Deoxycholate amphotericin for histoplasmosis in a patient with poor kidney function

Abstract

A 48-year-old male patient living with HIV presented to our hospital with fever and weight loss. On evaluation, he was found to have pancytopenia, deranged liver and kidney function. CD4 count was 13 cells/uL. Bone marrow examination done because of pancytopenia showed yeast forms of histoplasmosis. Although liposomal amphotericin B is preferred for induction, he was treated with deoxycholate amphotericin B despite poor kidney function because of financial constraints. He was treated for 12 days with intravenous amphotericin, during which his clinical condition significantly improved. He was discharged on oral itraconazole.

Background

Histoplasmosis is a neglected opportunistic infection in India.¹ The diagnosis of histoplasmosis is challenging in resource-limited settings. It is often misdiagnosed as tuberculosis (TB) due to similarities in the presentation.² With an increase in awareness and better availability of diagnostics, an increasing trend has been noted in its incidence. Severe disease is treated with an induction course of amphotericin B. Liposomal amphotericin B, being more efficacious and less nephrotoxic, is preferred over deoxycholate amphotericin B.³ However, in countries without pocket expenditure for healthcare, such treatments are expensive. We describe a case of disseminated histoplasmosis in a patient with renal failure treated with deoxycholate amphotericin B.

Case presentation

A 48-year-old male patient living with HIV presented with fever, fatigue and significant weight loss for 1 month. He was diagnosed with HIV 10 years back. He was put on antiretroviral therapy (ART), but he was non-compliant with the medications, and he discontinued ART medications 3 years before. At presentation, he was found to have hypotension, tachycardia and altered sensorium with a Glasgow coma scale of 13/15. On physical examination, he had oral candidiasis, ulcers on the hard palate and hepatosplenomegaly.

Investigations

Laboratory investigations showed pancytopenia, renal failure, hepatitis and features suggestive of disseminated intravascular coagulation (table 1). Although prehospital creatinine values were not available, the baseline creatinine value of 1.3 suggests a possible acute kidney injury or chronic kidney disease. However, the decrease in creatinine from 4.3 mg/dL at admission to 1.3 mg/dL at discharge suggests a definite possibility of acute kidney injury with or without a background kidney disease. Ultrasound abdomen showed bilateral grade 2 renal parenchymal changes of kidneys with maintained corticomedullary differentiation. CD4 count was 13 cells/uL. HRCT thorax showed cavitary changes in the left upper lobe and ill-defined ground glassing opacities in the right lower lobe. Bone marrow aspirate was done in view of pancytopenia. Staining for acid-fast bacilli (AFB) and GeneXpert in the bone marrow aspirate for Mycobacterium tuberculosis was negative. Mycobacterium Growth Indicator Tube (MGIT) culture at 6 weeks of incubation was also sterile.

Table 1.

Haematological and biochemical parameters on the day of admission and discharge

	Day of admission	Day of discharge	Reference range
Haemoglobin	4.3 g/dL	6.3 g/dL	13–17 g/dL
White blood cell	1.3 * 109/L	3.5 * 109/L	4-10 *109/L
Platelet	20*109/L	25 * 109/L	150-400 * 109/L
Urea	>240 mg/dL	72 mg/dL	16.6–48.5 mg/dL
Creatinine	4.3 mg/dL	1.3 mg/dL	0.7–1.2 mg/dL

Differential diagnosis

In an endemic region, TB is the first differential for patients with fever, weight loss and opacity on the chest X-ray. Lymphoma, histoplasmosis, cryptococcosis and visceral leishmaniasis were the other differentials. TB was less likely as staining for AFB, GeneXpert and MGIT culture were negative. However, the possibility of TB could not be completely ruled out. Since the patient hails from the South Indian state of Karnataka, which is non-endemic for visceral leishmaniasis, it was considered less likely. Pancytopenia, shock (suggestive of adrenal involvement) and palatal ulcers pointed towards a possibility of histoplasmosis. Bone marrow aspirate showed yeast forms of Histoplasma capsulatum.

Treatment

The patient was empirically started on injection meropenem at presentation. Oxygen therapy was initiated at 4 L/min through nasal prongs. Inferior vena cava-guided intravenous fluids and norepinephrine were initiated for shock. After the diagnosis of histoplasmosis was confirmed, meropenem was stopped, and deoxycholate Amphotericin B (1 mg/kg diluted in 5% dextrose solution) was infused daily over 1 hour. Prior to Amphotericin B administration, he was premedicated with 250 mL of normal saline containing 20 mEq Potassium chlorideover 2 hours. Once recovery from shock was noted, intravenous fluids and inotrope were gradually tapered. Postinitiation of amphotericin B, initial worsening of renal function was noted. However, this improved as the infusion rate was slowed and the amount of intravenous fluids in premedication was increased to 500 mL. Deoxycholate amphotericin B was given for 12 days, followed by which he was shifted to oral itraconazole (200 mg two times per day). Antiretroviral therapy was started after 10 days of amphotericin B.

