Disseminated Histoplasmosis with Unusual Presentation in a Heart Transplant Recipient

INTRODUCTION

Histoplasmosis is caused by a dimorphic fungus named Histoplasma capsulatum (HC), which is present in nature as a spore-producing mold and converts into yeast in human tissue after infection.^[1] It is endemic in the Mississippi and Ohio River Valleys of North America, Central and South America.^[2] Endemicity is seen in the eastern states (West Bengal, Assam) and some parts of North and South India.^[3] Histoplasma infection commonly occurs in the lungs by inhalation of aerosolized microconidia from the environment.^[4] Because it resembles other pulmonary infections such as pneumonia, tuberculosis, and sarcoidosis, it is unusual to suspect Histoplasma as a causative agent in non-endemic regions. Thus, it may disseminate to other organs and become fatal, especially in an immunocompromised patient.^[4]

Histoplasmosis can have an unusual clinical presentation in heart transplant (HTx) and other immunosuppressed patients, posing a challenge to diagnose it, especially in non-endemic regions.^[4] HTx recipients have a propensity for severe infection and spread of infection to other organs, given their inability to contain the infection, with significant associated morbidity and mortality.^[4,5] A heightened awareness among clinicians is required while evaluating infections in immunosuppressed patients for timely diagnosis. Pathogen isolation from clinical specimens remains the gold standard for diagnosing histoplasmosis, though histopathologic or direct microscopic identification is also considered a definitive diagnosis.^[6] Amphotericin B (AmB) is the drug of choice for severe or disseminated disease whereas itraconazole is recommended in milder cases and as “stepdown” therapy after initial treatment with AmB.^[1,7] We report a case of disseminated histoplasmosis with unusual clinical presentation in an HTx recipient.

CASE REPORT

A 45-year-old female, resident of Delhi, India, had undergone heart transplantation 14 years ago in October 2011. Her cardiac function deteriorated with a left ventricular ejection fraction of 35–40% since last 6 years. She was a known case of diabetes mellitus (DM) and hypothyroidism. She developed chronic kidney disease (CKD) 4 years ago. She was on medical management for CKD, DM, and hypothyroidism. The patient was on maintenance immunosuppressive therapy with tacrolimus, mycophenolate mofetil (MMF), and on regular follow-up.

In the 1^st week of April 2025, the patient presented with complaints of diarrhea for 10 days, 8–10 times/day, loose in consistency but not watery, and did not have mucous, pus, or blood in stool. She did not have a fever or signs of dehydration, and she was hemodynamically stable. She was initially treated with oral tinidazole without any relief. She was admitted to our hospital and laboratory stool workup was done – ova, cyst, Giardia, Clostridium difficile toxin was negative, and stool culture was sterile. She was treated with a course of intravenous metronidazole and ceftriaxone, after which the patient had symptomatic relief for 48 h. Again, the patient had a recurrence of similar frequent loose stools, which affected her well-being and appetite severely. A gastroenterology consultation was done. Ultrasound abdomen suggested mild hepatosplenomegaly and no other abnormalities. Lower gastrointestinal (GI) endoscopy reported multiple erosions with erythematous mucosa in the colon and rectum. Histopathology of colonic mucosal biopsy showed lymphohistiocytic infiltrate and small fungal elements surrounded by a clear halo inside the histiocytes, which was consistent with HC [Figure 1a-c]. The colonic lavage fluid GeneXpert was negative, suggesting no tuberculosis. Serum immunoglobulin M and deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) for cytomegalovirus were negative.

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Figure 1: (a) Multiple mucosal fragments from a colonic biopsy with maintained crypt architecture (a ×20) haematoxylin & eosin [H&E] stain. (b and c) One of the fragments at higher power. The lamina propria shows mild lympho-histiocytic cell infiltrate. Within the histiocytes, a few small round fungal particles are noted, surrounded by a clear halo, consistent with histoplasmosis (black arrows) (b ×200, c ×600) H&E stain.

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The patient’s immunosuppressive therapy was modified to decrease the level of immunosuppression – MMF was stopped, tacrolimus dose was reduced to achieve a lower blood level around 5 ng/mL, and prednisolone was started at 5 mg once daily. Treatment of histoplasma infection was started with oral itraconazole 200 mg 3 times daily. After 3 days of itraconazole, the frequency of loose motions decreased, but this clinical improvement lasted for a few days. Within 1 week, the patient had a recurrence of frequent loose motion despite being on itraconazole. She was readmitted, and laboratory tests of stool and blood were repeated; the test results were found to be unremarkable, and urinary Histoplasma antigen was negative.

Whole body positron emission tomography computerized tomography (PET-CT) scan showed a metabolically active cavitary lesion in the lower lobe of the right lung with mediastinal lymph nodes and a focus of fluoro-deoxy glucose (FDG) uptake in the D2 part of the duodenum and transverse colon [Figure 2a-i]. Magnetic resonance imaging of the brain did not detect any parenchymal lesion. High-resolution computerized tomography chest showed a thick-walled cavity in the lower lobe of the right lung, few mediastinal lymph nodes, and fibrotic changes in the lower lobe of the right lung [Figure 3].

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Figure 2: (a) Few focal increased fluoro-deoxy-glucose (FDG) uptake in thoracic and abdominal region, (b and c) fused positron emission tomography computerized tomography shows FDG avid cavitatory lesion in the right lung lower lobe, (d and e) subcarinal and right peribronchial lymph nodes, (f and g) nodular lesion in 2nd part of duodenum (blue arrow), (h and i) wall thickening in transverse colon (white arrow).

