Disseminated histoplasmosis in an immunosuppressed patient successfully treated with isavuconazole

Abstract

Histoplasmosis is an endemic fungal infection caused by the dimorphic fungus, Histoplasma capsulatum, which is treated with intravenous amphotericin B and oral itraconazole as first-line and second-line therapy. We report a case of a man in his early 70s treated with methotrexate and infliximab for rheumatoid arthritis who developed disseminated histoplasmosis. The patient was unable to absorb itraconazole due to intractable diarrhoea and developed a severe, anaphylactoid reaction or an immune reconstitution inflammatory syndrome when treated with liposomal amphotericin B. He was subsequently treated with isavuconazole and steroids and made a full recovery.

A literature review revealed other cases of histoplasmosis which were treated with isavuconazole including both primary pulmonary and disseminated presentations. Cases of blastomycosis which were treated with isavuconazole are also reviewed including those with severe immunocompromised statuses including solid-organ transplant and tumour necrosis factor-alpha antagonist recipients. Our report describes the potential role of isavuconazole in cases of histoplasmosis where first-line and second-line therapies have failed or are contraindicated (excluding meningitis).

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.

Outcome and follow-up

The patient had prolonged hospitalisation due to extreme weakness. Given his low oral intake and protein malnutrition, a gastrostomy tube was placed for feeding. He also required a Foley catheter for urinary retention. He spent 7 days in the ICU before being stable enough to transition to a step-down unit and eventually to a rehabilitation centre. He began to improve on isavuconazole and steroid treatment after about a week.

He was eventually discharged home on isavuconazole 372 mg intravenously daily via peripherally inserted central catheter line for a total of 30 days before being transitioned to oral isavuconazole at the equivalent dose of 372 mg daily.

He slowly improved over the next several weeks. Six months after discharge, the patient had fully recovered with above baseline exercise tolerance, unassisted activities of daily living and his pre-hospitalisation weight.

Serum and urine Histoplasma antigen tests were followed every 4 months (table 1) while patient was on isavuconazole 372 mg daily therapy. At 6 months post-discharge, the patient had made a full recovery and was tolerating oral isavuconazole without any side effects.

Table 1.

Relevant laboratory values relating to the treatment and monitoring of the patient’s histoplasmosis infection

Duration of treatment	Itraconazole level (µg/mL) on 200 mg orally two times per day (therapeutic >1.0 µg/mL)	Isavuconazole level (µg/mL) on 372 mg orally daily (measuring range 0.1–10 µg/mL)*	Histoplasma serum antigen level (ng/mL)	Histoplasma urine antigen level (ng/mL)	Histoplasma antibody immunodiffusion	Histoplasma antibody complement fixation
On admission			3.89
After 1 week			4.58		Not detected	<1:8
After 2 weeks	0.6
After 1 month		3.5
After 2 months		5.4	Not detected	Not detected	Not detected
After 4 months		6.9	Not detected	1.34	Not detected
After 6 months		4.9	Not detected	1.50	Not detected
After 10 months			Not detected	1.36		<1:8
After 1 year		6.1	Not detected	0.96	Not detected	<1:8
After 14 months			Not detected	0.53	Detected	<1:8

*Optimal isavuconazole drug levels have not been established; however, most patients achieve levels >1 mg/L with standard dosing. An upper limit associated with isavuconazole toxicity has not been determined. ^{16 17}

Isavuconazole serum drug level 10 days after starting isavuconazole was 3.5 µg/mL. Serum isavuconazole level was 4.94 µg/mL and his Histoplasma serum antigen test was negative. His Histoplasma urine antigen, which had always remained higher than his serum level, was 1.34 ng/mL. A summary of the patient’s drug levels and corresponding Histoplasma serologies are provided in table 1. The plan was to continue isavuconazole treatment for a minimum of 1 year, with Histoplasma serologies guiding whether or not lifelong treatment would be needed. After 14 months of treatment with isavuconazole, patient continued to do well. However, as he was started again on prednisone for his rheumatoid arthritis the decision was made to continue treating with isavuconazole until he no longer required immunosuppressive therapy. After 18 months of treatment, isavuconazole was stopped as he was no longer on steroids. He was monitored off antifungals thereafter and continued to do well with no signs or symptoms indicative of histoplasmosis reactivation.