Outcome and follow-up

Improvement in symptoms was seen within a week of starting amphotericin B. He recovered from the shock and his Glasgow Coma Scale improved to 15/15. There was an improvement in pancytopenia and renal function (table 1).

Discussion

Histoplasmosis is caused by Histoplasma capsulatum, a thermally dimorphic fungus. It is one of the most common endemic mycoses seen in patients with HIV.^4–6 A high concentration of fungus is found in soil contaminated with bird or bat excreta. The route of infection is the inhalational route. Bird handling, spelunking and construction are the high-risk activities associated with an increased risk of acquiring infection in endemic areas.^{2 7 8} Histoplasmosis was an uncommon infection in India, but there has been a steady increase in the number of cases recently. According to Randhawa, over 400 cases have been detected since the 1950s, with around 200 cases in the last decade alone.¹ Mild self-limiting pulmonary illness is the usual manifestation in immunocompetent individuals, while those with advanced HIV disease go on to develop progressive disseminated histoplasmosis.⁹ Common symptoms include fever, night sweats, fatigue, weight loss, nausea, vomiting and dyspnoea. On examination, there may be hepatosplenomegaly and lymphadenopathy. Isolated pulmonary involvement without dissemination is seen in <5% of cases.^{8 10} Severe disease manifests as a sepsis-like syndrome with multiorgan failure (including respiratory or renal failure) or concomitant meningitis.^{4 11–13} Bone marrow involvement can result in pancytopenia.⁶ Although there was some improvement in the blood counts, it did not normalise by the time of discharge as the patient had received only 12 days of in-hospital therapy. In a report by Notopuro et al, it took 3 months for the patient to recover from pancytopenia following initiation of treatment.¹⁴

Urinary antigen for histoplasmosis, although very sensitive and specific, is not available in most centres in India, owing to the cost of the kits.^{6 15} Microscopy, though of low sensitivity, is a rapid and inexpensive method. Diagnosis in our patient was on the basis of visualisation of yeast forms on bone marrow aspirate.^{6 13} Culture of the microbe is considered the gold standard but is time-consuming, and sensitivity depends on disease burden.¹³

The treatment of histoplasmosis depends on the severity of the disease. Mild disease is those with a single focus of infection (except central nervous system involvement) and mild clinical features. Mild disease is treated with itraconazole alone. Those with severe immunosuppression, disseminated disease, pancytopenia, features of sepsis and multiorgan dysfunction are considered to have moderate to severe disease.¹⁵ Moderate to severe disease requires an induction phase with amphotericin B followed by itraconazole for long-term maintenance once clinical improvement is noted. Amphotericin B is the preferred agent in moderate to severe disease due to its fungicidal action and faster clearance than itraconazole, a fungistatic agent.^{16 17} According to Johnson et al, liposomal amphotericin B is superior to amphotericin B deoxycholate in terms of better survival rate and lesser incidence of nephrotoxicity.³ The induction phase with amphotericin B was considered in our case as he presented with hypotension, altered sensorium, pancytopenia and multiple organ involvement (lung, renal failure and bone marrow involvement). Liposomal amphotericin B was not feasible due to financial constraints. Despite the higher risk of acute kidney injury, the patient was treated with deoxycholate amphotericin B. The patient improved clinically over the course of 12 days. His renal function, despite initial deterioration, reversed after completing the course of deoxycholate amphotericin. To reduce the chances of increasing nephrotoxicity, the premedication hydration and infusion time were increased. Although measures such as decreasing the dosage and increasing the duration between two doses are also suggested measures to decrease nephrotoxicity, they were not required for this patient. We report this case to highlight deoxycholate amphotericin’s utility as an alternative induction therapy agent in a patient with histoplasmosis with decreased renal function.

Learning points.

• Histoplasmosis can mimic tuberculosis as both primarily involve lungs, present with fever, cough, weight loss and show granulomas on histopathology.

• Direct microscopy can be helpful in some cases, particularly in places where the urinary antigen is not available.

• Amphotericin B deoxycholate is an alternative to liposomal amphotericin in resource-poor settings, even with underlying renal dysfunction, provided renal function is closely monitored.

Ethics statements

Patient consent for publication

Obtained.