Connecting the dots; Anti-PL7 Antisynthetase Syndrome, Infliximab, and Granulomas — A Case Report

Technical Summary: Connecting the Dots; Anti-PL7 Antisynthetase Syndrome, Infliximab, and Granulomas

Problem Statement
The paper addresses the diagnostic challenges associated with reactivated disseminated histoplasmosis in immunocompromised patients, particularly those with connective tissue disease-associated interstitial lung disease (ILD). The core difficulty lies in the non-specific clinical and radiological presentation of disseminated histoplasmosis, which frequently mimics other granulomatous conditions such as tuberculosis, sarcoidosis, and inflammatory bowel disease (specifically Crohn's disease). This diagnostic uncertainty is exacerbated in non-endemic regions and in patients with a remote history of exposure, where reactivation of latent infection decades after initial contact is often overlooked. The case highlights the risk of misdiagnosing fungal reactivation as a drug-induced sarcoid-like reaction or a flare of the underlying autoimmune condition, leading to inappropriate escalation of immunosuppression.

Methodology
This study is a single-case report detailing the clinical course of a 72-year-old male patient with anti-PL7-positive antisynthetase syndrome and fibrotic non-specific interstitial pneumonia (NSIP)/organizing pneumonia (OP). The methodology involves a retrospective analysis of the patient's clinical history, radiological imaging, microbiological evaluations, and histopathological findings.

• Clinical History: The patient was initially treated with mycophenolate mofetil. Due to new gastrointestinal symptoms (malaise, weight loss, colonic ulcers), he was provisionally diagnosed with Crohn's disease and switched to infliximab.
• Diagnostic Workup: Following the development of new pulmonary micronodules, the team conducted extensive microbiological evaluations, including bronchoalveolar lavage (BAL) fluid cultures and PCR for Mycobacterium tuberculosis and fungal pathogens, all of which were negative.
• Intervention and Biopsy: When corticosteroid treatment for a presumed infliximab-induced sarcoid-like reaction failed to halt radiological progression, a non-intubated thoracic surgical lung biopsy was performed.
• Microbiological Confirmation: Lung tissue was subjected to fungal culture, and urine antigen testing was performed.

Key Results

• Radiological Findings: High-resolution computed tomography (HRCT) revealed a stable fibrotic NSIP/OP pattern in the lower lobes but showed new, diffuse centrilobular and perilymphatic micronodules predominantly in the upper lobes.
• Histopathology: The lung biopsy demonstrated fibrosing NSIP with superimposed necrotising granulomas. Stains for acid-fast bacilli and fungi (Periodic acid-Schiff with diastase, Ziehl–Neelsen) were negative for visible organisms.
• Microbiological Confirmation: After four weeks of incubation, fungal culture of the lung tissue grew Histoplasma capsulatum. Urine Histoplasma antigen testing confirmed the diagnosis of reactivated disseminated histoplasmosis with both pulmonary and abdominal involvement.
• Clinical Outcome: The provisional diagnosis of Crohn's disease was rejected; the gastrointestinal lesions were reattributed to disseminated histoplasmosis. The patient was treated with liposomal amphotericin B followed by oral itraconazole. After 18 months of antifungal therapy, the patient achieved marked clinical improvement, complete resolution of dyspnea, and substantial radiological reduction of nodules.

Key Contributions

1. Reactivation Timeline: The case documents the reactivation of latent Histoplasma capsulatum more than four decades after the patient's last exposure to an endemic region (Suriname), illustrating that the latency period can extend far beyond typical clinical expectations.
2. Diagnostic Pitfalls: It highlights the specific risk of misinterpreting disseminated histoplasmosis as an infliximab-induced sarcoid-like reaction or a flare of the underlying ILD/IBD, particularly when initial microbiological screens (like BAL) are negative.
3. Gastrointestinal Mimicry: The report reinforces that gastrointestinal histoplasmosis can mimic Crohn's disease, leading to the initiation of TNF-α inhibitors which may further compromise immune control and accelerate dissemination.
4. Diagnostic Strategy: The case underscores the necessity of integrating exposure history (even remote), radiological patterns (diffuse micronodules), and specific antigen testing (urine) alongside tissue culture, rather than relying solely on initial negative microbiological screens or presumptive clinical diagnoses.

Significance and Claims
The authors claim that this case serves as a critical reminder for clinicians to maintain a broad differential diagnosis when new inflammatory granulomatous lung disease emerges in immunocompromised patients, even in the absence of recent travel to endemic areas. The paper asserts that reactivation of histoplasmosis must be considered in patients receiving prolonged immunosuppressive therapy, particularly TNF-α inhibitors, regardless of the time elapsed since initial exposure.

The significance of the report lies in its demonstration that a definitive diagnosis often requires a combination of clinical suspicion, radiological correlation, and invasive tissue sampling with prolonged culture incubation, as antigen testing and initial cultures may be insufficient or delayed. The authors conclude that early multidisciplinary assessment involving pulmonologists, radiologists, infectious disease specialists, and pathologists is essential to minimize diagnostic delays and ensure the timely initiation of appropriate antifungal therapy, thereby preventing the worsening of disseminated disease through inappropriate immunosuppression.