Delayed diagnosis of primary cutaneous histoplasmosis in a patient receiving tumour necrosis factor alpha inhibitor therapy

Summary

Primary cutaneous histoplasmosis (PCH) is a rare fungal infection, often misdiagnosed due to its polymorphic skin manifestations. We describe a woman in her 60s with rheumatoid arthritis receiving infliximab and long-term prednisone who presented with progressive, non-healing lesions of the left forearm. Initially treated as cellulitis without improvement, further investigation led to a diagnosis of PCH due to Histoplasma capsulatum confirmed by fungal culture. She was treated with systemic antifungal therapy with clinical resolution. This case underscores the importance of considering endemic fungal infections in immunocompromised individuals with persistent skin lesions, the value of early biopsy with cultures and careful management of immunosuppression.

Background

Histoplasmosis is caused by Histoplasma capsulatum and is usually acquired via inhalation, leading to pulmonary disease. Primary cutaneous histoplasmosis (PCH) is rare, resulting from direct cutaneous inoculation. Although described more often in immunocompetent hosts, it can occur in immunosuppressed patients and be easily overlooked. Tumour necrosis factor-α (TNF-α) inhibitors and corticosteroids increase susceptibility to endemic mycoses. Misdiagnosis as bacterial cellulitis can delay appropriate treatment.

Case presentation

A woman in her 60s with rheumatoid arthritis (RA) (on infliximab and prednisone), type 2 diabetes mellitus, hypertension and interstitial lung disease presented with approximately 2 months of progressive swelling and erythema of the left hand and wrist and non-painful nodular/indurated lesions on the left forearm (figure 1). She had received a prior course of oral cephalexin without improvement. Approximately 8 months earlier, she experienced a similar episode treated as cellulitis with prolonged antibiotics; symptoms never fully resolved.

Figure 1. Lesions on left forearm and area of cellulitis on left wrist.

She denied trauma, aquatic exposures or pet contact but reported frequent gardening. Medications included methylprednisolone 16 mg/day, leflunomide, infliximab (last infusion approximately 1 month prior to presentation), metformin, fenofibrate and losartan. She was born in Guyana, moved to the USA in 1983, and previously worked as a farmer. She denied tobacco, alcohol or drug use and had no known tuberculosis exposure. On examination, she was afebrile with stable vital signs. Dermatological evaluation revealed a well-demarcated red-to-violaceous indurated plaque on the left forearm with erythema extending to the wrist and surrounding oedema but no regional lymphadenopathy (figure 1). Musculoskeletal exam showed mild synovitis of the left wrist and third metacarpophalangeal joint.

Investigations

Laboratory tests showed haemoglobin 10.6 g/dL (reference 12.0–16.0), white blood cell count 8.83×10⁹/L (4.0–10.0), C-reactive protein 4.0 mg/L (<0.5), erythrocyte sedimentation rate 24 mm/hour (0–20). Radiography and MRI of the left forearm/wrist showed soft tissue swelling without osteomyelitis. Chest CT was obtained to evaluate pulmonary or disseminated histoplasmosis given the patient’s immunosuppression and showed no pulmonary nodules or mediastinal lymphadenopathy. Dermatology performed a punch biopsy of the forearm lesion for histopathology and bacterial, mycobacterial (acid-fast bacilli) and fungal cultures.

Additional testing:

• HIV antigen/antibody test negative; hepatitis B non-immune; hepatitis C antibody negative.

• Interferon-γ release assay for tuberculosis negative.

• Serum (1→3)-β-d-glucan assay negative.

• Histoplasma urine antigen undetectable; serum Histoplasma antigen low positive at 0.37 ng/mL (reference: negative<0.20 ng/mL).

• Serum cryptococcal antigen negative.

• Serum Aspergillus galactomannan mildly elevated at 0.59 (reference<0.50).

• Blood cultures for fungi were obtained and remained without growth.

Histopathology (H&E) of the punch biopsy showed septal panniculitis with granulomatous inflammation and a background of interface dermatitis, consistent with an erythema nodosum-like pattern in the setting of connective tissue disease. Multiple deeper levels were examined. Special stains (periodic acid-Schiff, Grocott methenamine silver and acid-fast stains) did not reveal organisms.

Preliminary fungal culture from biopsy material revealed mold-like organisms. At 4 weeks, the culture speciated as H. capsulatum. Cultures on Sabouraud dextrose agar showed white to buff, cottony colonies consistent with the mycelial phase (figure 2). Lactophenol cotton blue preparation showed septate hyphae with tuberculate macroconidia and numerous microconidia (figure 3). The sequence of events is summarised in a relative timeline (figure 4).

Figure 2. White, cottony growth maturing to tan/brown with a velvety texture.

Figure 3. Septate hyphae with characteristic tuberculate macroconidia and smooth microconidia (mould phase).