Discussion

To determine the utility of isavuconazole treatment for histoplasmosis, a PubMed, MEDLINE, Embase Web of Science and Google Scholar search was conducted using the search terms: treatment of histoplasmosis, treatment of histoplasmosis with isavuconazole, treatment of disseminated histoplasmosis in the immunocompromised and alternative treatments for disseminated histoplasmosis.

A total of 12 cases, including the current case report of histoplasmosis treated with isavuconazole, were found and the results are summarised in table 2. Eight of 12 (67%) cases were disseminated infections,^4–7 3 of 12 (25%) were primary pulmonary infections⁵ and 1 of 12 (8%) was of a local infection following a puncture wound.⁸ Most cases occurred in an immunocompromised host (data not available for all cases). Nine of the 12 cases (75%) treated with isavuconazole resulted in a successful outcome with either full or partial improvement.^4–8 Although information on long-term follow-up for all cases was not available, isavuconazole treatment was generally given for an extended period, ranging from 6 months to lifelong therapy. Treatment successes and failures were seen in both disseminated and primary pulmonary presentations. No cases reported serious adverse events due to isavuconazole and no subjects discontinued isavuconazole due to adverse events or tolerability issues.

Table 2.

Summary of reported cases of histoplasmosis treated with isavuconazole

Case (author)	Age (years)	Gender (M/F)	Underlying disease	Clinical presentation	Antifungal therapy	Outcome
1	70s	M	Hypertension, rheumatoid arthritis	Disseminated histoplasmosis (bone marrow, lungs)	Fluconazole was started empirically and then switched to itraconazole 200 mg orally two times per day. After 10 days of itraconazole, the patient was started on 4 mg/kg intravenously of liposomal amphotericin B but had anaphylaxis. He was then started on isavuconazole 372 mg intravenously every 8 hours for 6 doses, followed by 372 mg intravenously daily thereafter.	Success, remained well on isavuconazole after 6 months.
2 Finniss et al7	50s	F	HIV/AIDS, coronary artery disease, hypertension, stroke, chronic obstructive pulmonary disease	Disseminated histoplasmosis (oesophagus)	Fluconazole 200 mg orally daily was started then discontinued. The patient was then started on itraconazole 200 mg orally three times a day for 2 days, then 200 mg two times per day which was then stopped because the patient could not afford it. The patient was then switched over to isavuconazole 372 mg every 8 hours for 6 doses then 372 mg daily thereafter.	Success, recovered and discharged from hospital, no further follow-up available.
3 Wiley et al6	50s	M	None	Disseminated histoplasmosis (heart valves)	Liposomal amphotericin B was switched to itraconazole due to progressive renal insufficiency. The patient was then switched to isavuconazole due to prolonged QT interval.	Success, recovered well after several months, given lifelong isavuconazole.
4 Thompson et al5	Phase 3 open-label trial (N=7)			Disseminated histoplasmosis (CNS, unknown) (4) Primary pulmonary histoplasmosis (3)	Isavuconazole 200 mg (administered as isavuconazonium sulfate 372 mg) every 8 hours for 6 doses as primary therapy. This was followed by isavuconazole 200 mg daily. Patients were treated for a median of 180 days (range 85–327 days).	Complete clinical and radiographic success was observed in one patient with CNS involvement after 178 of days of treatment (1). Partial success was seen in two patients with disseminated disease and one with lung disease (3). Stable disease in one patient with lung disease (1). Progression seen in one patient with disseminated disease and one with lung disease (2).
5 Mazzella et al4	30s	M	HIV/AIDS	Disseminated histoplasmosis (liver, bone marrow)	Liposomal amphotericin B 3 mg/kg was given on day 22 then on day 39, the patient was switched to itraconazole 200 mg two times per day. At week 10, the patient relapsed with subtherapeutic levels of itraconazole. Liposomal amphotericin B with oral itraconazole (liquid suspension given low drug levels with capsules) was then started. Due to continued subtherapeutic levels, itraconazole was switched to posaconazole 400 mg liquid suspension at week 18. Therapy then continued with liposomal amphotericin B and oral isavuconazole (loading dose 200 mg every 8 hours for 48 hours) followed by 200 mg once daily thereafter.	Success, full clinical recovery and remains well after 1 year on isavuconazole.
6 Le et al8	60s	M	Gout, ankylosing spondylitis	Local histoplasmosis (septic arthritis of wrist following puncture wound)	Isavuconazole 327 mg orally was prescribed for 83 days.	Success and full recovery after 7-month follow-up.

