Disseminated histoplasmosis in an immunosuppressed patient successfully treated with isavuconazole

Background

Histoplasma capsulatum is a dimorphic fungus that grows in a hyphal form in soil associated with bird or bat droppings. In the USA, Histoplasma is mainly found in the soil of the central and eastern states, especially the Ohio and Mississippi River valleys, but has a global distribution including Baja California, Central and South America, Africa, Asia and Australia. When spores are inhaled, they transform into a pathogenic yeast phase in the lungs (alveoli) that can travel via the bloodstream to various parts of the body and cause a wide spectrum of disease. Although most people who inhale spores have subclinical or self-limited disease and do not require treatment, immunocompromised patients, especially those with altered cellular immunity, such as those with HIV, solid organ and haematopoietic transplants, on tumour necrosis factor (TNF)-alpha inhibitor or steroids, and those and with progressive disseminated disease or chronic pulmonary disease, should be treated.1

Liposomal amphotericin B (3.0–5.0 mg/kg/day for 1–2 weeks) is the preferred agent for initial therapy of severe or disseminated disease.2 Itraconazole (200 mg three times a day for 3 days, then once daily for 6–12 weeks) may be used for ‘step-down’ therapy following response to amphotericin B and for initial therapy for patients with mild but prolonged symptoms (>1 month). Itraconazole solution is preferred to capsules, but to maximise absorption, itraconazole capsules require high gastric acidity and should be taken with a carbonated drink (soda), and the use of concomitant antacids, H2 blockers and proton pump inhibitors should be avoided. Despite the widespread availability of these therapies, clinicians may encounter treatment challenges due to the potential malabsorption of itraconazole and the toxicity associated with amphotericin B. Thus, alternative treatment options are needed.

Isavuconazole is a newer, water-soluble triazole with broad-spectrum antifungal activity and a good safety profile. It is available in both intravenous and oral forms. Its mechanism of action is to inhibit the fungal cytochrome P450 lanosterol 14-alpha-demethylase (CYP51) enzyme that catalyses the conversion of lanosterol to ergosterol impairing fungal cell membrane synthesis, thereby increasing cell membrane permeability leading to cell lysis and death. Isavuconazole is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis.

In vitro studies have demonstrated that isavuconazole has activity against yeasts including Candida spp (but not C. glabrata and C. krusei), Cryptococcus spp, moulds, including some Aspergillus spp, Mucorales and dimorphic fungi.3 Isavuconazole has been reported to have in vitro activity against histoplasmosis but not an approved indication, and its use in clinical practice for treatment of histoplasmosis is limited.

We report a case of disseminated histoplasmosis in an immunocompromised host who experienced amphotericin toxicity and itraconazole intolerance, and was subsequently successfully treated with isavuconazole. We also review the literature and provide a case series of 12 reported cases of histoplasmosis treated with isavuconazole. This report explores the challenges of treating histoplasmosis and provides information on the clinical use of isavuconazole for treatment when first-line and second-line therapies are ineffective or contraindicated (excluding meningitis).

Case presentation

A man in his early 70s, with an extensive travel history and a history of hypertension and rheumatoid arthritis on methotrexate and infliximab, presented to the emergency department (ED) with generalised weakness, shortness of breath and hiccups for 1 month. Symptoms started shortly after being treated for an episode of shingles. Due to the hiccups, he was unable to eat and experienced a 15-pound weight loss. He was seen by his primary care doctor where routine blood work was done that showed elevated liver enzymes. He denied any fever, nausea, vomiting, diarrhoea or abdominal pain.

The patient was a lifelong non-smoker with no history of alcohol or drug use. He was born in South Asia but lived most of his adult life in West Coast of the USA. He denied any known sick contacts and had no travel history within the last year. He had a medical history of extended spectrum beta lactamase Escherichia coli prostatitis and underwent transurethral resection of the prostate 3 years prior to admission with full resolution.

Upon presentation to the ED, his vital signs were as follows: temperature was 97.7°F; blood pressure, 111/73 mm Hg; heart rate, 99 beats/min; respiration rate, 18/min; and oxygen saturation, 99% on room air. Overnight, he developed a fever of 101.7°F. He had white cell count of 11.9 x 10⁹/L with a differential of 63.5% neutrophils, 22.8% lymphocytes, 11.9% monocytes and 0.5% eosinophils. Abnormal laboratory tests included: sodium 129 mmol/L; alkaline phosphatase, 409 U/L; aminotransferase, 151 U/L; alanine aminotransferase, 161 U/L; total bilirubin, 1.0 mg/dL; direct bilirubin 0.2 mg/dL; and erythrocyte sedimentation rate, 66 mm/hour. His serum creatinine was initially 1.42 mg/dL, which returned to 1.16 mg/dL with fluid resuscitation. He was started on empirical vancomycin and ceftriaxone for possible sepsis.

