Pulmonary nodules in chronic nonbacterial osteomyelitis—the importance of considering histoplasmosis in endemic regions: comment on the article by Hospach et al

We read with great interest the national cohort study reported by Hospach et al on the clinical and radiologic spectrum of pulmonary involvement in pediatric chronic nonbacterial osteomyelitis (CNO).1 Their study expands our understanding of this uncommon extraosseous CNO manifestation and provides useful descriptors of lesion size, distribution, and evolution under therapy. In settings outside central Europe and North America, however, we believe the differential diagnosis of pulmonary nodules in CNO warrants explicit consideration of endemic mycoses, particularly histoplasmosis, given overlapping image phenotypes and the frequent use of immunosuppressive therapy in this population. In endemic regions of the Americas and parts of the United States, Histoplasma capsulatum is a leading cause of solitary or multiple pulmonary nodules in children and adolescents.2 Histoplasmosis is endemic across all regions, but its true burden remains underestimated due to the absence of mandatory reporting. A recent systematic review based on published data demonstrated that histoplasmosis is more widespread in Brazil than previously recognized, characterized the disseminated form as the most severe presentation, and confirmed that the most vulnerable populations are those most frequently represented in available reports.3 Pulmonary nodules caused by H capsulatum in children typically present as small, well-defined solid lesions, which may be solitary or multiple. Calcification is common, particularly in healed infections, and may involve the nodule or associated hilar or mediastinal lymph nodes. Satellite lesions may be present, supporting a granulomatous process. Cavitation is uncommon, and ground-glass halo or significant contrast enhancement is not typical.4-6 According to the Infectious Diseases Society of America (IDSA) guidelines, both calcified and noncalcified nodules may occur in asymptomatic pulmonary histoplasmosis, and the absence of calcification does not exclude the diagnosis.6 These considerations are clinically relevant in CNO given the rarity of pulmonary involvement and the increased susceptibility to endemic fungal infections associated with immunosuppressive therapy. Tumor necrosis factor inhibitors are most strongly associated with disseminated histoplasmosis, whereas methotrexate monotherapy confers lower risk; this risk increases substantially with biologic combinations or concomitant high-dose glucocorticoids.6, 7 The current IDSA guideline defines specific risk categories for disseminated histoplasmosis in immunosuppressed hosts.6 We illustrate these considerations with a concise vignette from our service. A 13-year-old female patient underwent whole-body magnetic resonance imaging (WBMRI) for follow-up of CNO. The study demonstrated persistent inflammatory bone marrow edema in the medial portion of the left clavicle, like the prior examination, and new inflammatory edema in the left cuboid. An incidental 0.7-cm pulmonary nodule was identified in the right upper lobe on the axial Volumetric Interpolated Breath-hold Examination (VIBE) T1 sequence (Figure 1). Given the limited pulmonary assessment of WBMRI, chest computed tomography (CT) was performed. CT demonstrated a solid 0.7-cm nodule in the basal segment of the right lower lobe, with peribronchovascular interstitial thickening and adjacent satellite micronodules. A prominent subcarinal lymph node (1.2 × 1.0 cm) and calcified mediastinal and right hilar lymph nodes were also observed, forming a radiologic pattern suggestive of a granulomatous process. Abdominal ultrasonography showed a spleen of normal size and morphology with multiple punctate echogenic foci, consistent with residual granulomas. A screening result for Mycobacterium tuberculosis using an interferon-γ release assay was negative. Immunodiffusion testing for anti-Histoplasma antibodies was positive for the M band, whereas the urine antigen test result was negative. In accordance with the 2025 IDSA recommendations for asymptomatic pulmonary histoplasmosis, antifungal therapy was not initiated, and clinical and radiologic surveillance was adopted, with treatment reserved for evidence of disease progression or new clinical or radiologic findings.6 In immunosuppressed patients, the differential diagnosis of pulmonary nodules is broad, with infectious etiologies representing a primary concern. In this context, considerations include tuberculosis, histoplasmosis, aspergillosis, mucormycosis, and pulmonary nocardiosis.8, 9 WBMRI has become an established imaging modality for the diagnosis and longitudinal monitoring of CNO in pediatric patients, allowing comprehensive skeletal evaluation without exposure to ionizing radiation.10, 11 Chest CT remains the imaging modality of choice for the evaluation of pulmonary nodules, providing superior spatial resolution compared with MRI and conventional radiography, particularly for lesions smaller than 1 cm.8 From a practical standpoint, when incidental pulmonary nodules are identified on whole-body MRI in children with CNO living in endemic regions, we propose a stepwise approach. First, pulmonary nodules should be further characterized with a chest CT scan, which provides essential information on nodule morphology, satellite lesions, and hilar or mediastinal lymphadenopathy. Second, clinicians should recognize that imaging findings alone cannot confirm or exclude fungal infection. Imaging findings should be interpreted along with clinical and epidemiologic data to ensure adequate infectious screening. This includes assessment of exposure history and symptoms suggestive of active disease, screening for tuberculosis using interferon-γ release assay or tuberculin skin testing, and serologic testing for H capsulatum. When available, urine antigen testing may assist in distinguishing acute or chronic pulmonary histoplasmosis from subacute forms.12 These results are particularly relevant when determining the need for observation versus antifungal therapy before escalation of immunosuppressive treatment. In summary, although the radiologic pattern of pulmonary involvement described by Hospach et al in CNO is informative, histoplasmosis should be considered in the differential diagnosis of pediatric pulmonary nodules in endemic settings to avoid misclassification and ensure safe immunosuppressive use. Although histoplasmosis is not endemic in Germany and Austria, where the study cohort was recruited, sporadic or imported cases may still occur due to increasing population mobility and migration. Written informed consent was obtained from the patient's legal guardian for publication of the clinical and imaging information included in this Letter. Disclosure form. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.