Figure 4. Relative timeline of key clinical events. Approximate intervals shown: prior antibiotic-treated ‘cellulitis’ within complete resolution (~8 months prepresentation)→index presentation and biopsy (Day 0)→mould-like fungal growth on culture prompting empiric voriconazole initiation and discontinuation of infliximab (Day 3)→culture speciation as Histoplasma capsulatum (Week 4)→clinical improvement with antigen down-trend (Months 1–3) →voriconazole discontinued because of intolerance after clinical resolution (Month 8)→ cautious reintroduction of etanercept (Month 9)→serial antigen surveillance every 2 months without recurrence (Months 9–20). TNF-α, tumour necrosis factor-α.

Differential diagnosis

• H. capsulatum: favoured by gardening exposure, biopsy culture/speciation, localised panniculitis pattern, low/negative antigens in localised disease and absence of pulmonary/systemic involvement.

• Sporothrix schenckii complex: less likely—no sporotrichoid spread; cultures did not yield Sporothrix.

• Blastomyces dermatitidis: less likely—no verrucous/ulcerative lesions or pulmonary findings; culture confirmed Histoplasma.

• Coccidioides spp.: unlikely—no compatible endemic travel; cultures not consistent.

• Atypical mycobacteria (eg, M. marinum, rapidly growing nontuberculous mycobacteria (NTM): considered for chronic nodules; no aquatic/trauma exposure; acid-fast bacilli (AFB) stains/cultures negative.

• Nocardiosis: considered in immunosuppression; AFB studies negative and fungal culture identified Histoplasma.

• Bacterial cellulitis/erysipelas: initial working diagnosis; failure of appropriate antibiotics and chronic induration argue against.

• Non-infectious mimics (erythema nodosum, rheumatoid nodules, vasculitis, pyoderma gangrenosum): Erythema nodosum (EN) like septal panniculitis can accompany histoplasmosis; culture-proven infection and antifungal response make these unlikely.

Treatment

TNF-α inhibitor therapy (infliximab) was withheld at diagnosis, and glucocorticoids were minimised in collaboration with rheumatology. Because preliminary fungal culture from the biopsy demonstrated mould-like organisms, we initiated empiric oral voriconazole. Four weeks later, the culture speciated as H. capsulatum. Although itraconazole is the guideline-preferred therapy for non-disseminated histoplasmosis, we selected voriconazole due to anticipated absorption variability and drug–drug interaction burden with itraconazole in this patient’s polypharmacy, and we pursued close therapeutic drug monitoring (TDM) and toxicity surveillance, consistent with use of alternative triazoles when itraconazole is contraindicated, not tolerated or impractical.^{1 2} Voriconazole was administered as 400 mg orally every 12 hours for two loading doses, then 200 mg every 12 hours for maintenance. We obtained voriconazole trough approximately 5 days after initiation; the level was 3.0 µg/mL (target 1.0–5.5 µg/mL), supporting adequate exposure. Liver enzymes were monitored at baseline and periodically, potential drug interactions were reviewed and managed and the patient was counselled about photosensitivity and visual/neurologic adverse effects. Although the intended duration was 12 months given ongoing immunosuppression, voriconazole was discontinued after 8 months due to intolerance following clinical improvement and down-trending antigens. Post-therapy surveillance consisted of serum and urine Histoplasma antigen testing every 2 months for 12 months, all negative, with no clinical relapse.

Outcome and follow-up

Clinical resolution of the forearm lesions was documented on follow-up (figure 5). Serial Histoplasma antigen testing showed serum 0.37 ng/mL pretreatment→<0.20 ng/mL by month 3 and remained negative through month 12; urine antigen was undetectable at all time points. No clinical, radiographic or laboratory evidence of pulmonary or disseminated histoplasmosis emerged during treatment or follow-up. Infliximab was held throughout antifungal therapy; an RA flare was managed with a short course of oral corticosteroids and ongoing leflunomide. Subsequently, TNF-α inhibitor therapy was cautiously reintroduced with etanercept under close infectious diseases and rheumatology supervision without recurrence of infection.

Figure 5. Clinical resolution of forearm lesions following completion of antifungal therapy.

Discussion

PCH arises from direct inoculation and can mimic bacterial cellulitis or panniculitis. In immunosuppressed hosts particularly those receiving TNF-α inhibitors and corticosteroids, disseminated disease is more typical, which can bias clinicians away from considering localised primary cutaneous infection.^3–6 In this case, a localised lesion at a plausible inoculation site (forearm) with gardening exposure, absence of systemic symptoms, negative chest imaging, undetectable urine antigen and low-level serum antigen at baseline, negative fungal blood cultures and culture-proven Histoplasma from skin biopsy supported PCH over dissemination. The erythema nodosum-like septal panniculitis pattern with negative special stains falls within the reported histopathological spectrum and underscores the limited sensitivity of stains in pauci-organism disease; culture remains decisive.^{5 7}