CNS, central nervous system.

A total of 14 cases of another endemic mycosis, Blastomyces spp, treated with isavuconazole were also reviewed. Ten of the 14 (71%) cases were in disseminated blastomycosis infections (central nervous system (CNS), cutaneous, joint, bone, prostate), 4 of 14 (29%) cases were in primary pulmonary infections and 7 of 14 (50%) were in immunocompromised patients (6 solid-organ transplant, 1 TNF-alpha inhibitor recipient). Patients were transitioned to isavuconazole for either adverse drug effect or drug–drug interactions with liposomal amphotericin B, for median duration of 255 days (range, 31–430 days). Eleven of the 14 cases (79%) treated with isavuconazole were considered cured after median duration of 255 days of treatment.⁹

The treatment of patients with serious, invasive and disseminated fungal infections, including histoplasmosis, especially in the immunocompromised host, poses a challenge.⁴ Although effective therapies are available, many antifungal agents have toxicity or tolerability issues that limit their effectiveness. Thus, additional treatment options for histoplasmosis with improved safety and tolerability profiles are highly desired.

In our patient, liposomal amphotericin B was thought to have induced anaphylaxis or an IRIS-like reaction during the first dose. This was most likely precipitated by the removal of our patient’s immunosuppressive therapy (infliximab, etc). The incidence of histoplasmosis is higher in patients receiving anti-TNF monoclonal antibodies (eg, infliximab) than in patients receiving soluble TNF-alpha receptors (eg, etanercept). IRIS occurs in 9.2% of this patient population with a median time of onset of IRIS symptoms being 6 weeks after the cessation of TNF-alpha inhibitors.¹⁰

Although IRIS is more classically described with the introduction of antiretroviral therapy in patients with HIV and concomitant opportunistic infections,¹¹ there have been cases described in the literature of IRIS associated with disseminated histoplasmosis when TNF-alpha inhibitors have been stopped and liposomal amphotericin B started.¹² In this case report, a patient taking infliximab for Crohn’s disease developed fever, hypotension, tachycardia and hypoxaemia 6 hours after receiving liposomal amphotericin B for disseminated histoplasmosis. He was felt to have had a ‘paradoxical worsening’ with treatment and exacerbation of IRIS, similar to our patient. In our case, our patient’s IRIS-like symptoms improved with the concurrent use of methylprednisolone while being started on isavuconazole.

It was difficult to determine in our patient whether his symptoms immediately following the first dose of amphotericin B were due to anaphylaxis or IRIS. The use of glucocorticoids for the treatment of his reaction resulted in rapid improvement of his condition which would have been similar in either anaphylaxis or IRIS where steroids are used for treatment. The measurement of a biomarker, such as serum mast cell tryptase for the diagnosis of anaphylaxis, may have been useful in distinguishing the two processes, but was not done.

Isavuconazonium sulfate is a water-soluble prodrug that is hydrolysed in the blood to its active component isavuconazole. It has been FDA approved for therapy of aspergillosis and mucormycosis and is available as intravenous and oral formulations. It has few drug interactions and can be safely given to renally impaired patients as it does not require cyclodextrin coadministration. Isavuconazole is limited in its use in that it cannot be used in pregnant or breastfeeding patients or in patients with hepatic impairment.

