Mulch pneumonitis in chronic granulomatous disease: More than just a fungal infection

Mulch pneumonitis is a rare form of acute fungal pneumonitis characterized by a severe inflammatory response in patients with chronic granulomatous disease (CGD) following exposure to decaying organic matter, such as mulch, leaves or wood chips.1, 2 Although it is frequently mentioned in CGD literature, it remains exceptionally rare, with just over a dozen cases reported worldwide and none documented in Europe to date.1, 3-12 Given its high mortality, mulch pneumonitis—and the potential underlying diagnosis of CGD—should be considered in cases of unexplained pneumonitis, even in previously healthy patients.2 We present an illustrative case from Europe. A previously healthy 8-year-old girl with a two-week history of fevers, cough and tachydyspnea, developed hypoxemic respiratory insufficiency. Initial treatment with oral clarithromycin was discontinued by the patient after 2 days. A chest X-ray conducted in the emergency department revealed diffuse, partially confluent bilateral infiltrates (Figure 1A), raising suspicion for atypical pneumonia. The child was admitted, and azithromycin was started alongside low-flow nasal oxygen supplementation. Despite these measures, her respiratory status continued to deteriorate, leading to her transfer to the pediatric intensive care unit the following day. Worsening hypoxemia, evidenced by increasing desaturation, necessitated high-flow oxygen therapy, while her inflammatory markers continued to rise (Figure 2). Chest computed tomography indicated mediastinal and hilar lymphadenopathy, bilateral symmetric interstitial consolidations, ground-glass opacities, and bronchial wall thickening (Figure 1B). Methylprednisolone (2 mg/kg/day) was administered for 3 days, followed by a switch in antibiotic therapy to cefriaxone, but no improvement was observed. She was intubated for a bronchoalveolar lavage but remained on invasive ventilation for 4 days, with a maximal documented oxygenation index of 20, compatible with pediatric acute respiratory distress syndrome.13 Material obtained from the lavage showed an abundance of neutrophil granulocytes, though direct microscopy did not reveal any bacteria or fungi. Given these findings and a suspicion of interstitial lung disease, three additional pulses of methylprednisolone (10 mg/kg/day) were administered. Immunological work-up revealed a negative nitroblue tetrazolium test (NBT) and negligible increase in fluorescence intensity following stimulation with phorbol myristate acetate in the dihydrorhodamine (DHR) test, indicative of CGD. Consequently, empirical antimicrobial treatment was initiated with intravenous voriconazole (8 mg/kg twice daily), supplemented by broader empiric antimicrobials including co-trimoxazole (6 mg TMP/kg twice daily) and meropenem (20 mg/kg three times a day) while awaiting further diagnostic results. Immunosuppression was maintained with prednisolone at 2 mg/kg/day. Histological investigation of an open lung biopsy specimen revealed granulomatous inflammation with microabscesses and thin, septated hyphae. Cultures from the bronchoalveolar lavage fluid confirmed the growth of Aspergillus fumigatus, susceptible to both amphotericin B (minimum inhibitory concentration 0.25 mg/L) and voriconazole (minimum inhibitory concentration 0.19 mg/L). Panfungal PCR and sequencing on lung tissue confirmed the presence of Aspergillus fumigatus. Consequently, meropenem was discontinued, and the co-trimoxazole dose was adjusted to a prophylactic level (3 mg TMP/kg twice daily). Upon later detailed questioning, the patient reported playing in old sawdust a few days before her initial fever. This exposure history, combined with acute high fevers and tachydyspnea progressing to respiratory insufficiency, was consistent with a diagnosis of mulch pneumonitis. The patient responded well to the combination of voriconazole and steroids. Her condition improved, allowing for tapering off high-flow oxygen support, and she was discharged from the intensive care unit within 1 week. An MRI-thorax performed 2 weeks after initiating antifungal treatment revealed no significant improvement (Figure 1C). However, due to continued clinical progress, voriconazole was switched to oral after 3 weeks (9 mg/kg twice daily), and the patient was discharged to outpatient care 4 weeks after starting antifungal therapy. There was no family history of immunodeficiency, severe or unusual infections, or unexplained inflammation, and no consanguinity. Targeted next-generation sequencing for CGD genes (details available on provider's website14) identified a known pathogenic homozygous variant at NM_000265.5(NCF1):[c.75_76del][p.