Itraconazole is the guideline-preferred triazole for non-disseminated histoplasmosis and as step-down therapy for disseminated disease, with TDM recommended.¹ Contemporary practice data similarly show itraconazole is favoured, while alternative triazoles are used less commonly and with more limited clinical evidence.² We used voriconazole due to anticipated challenges with itraconazole exposure and interactions in a polypharmacy setting and instituted TDM and toxicity surveillance. Preliminary culture suggested a mould; empiric voriconazole was reasonable while infliximab was withheld pending speciation; after H. capsulatum was confirmed, on-target troughs and good tolerance supported continuation. Voriconazole has in vitro activity against H. capsulatum and has been used successfully as a second line agent in clinical series and case reports when amphotericin B and or itraconazole were not feasible. When used, expert guidance recommends routine TDM and toxicity surveillance.^{1 2}

Regarding duration, we initially planned a 12-month triazole course given the patient’s immunosuppression and expert observational data suggesting that patients exposed to TNF-α inhibitors may warrant treatment durations closer to those used for secondary disseminated cutaneous involvement when feasible.^{8 9} However, therapy was discontinued at 8 months because of intolerance. To mitigate relapse risk, we instituted intensive post-therapy surveillance with serum and urine Histoplasma antigen testing every 2 months for 1 year after stopping antifungal therapy. All tests remained negative, and the patient has remained symptom free.

TNF-α inhibitors impair granuloma integrity and macrophage fungicidal activity, increasing susceptibility to endemic mycoses, with histoplasmosis being the most frequently reported endemic fungal infection in this setting.^{3 4 10 11} Concomitant glucocorticoids further elevate risk, particularly at doses above 10–15 mg/day prednisone equivalent.¹² Consistent with observational data and expert guidance, we withheld infliximab during active infection and minimised corticosteroids when feasible.^{1 8 10} Resuming biologics requires balancing relapse risk with autoimmune disease control; observational series suggest relapse is uncommon with cautious re-introduction under antifungal coverage and close monitoring.^{8 9} We reintroduced TNF-α blockade after sustained clinical improvement and repeatedly negative antigens, with ongoing surveillance and no recurrence.

We did not use secondary antifungal prophylaxis, which is generally reserved for select high-risk settings and not routinely recommended for other immunosuppressed patients; given localised disease and drug intolerance, structured surveillance was chosen instead.¹

This case mirrors prior reports in which PCH mimicked cellulitis/panniculitis and histology demonstrated an erythema nodosum-like septal panniculitis pattern with negative special stains, reinforcing the need for early biopsy with cultures and highlighting the limited sensitivity of stains in localised disease.^{5 7 13} Mildly elevated galactomannan likely reflects cross-reactivity and should be interpreted cautiously.¹ Practically, immunosuppressed patients with antibiotic-refractory ‘cellulitis’, early biopsy with bacterial, mycobacterial and fungal cultures is critical.

Evidence guiding the optimal triazole choice, total treatment duration in TNF-α exposed patients and timing of biological resumption remains limited to retrospective series and expert opinion.^{1 2 8–10}

Patient’s perspective.

My mom is in her 60s and has severe Rheumatoid arthritis. In 2024, she developed a skin infection caused by a fungus. At first, she thought it was cellulitis because she had had it the year before and was on an IV antibiotic for 8 weeks. At first, it presented itself as the same symptoms as the cellulitis, but after several courses of antibiotics and no relief, the doctors had to dig a little deeper.

At first, her thumb was red, swollen, and felt very hard. After a few weeks, the redness and swelling began to spread from her hand and arm to her elbow. They were also red and had swollen welts on her forearm. The doctors couldn’t figure out what it was, so the dermatologist took a biopsy, and then it came back as a fungal infection. Before the doctors knew what was wrong, she was feeling weak and had no energy, and she had difficulty eating. She had a lot of nausea.

Once we knew it was a fungal infection, the doctors stopped the antibiotics and started antifungal medicine. My mom had regular blood tests and check-ups. The medicine made her tired and nauseous sometimes, but after a few weeks the redness and swelling started to go down. We paused some of her arthritis medicines and then slowly restarted them with the doctors watching closely. It’s been a long process, but with the doctors’ help and our family’s support, she is recovering and getting back to her routine, and we are careful with her skin to avoid new infections.

Learning points.

• In immunosuppressed patients, ‘cellulitis’ that fails to respond to appropriate antibiotics should prompt early biopsy with fungal and mycobacterial cultures; primary cutaneous histoplasmosis (PCH) can present with cellulitis- or panniculitis-like features.

• Septal panniculitis with granulomatous inflammation may represent an erythema nodosum-like reaction and does not exclude PCH; culture remains the diagnostic gold standard.

• Itraconazole is the guideline-preferred therapy for non-disseminated histoplasmosis; alternative triazoles (eg, voriconazole) may be considered when patient-specific factors warrant, with therapeutic drug monitoring.

• Excluding disseminated histoplasmosis in immunosuppressed hosts requires targeted evaluation (antigen testing, chest imaging, and, when indicated, fungal blood cultures).

• Management of immunosuppression including withholding tumour necrosis factor-α inhibitors and minimising corticosteroids is integral to successful treatment; biologics may be cautiously resumed after sustained remission with close monitoring.