An acute hepatitis panel (hepatitis B antibody IgM, hepatitis B core antibody IgM, hepatitis B core antibody total, hepatitis B surface antigen, hepatitis B surface antibody, hepatitis A antibody IgM and hepatitis C antibody), Epstein-Barr virus serologies, cytomegalovirus PCR, SARS CoV-2 PCR, influenza A and B antibody, HIV-1 fourth-generation antibody and Legionella urinary antigen tests were all negative. Bacterial, fungal and viral blood, urine and respiratory cultures were sent and yielded no growth. A urine culture grew methicillin-resistant Staphylococcus aureus with low colony counts, which was considered a contaminant.

While a chest X-ray and abdominal ultrasound were unremarkable, a CT scan of the chest with contrast showed multiple, uncalcified pulmonary micronodules in both lungs, bilateral pulmonary emboli and prominent mediastinal and portacaval lymph nodes, as well as multiple shotty central mesenteric lymph nodes. The patient underwent bronchoscopy with a guided transbronchial needle core biopsy and fine needle aspiration of a lymph node. Routine, acid-fast bacillus and fungal stains from bronchoscopy samples were negative and cytology showed no malignant cells. A Grocott methenamine silver (GMS) stain was negative for fungal organisms. Fine needle aspiration pathology of the lymph node showed anthracotic lymphoid tissue with focal granulomatous inflammation with necrosis and showed no evidence of malignancy or infection based on histopathology.

The 1,3-beta-d glucan assay (Fungitell assay, Associates of Cape Cod, East Falmouth, Massachusetts, USA) was elevated to >500 pg/mL prompting the work-up for a possible fungal infection. Coccidiomycosis immitis immunodiffusion tests as well as enzyme immunoassay (EIA) [IgG, IgM and complement fixation (CF)] were negative as were Cryptococcus antigen, Blastomyces and Aspergillus antibodies. The patient was empirically started on fluconazole while awaiting confirmation of diagnosis. While his Histoplasma antibody immunodiffusion was negative and complement fixation was <1:8, his Histoplasma serum antigen was positive at 3.89 ng/mL and the patient was started on empirical itraconazole 200 mg orally two times per daily for a presumptive diagnosis of histoplasmosis. A lumbar puncture was obtained and cerebrospinal fluid studies were negative for Histoplasma complement fixation, gram stain, India ink and fungal cultures.

The patient underwent a bone marrow biopsy due to concern for possible malignancy, which showed diffuse fungal elements identified on the GMS stain, with collections of histiocytes, consistent with disseminated histoplasmosis. One month after bronchoscopy, bronchoalveolar lavage fungal cultures returned positive for H. capsulatum with DNA probe confirmation. Karius blood test for pathogen detection (Karius Laboratory, Redwood City, California, USA) detected H. capsulatum at 150 DNA molecules per microlitre (MPM), reference interval <10 MPM in the blood.

Treatment

The patient was continued on itraconazole 200 mg orally two times per day given with an acidic beverage to help absorption. All antacids were discontinued. His lethargy, weight loss and dyspnoea initially improved, but soon he began to have diarrhoea and poor oral intake, weakness, fatigue and his overall condition deteriorated. The itraconazole level after 10 days of treatment was subtherapeutic at 0.6 µg/mL (therapeutic range >1.0 µg/mL) likely due to malabsorption from the diarrhoea. His Histoplasma serum antigen test had also risen from 3.89 ng/mL to 4.58 ng/mL.

He was started on intravenous, liposomal amphotericin B at a dose of 4 mg/kg. During the first infusion, he had immediate rigours, hypotension and hypothermia consistent with anaphylactic shock and was transferred to the intensive care unit (ICU) for vasopressor support. The patient’s reaction to liposomal amphotericin B was thought to be due to either anaphylaxis or an immune reconstitution inflammatory syndrome (IRIS); thus, he was also started on methylprednisolone 30 mg daily which was tapered over the following 6 weeks.

As the patient was intolerant to liposomal amphotericin B and had malabsorption of itraconazole, the treatment options for disseminated histoplasmosis in his case were limited. With the permission of the hospital and the patient, the decision was made to initiate treatment with isavuconazole. The risks, benefits and safety profile of the off-label use of isavuconazole for treatment of disseminated histoplasmosis were discussed with the patient and he consented to treatment. He was initially started on isavuconazole 372 mg intravenously every 8 hours for 6 doses as a loading regimen, and then maintained on 372 mg intravenously daily for 30 days. He was then transitioned to oral isavuconazole 372 mg daily for 18 months. Therapeutic drug monitoring of isavuconazole levels as well as complete blood count and comprehensive metabolic panel, were drawn every month to monitor the patient for side effects while on isavuconazole therapy.