(Tyr26Hisfs*26)], resulting in p47phox deficiency. Despite being the most common pathogenic mutation in NCF1, this variant was initially missed by whole-exome sequencing, due to the presence of two highly homologous NCF1 pseudogenes. Both pseudogenes carry the same two-nucleotide deletion, and this NCF1 variant is believed to have originated independently in numerous pedigrees due to frequent recombination events with its pseudogenes.15 Antifungal therapy continued with voriconazole, targeting trough concentrations between 1 and 5 mg/L. It was changed to posaconazole (target Ctrough >1.25 mg/L) after 6 weeks due to its superior adverse effect profile. The patient experienced dyspnoea with physical activity during the first months after presentation, but this improved significantly after 3 months. A follow-up MRI of the thorax at 3 months revealed decreasing yet persistent interstitial changes (Figure 1D); concurrent lung function tests indicated a restrictive pattern, with forced vital capacity (FVC) at 62% of the expected level for age. Prednisolone was gradually tapered over several months. However, upon reducing the dosage below 0.1 mg/kg/day, the patient developed fevers and elevated C-reactive protein (CRP) levels, with no measurable procalcitonin. In the absence of clinical signs of new infection and following steroid dose reduction, the fever was considered inflammatory, so the steroid dose was increased. This pattern of recurrent fevers and CRP elevations with steroid tapering continued for over a year until the patient commenced conditioning for hematopoietic stem cell transplantation (HSCT). Despite these inflammatory episodes, the patient's lung function gradually improved, with FVC normalizing before HSCT. With the initiation of HSCT conditioning, posaconazole was replaced by intravenous liposomal amphotericin B (3 mg/kg once-daily), administered until day +5, then adjusted to once every second day due to suspected nephrotoxicity. Post-HSCT, antifungal prophylaxis with posaconazole and immunosuppression were continued until +6 months. At this point, MRI showed further improvement, although interstitial lung changes and bronchiectasis remained (Figure 1F). The clinical symptoms did not reappear after discontinuation of the antifungals and immunosuppression. Timely testing with DHR and NBT enabled the diagnosis of CGD in the acute phase, optimizing therapeutic decisions. This case highlights the value of functional testing in the genetics era, as functional results indicating CGD were available within hours, whereas the genetic diagnosis took an additional 4 months due to limitations of whole-exome sequencing. Nearly half of all genetically diagnosed cases of mulch pneumonitis had p47phox deficiency.1, 7, 11 In about half of these cases, mulch pneumonitis was the initial presentation of CGD, as in our patient.1, 7 The prolonged inflammation and challenges in steroid tapering described here are not widely documented but align with the recognized pro-inflammatory phenotype in CGD patients.2 The underlying mechanisms of inflammation in CGD remain incompletely understood, but the absence of functional NADPH-oxidase as a negative feedback mechanism to control inflammation is a major factor.16 In CGD, phagocytes cannot effectively clear microbial material or cellular debris, resulting in their accumulation at infection sites and triggering persistent cell activation and an exaggerated inflammatory response, characterized by overproduction of cytokines such as IL1ß, IL8, IL18 and TNFα.17, 18 In our patient, repeated chest MRIs showed persistent but receding inflammatory infiltrates at both 3 and 11 months post-initial symptoms. The MRI at 11 months (Figure 1E) also revealed bronchiectasis, indicating tissue damage and scarring from prolonged inflammation. Cultures from a repeat bronchoalveolar lavage at 11 months were negative for fungi or other microorganisms, suggesting the inflammation was not driven by active infection. Although amphotericin B or combination antifungal therapies are typically used for mulch pneumonitis,1, 3, 5, 8, 10 we chose a single-agent approach with voriconazole after Aspergillus fumigatus was isolated in monoculture from the bronchioalveolar lavage and panfungal PCR tested negative for other fungi. This strategy was successful, suggesting its potential utility in similar cases and potentially minimizing side effects associated with combination antifungal therapies in severely ill patients. In conclusion, we report a case of mulch pneumonitis as the presenting symptom of autosomal-recessive CGD in an 8-year-old girl, requiring prolonged immunosuppression and antifungal therapy. Maarja Soomann: Conceptualization; investigation; writing – original draft; visualization; writing – review and editing; methodology; data curation; software. Seraina Prader: Investigation; visualization; writing – review and editing. Tayfun Güngör: Investigation; writing – review and editing; resources. Jana Pachlopnik Schmid: Resources; writing – review and editing; investigation. Adilia Warris: Investigation; writing – review and editing; visualization. Johannes Trück: Investigation; supervision; writing – review and editing; methodology; visualization; conceptualization; writing – original draft. We would like to thank the family and all colleagues who contributed to the management of this patient at various stages of her journey. This work was funded by institutional funds only. None of the authors have any conflicts of interest related to this work. Not required for case reports under Swiss regulations. Written informed consent was obtained from the parents. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.70002.