A 41-year-old man receiving the tumor necrosis factor-alpha inhibitor adalimumab for psoriasis died of hemophagocytic lymphohistiocytosis triggered by disseminated histoplasmosis, and the diagnosis hinged on a small punch biopsy of subtle acneiform papules on his forehead. According to a case report published in Dermatology and Therapy, his bone marrow biopsy showed hemophagocytosis but was negative for fungal organisms on Grocott methenamine silver staining, while the skin specimen demonstrated numerous tissue-invasive microorganisms that molecular testing identified as Histoplasma capsulatum. The case illustrates how sparse, nonspecific skin lesions can provide accessible tissue for organism-specific confirmation even when staining of another tissue is negative.
Hemophagocytic lymphohistiocytosis is a rare, life-threatening hyperinflammatory syndrome characterized by uncontrolled activation of cytotoxic lymphocytes and macrophages, leading to multiorgan injury. In adults it is most often secondary to infection, malignancy, autoimmune disease, or immunosuppressive therapy. Identifying the underlying trigger is one of the central diagnostic challenges, because the cause frequently remains unidentified despite extensive workup yet is critical to guiding targeted therapy. Disseminated histoplasmosis is an uncommon but recognized infectious trigger, particularly in immunosuppressed patients, and the risk of severe or disseminated disease is increased by tumor necrosis factor-alpha inhibition.
The patient’s illness began approximately five months before admission with progressive abdominal pain, early satiety, weakness, fatigue, and an unintentional 40-pound weight loss. His psoriasis had been well controlled on adalimumab, although the exact duration of therapy was unknown and his last documented dose was 15 days before transfer to the reporting tertiary center. Relevant exposures included prior residence in Arkansas and southern California, a one-week trip to Belize three months before symptom onset, and a cave tour at Shasta Caverns in northern California two months after symptoms began. No direct bat or animal exposure was reported.
Three days before transfer he presented to an outside hospital with near-syncope, hypotension, and concern for sepsis and gastrointestinal bleeding. Initial laboratories showed leukopenia of 2.2 × 10⁹ per liter, anemia with hemoglobin of 6.7 grams per deciliter, thrombocytopenia of 63 × 10⁹ per liter, hyponatremia, and acute kidney injury, along with elevated alkaline phosphatase. Imaging demonstrated hepatosplenomegaly with a spleen measuring 16.4 centimeters. A bone marrow biopsy performed one day before transfer showed a normocellular marrow with increased macrophages and hemophagocytosis, without blasts or malignancy; acid-fast bacilli and Grocott methenamine silver stains were negative. Dexamethasone 20 milligrams intravenously daily was initiated before transfer.
On hospital day 0 at the tertiary center, his temperature reached 38.7 degrees Celsius, with a white blood cell count of 2.18 × 10⁹ per liter, hemoglobin of 7.9 grams per deciliter, and platelets of 31 × 10⁹ per liter. Fibrinogen was 115 milligrams per deciliter and triglycerides 205 milligrams per deciliter, the latter subsequently rising to 325 milligrams per deciliter while fibrinogen fell to 71 milligrams per deciliter. Ferritin peaked at 89,920 nanograms per milliliter on hospital day 5, and soluble interleukin-2 receptor was elevated at 4355.1 picograms per milliliter against a reference range of 175.3 to 858.2. He met at least six of the HLH-2004 criteria: fever, splenomegaly, cytopenias affecting at least two lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, and hyperferritinemia. Final results for natural killer cell function and an HLH genetic panel were not available in the medical record.
The search for alternative infectious and malignant triggers was unrevealing. Blood cultures and testing for HIV, cytomegalovirus, herpes simplex virus, viral hepatitis, tuberculosis, Cryptococcus, blood parasites, West Nile virus, Leptospira, and Strongyloides were negative. Epstein-Barr virus polymerase chain reaction detected low-level viremia of 223 international units per milliliter, with serology consistent with prior infection. Flow cytometry showed no blasts or aberrant populations, and duodenal biopsy showed reactive changes without malignancy. However, serum beta-d-glucan exceeded 500 picograms per milliliter, and the serum Aspergillus galactomannan assay was positive on hospital days 0 and 3, complicating the fungal differential.
