typhoidal H and paratyphoidal H antigen.
Peripheral smear showed presence of schistocytes with a corrected reticulocyte
count of 1.8%. Lactate dehydrogenase (LDH) was found to be elevated (579
IU/l) and direct coomb’s test was positive. Vitamin B12 and folate levels
were normal. Electrocardiogram (ECG) showed right bundle branch block with
S1Q3T3 pattern (Figure 1).
B type natriuretic peptide levels (211.6 pg/ml) were elevated. Echocardiography
showed moderate pulmonary arterial hypertension (Pulmonary artery systolic
pressure- 43+10 mm of Hg), moderate tricuspid regurgitation and prominent
right atrium and ventricles. Left ventricle ejection fraction was 70%. Minimal
pericardial effusion was also noted. CT pulmonary angiogram was normal.
USG Venous Doppler of all four limbs were normal.
Bone marrow aspirate showed mild relative erythroid hyperplasia with both intracellular
and extracellular yeast with morphology suggestive of Histoplasma capsulatum
). Histoplasma serology however was negative. CD4 count was 454/mcl
(39.9%). IgA, IgG and IgM levels were normal. Anti-nuclear antibody (ANA) and
Anti ds DNA were negative. Fibrinogen levels (< 150mg/dl) were decreased. Triglycerides
(304 mg/dl) and ferritin levels (> 2,000ng/ml) were increased.
Patient was started on intravenous liposomal amphotericin B. His fever resolved
on day 4 of liposomal amphotericin B. His dyspnea, however resolved on day 10
of liposomal amphotericin B. On day 13, he was shifted to itraconazole therapy.
Follow up platelet count and total leucocyte count after 12 days of therapy was
1.8 lakh/cu.mm and 4500/cu.mm respectively. The hemoglobin at three weeks after
the initiation of therapy was 9.4g/dl. No blood was transfused during or after
the hospital stay. Follow up echocardiography on day 5 of amphotericin B revealed
mild pulmonary arterial hypertension (pulmonary artery systolic pressure- 36+
10mm of Hg) and trivial tricuspid regurgitation. Right atrium and right ventricles
were normal in size. He resumed his normal daily activities within a week of
discharge. He continued to take itraconazole for four months and discontinued
on his own. He returned to follow up one year later from the time of discharge
for routine checkup. His complete blood count was normal (hemoglobin- 14.6g/dl,
total leucocyte count- 7430/ cu.mm, platelet count- 3 lacs/ cu.mm). 2D echocardiography
showed a pulmonary artery systolic pressure of 31+ 10 mm of Hg and trivial tricuspid
Histoplasmosis has widespread distribution in the western world but it is also endemic in many parts of South-East Asia. It has been reported in India since the 1950s with variable histoplasmin sensitivity rates (0-12.3%) [3, 4]. Its spread and increasing incidence has largely been attributed to the HIV pandemic and increasing use of immunosuppressive agents in transplant recipients and patients with rheumatological disorders. However, cases have been reported time and again in immunocompetent individuals. In a review by Kathuria et al., 61 cases of histoplasmosis in immunocompetent adults was reported between 1995 and 2011 from India . Three large studies from Delhi and South India reported 80 cases of disseminated histoplasmosis in ten years. Most of the cases were reported from the Gangetic delta . Histoplasmosis can also get complicated with secondary Haemophagocytic lymphohistiocytosis (HLH) as a result of a cytokine storm due to an overwhelming activation of lymphocytes and macrophages. This condition may be rapidly fatal if the cause is not discovered and treated adequately. In a review by Sonavane et al., thirty-eight cases of Histoplasmosis associated HLH have been reported worldwide, of which eight cases were from India. Most cases have been reported in the immunocompromised hosts . Anemia in histoplasmosis is common and is mostly because of the bone marrow involvement and/or rarely due to secondary HLH. However, the case described above also had a component of coomb’s positive hemolytic anemia. To the best of our knowledge, only two such cases have been reported but the pathophysiology of such an occurrence is still not clear [7, 8].
Another important clinical feature that our patient had was pulmonary arterial
hypertension. The patient had acute worsening in shortness of breath and the
ECG showed S1Q3T3 pattern. CT pulmonary angiogram showed no abnormality. We could
not explain pulmonary hypertension in our patient as he was asymptomatic prior
to this presentation and we could not find any reports that linked histoplasmosis
with pulmonary hypertension. However, an interesting finding was noted in our
patient. With successful treatment, there was a significant reduction in pulmonary
artery systolic pressure (53mm of Hg to 41mm of Hg) on follow up echocardiography.
The diagnosis in our patient was confirmed by spotting the typical morphology
of histoplasmosis on giemsa staining of bone marrow aspirate. The sensitivity
of direct demonstration and culture in progressive disseminated histoplasmosis
is 76% and 74% respectively [1
]. For disseminated histoplasmosis,
amphotericin B is given for 7-14 days followed by oral itraconazole for up to
a year. Our patient stopped his treatment after four months of initiation. Considering,
he was asymptomatic even after eight months of discontinuation and wasn’t willing
to start treatment again, we decided to follow him up closely. Management of
secondary HLH requires treatment of the primary disease; however, the chemoimmunotherapy
for HLH including steroids, etoposide and cyclosporine may be required in certain
Histoplasmosis is increasingly being reported from the Indian subcontinent, especially in individuals without any risk factors for the disease. We report this case to highlight the atypical and rare manifestations that can be associated with this disease.
The authors declare no competing interests.
NG was the primary care physician and prepared the first draft of the report. KSV, AM and APAK were part of the treating unit and were directly involved in the patient care. KSV and AM helped in review of literature. AK and NW were overseeing patient management and helped in review of literature. NW reviewed the final draft.
Figure 1: ECG showing S1Q3T3 pattern
Figure 2: bone marrow aspirate showing small extracellular cellular yeast cells with a false appearance of capsule around them
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