Clinical Report: Skin Biopsy in Fatal Histoplasmosis-Associated HLH

Overview

This case describes fatal Histoplasma capsulatum-associated hemophagocytic lymphohistiocytosis (HLH) in a 41-year-old man receiving adalimumab for psoriasis. Bone marrow fungal stains were negative, but biopsy of sparse acneiform papules showed numerous invasive organisms, and molecular testing identified H. capsulatum. The report highlights the diagnostic contribution of targeted skin sampling in an immunosuppressed patient with suspected infection-associated HLH.

Background

HLH is a life-threatening hyperinflammatory syndrome associated with multiorgan injury, and secondary cases in adults may be triggered by infection, malignancy, autoimmune disease, or immunosuppressive therapy. Identifying the underlying cause can be difficult despite extensive investigation, but is important for directing targeted treatment. Skin findings in HLH are variable and often nonspecific; biopsy of a clinically relevant lesion may help identify an infectious trigger. Disseminated histoplasmosis is a recognized, uncommon cause of secondary HLH, and TNF-α inhibitor exposure is associated with risk of severe or disseminated histoplasmosis.

Data Highlights

Key Findings

• The patient had progressive abdominal symptoms, weakness, fatigue, and unintended 40-lb weight loss over approximately 5 months before admission.
• At least six HLH-2004 diagnostic domains were met, including fever, splenic enlargement, multilineage cytopenias, hemophagocytosis, and marked hyperferritinemia.
• Initial bone marrow fungal staining was negative, while biopsy of subtle acneiform papules demonstrated numerous invasive organisms.
• Subsequent molecular testing of the cutaneous findings identified Histoplasma capsulatum.
• The case authors describe the patient as having fatal histoplasmosis-associated HLH while receiving adalimumab, a TNF-α inhibitor.
• The supplied IDSA guidance context identifies TNF-α inhibitors, including adalimumab, among biologic response modifiers frequently reported in severe or disseminated histoplasmosis; CDC material also lists TNF-inhibitor use as a histoplasmosis risk factor.

Clinical Implications

In patients with suspected HLH, the source advises considering the suspected trigger and type of immunosuppression; TNF-α inhibitor exposure should raise concern for invasive fungal infection. The case authors report that focused assessment and sampling of recently developed or atypical skin lesions can reveal an infectious source when other investigations, including bone marrow fungal staining, are unrevealing.

Conclusion

This fatal case documents species-level molecular confirmation of H. capsulatum from cutaneous lesions in a patient with HLH and adalimumab exposure. It illustrates the diagnostic value reported for biopsy of subtle skin lesions in the evaluation of suspected infection-associated HLH.

Related Resources & Content

1. Case report authors, Dermatology and Therapy, 2026 — Diagnostic Value of Skin Biopsy in Fatal Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Report
2. Infectious Diseases Society of America, Clinical Infectious Diseases, 2025 — 2025 Clinical Practice Guideline Update on Histoplasmosis: Treatment of Mild or Moderate Acute Pulmonary Histoplasmosis in Adults, Children, and Pregnant People
3. Frontiers in Oncology — Case Report: Ultrasound-guided percutaneous splenic biopsy as a lifesaving diagnostic modality in B-cell lymphoma presenting as hemophagocytic lymphohistiocytosis: a report of two cases
4. ASCO Publications — Rare Case of Infratentorial Non-Langerhans Cell Histiocytosis With Lethal Outcome Presenting Multiple Diagnostic Difficulties
5. ASCO Publications — Rare Case of Infratentorial Non-Langerhans Cell Histiocytosis With Lethal Outcome Presenting Multiple Diagnostic Difficulties
6. Frontiers in Immunology — Case Series: Diagnosis of Lymphoma via Transjugular Liver Biopsy in Patients with Hemophagocytic Lymphohistiocytosis and Severe Thrombocytopenia
7. Diagnostic Value of Skin Biopsy in Fatal Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Report
8. 2025 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Histoplasmosis
9. 2025 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Histoplasmosis: Treatment of Mild or Moderate Acute Pulmonary Histoplasmosis in Adults, Children, and Pregnant People | Clinical Infectious Diseases | Oxford Academic
10. Frontiers | Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis in the Gulf Cooperation Council: a modified Delphi approach
11. Diagnostic Value of Skin Biopsy in Fatal Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Case Report | Dermatology and Therapy | Springer Nature Link