Dermatology was consulted on hospital day 2 to evaluate newly appreciated cutaneous findings: subtle pink-to-violaceous, mildly purpuric acneiform papules on the forehead. A 4-millimeter punch biopsy obtained the next day showed numerous small, spherical-to-ovoid basophilic organisms with eccentric, crescent-shaped nuclei within the dermis. The preliminary report described invasive microorganisms suspicious for leishmaniasis while retaining fungal infection, including histoplasmosis, in the differential. A urine Histoplasma antigen specimen collected on hospital day 2 resulted positive on day 4, and fungal PCR with reflex next-generation sequencing of the skin specimen detected Histoplasma capsulatum 28S ribosomal DNA, providing species-level molecular confirmation.
HLH-directed therapy included continued dexamethasone, ruxolitinib 10 milligrams twice daily, and a single dose of rituximab while the low-level EBV viremia remained under consideration. Etoposide 150 milligrams per square meter was scheduled but repeatedly withheld because of severe gastrointestinal hemorrhage and was never administered. Recurrent small-bowel bleeding required multiple embolization procedures and, on hospital day 5, exploratory laparotomy with small-bowel resection. Liposomal amphotericin B 3 milligrams per kilogram every 24 hours was started on hospital day 5. Despite these interventions, the patient died on hospital day 6 from refractory hemorrhagic shock and multiorgan failure. Autopsy demonstrated histoplasmosis involving the liver, spleen, lungs, kidneys, adrenal glands, lymph nodes, intestines, and right testis, along with multifocal aspergillosis in both lungs.
The authors emphasize that diagnostic yield may depend on the tissue sampled. Because multiple fungal biomarkers were abnormal and autopsy also demonstrated pulmonary aspergillosis, identification of H. capsulatum in the skin was particularly valuable. They note that cutaneous findings in HLH may reflect the syndrome itself, secondary effects such as coagulopathy, or the underlying trigger, which may explain variable biopsy results, since lesions caused by direct fungal involvement are more likely to demonstrate organisms. Cutaneous or mucosal findings have rarely been reported in histoplasmosis-associated HLH and include erythema nodosum, morbilliform eruptions, cellulitis-like plaques, and oral ulcerations; in several published cases skin biopsy was nondiagnostic or not performed, while in one case biopsy of a cellulitis-like plaque showed yeast forms confirmed by culture and PCR.
The report carries important caveats. It is limited by its retrospective nature, the unavailability of final natural killer cell function and genetic panel results, and the absence of fungal special stains on the skin specimen. The coexistence of disseminated histoplasmosis and pulmonary aspergillosis further complicates attribution of the abnormal fungal biomarkers and clinical deterioration to a single pathogen. No established treatment protocol exists for histoplasmosis-associated HLH, and published reports do not establish whether antifungal therapy should precede or accompany HLH-directed treatment; in a review of 30 immunocompromised patients, variable treatments, illness severity, and outcomes precluded comparative conclusions. The authors conclude that dermatologists should maintain a low threshold to biopsy new, atypical, or evolving skin lesions in immunosuppressed patients with unexplained systemic inflammation, particularly those receiving tumor necrosis factor-alpha inhibitors, and that residence outside a classically endemic region should not exclude histoplasmosis in a compatible clinical context.
Subject of Research: Skin biopsy diagnosis of fatal histoplasmosis-associated hemophagocytic lymphohistiocytosis in an adalimumab-treated patient
Article Title: Diagnostic Value of Skin Biopsy in Fatal Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Report
Article References: Roland-McGowan, J., Seervai, R. N. H., Lee, C., Koon, S. M., & Keller, J. J. (2026). Diagnostic Value of Skin Biopsy in Fatal Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Report. Dermatology and Therapy. https://doi.org/10.1007/s13555-026-01959-9
Image Credits: AI Generated
DOI: 10.1007/s13555-026-01959-9
Keywords: hemophagocytic lymphohistiocytosis, histoplasmosis, skin biopsy, Histoplasma capsulatum, adalimumab, TNF-alpha inhibitor, dermatopathology, disseminated fungal infection, immunosuppression, case report, hyperferritinemia, molecular testing
News Source: Ophelia Keating. (October 29, 2026). Skin Biopsy Revealed Fatal Fungal Trigger of Hyperinflammation When Marrow Testing Failed. Scienmag.