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Figure 3: High -resolution computerizsed tomography chest shows thick a thick-walled cavity in the right lung lower lobe, few mediastinal lymph nodes, and extensive fibrotic changes in the lower lobe of the right lung.

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In view of disseminated histoplasmosis, the patient was given intravenous liposomal AmB at 3 mg/kg once daily for 3 weeks and she improved markedly. Then, AmB was bridged with oral itraconazole 200 mg twice daily and she was discharged home. A lower level of immunosuppression was continued till the completion of AmB course. Now, 4 months on follow-up, the patient is asymptomatic and doing well on itraconazole.

DISCUSSION

Histoplasmosis is a serious opportunistic infection in people who have undergone heart transplantation and it poses a significant threat to life. However, it is rare in non-endemic regions. Histoplasmosis is primarily acquired by inhalation of microconidia (spores) through the lungs.^[1] This dimorphic fungus converts from microconidia to yeast in macrophages in the lungs and then disseminates widely, especially in immunocompromised patients.^[1,4] Disseminated disease is common in an immunosuppressed state, occurring in 64–81% of patients, and pulmonary involvement is almost always observed.^[4,5] Whereas pulmonary manifestation is the most common, some organ transplant patients may have atypical clinical presentation^[5] as occurred in our patient who had GI symptoms exclusively. Histoplasma infection with GI symptoms was reported in 3–12% of disseminated cases in transplant recipients.^[8] It can cause chronic diarrhea, abdominal pain, GI bleeding, and malabsorption. On endoscopy, it often appears as mucosal ulcerations or granulomatous lesions that can mimic other infections such as intestinal tuberculosis or inflammatory bowel disease.^[8] In our patient, lower GI endoscopy showed erosions, erythematous mucosa, and tuberculosis was ruled out.

Most cases tend to occur within the first 2–3 years after transplantation (median time varies in different studies) when immunosuppressive therapy is most intense.^[4,5,9] However, late presentations can occur,^[4] as seen in our patient who developed disseminated histoplasmosis 14 years after HTx. This underscores that long-term transplant survivors remain at risk, especially if freshly exposed to the pathogen or if latent HC infection reactivates under continued immunosuppression.^[4] Our patient was on maintenance immunosuppressive therapy for the last 14 years which was a strong risk factor for getting a fresh infection.

T-cell-mediated immunity, particularly granuloma formation and macrophage activation, is essential to contain HC infection and spread. In immunosuppressed hosts, granulomatous responses may be blunted, allowing unchecked proliferation and dissemination of the fungus.^[10]

Multiple diagnostic modalities are available to diagnose histoplasmosis. Demonstration of the organism through histopathology or culture is the gold standard for diagnosing HC.^[6] Histopathology of the colonic mucosal biopsy confirmed the presence of HC in our patient.

Cultures for HC can confirm the diagnosis but are often slow (taking weeks) with low yield. Fungal blood cultures are positive in only ~50% of disseminated cases.^[6] In our patient, blood and stool cultures were negative, which was not uncommon in disseminated histoplasmosis unless the patient is significantly fungemic. Molecular diagnostics such as PCR-based assays for histoplasma DNA on clinical specimens are emerging as useful tools, especially in cases with unusual presentations.^[6]

Histoplasma polysaccharide antigen can be detected in the urine and serum of patients with disseminated or acute pulmonary histoplasmosis. In transplant recipients, the urine antigen test has a reported sensitivity of around 90–95% in disseminated disease.^[6] In our patient, the urine histoplasma antigen was negative, possibly due to prior antifungal exposure (the patient received itraconazole before the urinary antigen test).

Our case also illustrated the utility of FDG PET-CT scanning in suspected systemic infection in immunosuppressed patients. PET-CT helped to localize the infective foci (lung and duodenum), ruled out infection spread in other organs, including the brain and also helped to negate other potential pathologies like malignancy.

Treatment of disseminated histoplasmosis in HTx recipients requires careful management of immunosuppression to balance the allograft survival and, at the same time, treat the infection effectively with antifungal therapy. AmB is the drug of choice for induction therapy. A 1–2 week course of liposomal AmB at 3–5 mg/kg daily is typically given for acute disseminated disease or longer (4–6 weeks) if the central nervous system is affected.^[1,7] At first, we started the treatment with itraconazole because our patient had isolated GI symptomatology and she was a diagnosed case of CKD with creatinine of 2.8 mg/dL. However, when her symptoms persisted even with itraconazole treatment and PET scan confirmed disseminated disease, we administered a 3-week course of liposomal AmB which led to marked clinical improvement. Then, we put her on itraconazole 200 mg twice daily as stepdown therapy. After induction with AmB, the recommended stepdown therapy is itraconazole, a highly active oral azole, for at least 12 months.^[7] Our patient was discharged on itraconazole and will require prolonged therapy. Therapeutic drug monitoring of itraconazole levels is advisable to ensure adequate absorption and to adjust the dose if needed.^[7] Now, at 4-month follow-up, the patient is asymptomatic and doing well.

CONCLUSION

Disseminated histoplasmosis is a serious opportunistic infection in HTx patients. Chronic immunosuppression is the major risk factor for acquiring Histoplasma infection. Diagnosing histoplasmosis in immunosuppressed patients with atypical clinical presentation is challenging. Diarrhea was the only manifestation in our patient, HC was diagnosed from colonic mucosal biopsy, and the patient was treated effectively with initial AmB followed by itraconazole. Management also required judicious adjustment of immunosuppressive drugs to aid effective treatment of infection while preventing allograft rejection. Although an uncommon fungal infection in non-endemic regions, histoplasmosis should be suspected in HTx recipients with exclusive GI symptoms.