At the current time in the USA, there is no generic equivalent for isavuconazonium sulfate and it is only available as the brand name Cresemba. A single 186 mg capsule can cost up to $121.16 each,¹³ and up to $1498 for 14 186 mg capsules.¹⁴ There are coupons and drug assistance programmes through the manufacturer as use of this drug for some patients may be cost prohibitive.

In our case, our patient was unable to be treated with either itraconazole or amphotericin B, due to malabsorption and severe drug reaction. This occurred as well in 1 of the 11 cases reviewed, where subtherapeutic itraconazole levels in a patient with advanced HIV secondary to malabsorption forced the consideration of an alternative treatment option.⁴

Itraconazole is only available in oral formulations (capsule or solution) and requires an acidic environment to maximise absorption. For this reason, it is advised that it not be taken with antacids and given with an acidic beverage. Itraconazole often has poor tolerability due to side effects of diarrhoea (3%–11%) and nausea (3%–11%) making compliance and absorption difficult. Isavuconazole is available in oral and intravenous formulations, which help to overcome some of its gastrointestinal side effects.

Because of itraconazole’s unpredictable absorption, the Infectious Diseases Society of America (IDSA) recommends monitoring serum levels in patients receiving itraconazole for the treatment of histoplasmosis.¹⁵ Therapeutic drug monitoring for isavuconazole is not required as consistent serum drug concentrations have been shown with standard dosing. ^{16 17} Optimal serum drug levels for isavuconazole have not been established.

IDSA guidelines for the management of histoplasmosis have not been updated in the last 15 years.¹⁵ In that time, new antifungal therapies, including isavuconazole, have become available. The increase use of immunomodulatory therapies has also increased the population at risk of histoplasmosis.

A recent article titled Management of Histoplasmosis by Infectious Disease Physicians¹⁸ concluded that new IDSA guidelines must reflect the increasing challenges of histoplasmosis management that physicians face, especially in immunocompromised patients, while including updated guidance for treatment. There is a need to examine the role of therapies such as isavuconazole. Only one case of CNS involvement was reported here; thus, there is limited evidence to support the use of isavuconazole for Histoplasma meningitis. The use of isavuconazole for the treatment of disseminated histoplasmosis and other endemic mycoses has not been previously well studied. Thus, while further large scale and long term research with outcome data is needed, isavuconazole may be a reasonable option for the treatment of histoplasmosis (and other mycoses), especially when other traditional treatment options are prohibitive either due to malabsorption, drug interactions or adverse effect profile.

Patient's perspective.

"At first when I was hospitalized, I believed that I was infected with bacteria as a result of eating rotten pomegranate. I had lost my appetite, was suffering from constant hiccups, and generally not feeling well. Even after five weeks, my doctors were unable to detect the ailment. Then they confirmed that I had a fungal infection called histoplasmosis. Their initial therapy did not work. Then after consulting with many infectious disease experts, isavuconazole was started as a treatment. All this while in the hospital I felt the end was near. However, with constant attention from all my doctors, my family’s unflinching support, and my wife's constant prayers and care, I pulled through from a very serious condition. Having lost almost 25 pounds in seven weeks in the hospital, I fully recovered in six months and regained my strength and weight."

Learning points.

• Disseminated histoplasmosis is a rare diagnosis that must be considered in immunosuppressed hosts, especially those on tumour necrosis factor-alpha inhibitors.

• Immune reconstitution inflammatory syndrome is an observed phenomenon in the treatment of acute disseminated histoplasmosis, and the use of steroids in conjunction with antifungal treatment may be successful in mitigating the severity of its symptoms.

• The use of antifungal therapies such as isavuconazole, which are not yet widely studied in disseminated histoplasmosis, may be helpful in the treatment of this infection.

Ethics statements

Patient consent for publication

Obtained.