Nebulized granulocyte macrophage‐colony stimulating factor to stabilize lung function in nontuberculous mycobacteria pulmonary disease in cystic fibrosis

To the editor, Nontuberculous mycobacteria (NTM) are opportunistic pathogens that can infect people with underlying pulmonary conditions, such as cystic fibrosis (CF), and cause chronic pulmonary infection.1 The rapid-growing Mycobacterium abscessus complex (MABSC) is the second most common NTM species causing pulmonary disease.2 MABSC includes M. a. abscessus, M. a. massiliense, and M. a. bolletii.2 Typical MABSC treatment is divided into two phases.1 The induction phase consists of a three- to-four-drug regimen for 3–12 weeks.1 Treatment guidelines suggest oral macrolide and intravenous (IV) amikacin, in addition to one or more of the following IV agents: imipenem, tigecycline, or cefoxitin.1 The maintenance phase consists of a multidrug regimen: oral azithromycin (continued from induction phase) and nebulized amikacin, in addition to 2–3 of the following oral agents: clofazimine, moxifloxacin, minocycline, and linezolid.1 MABSC susceptibilities and provider experience facilitate chosen treatment regimens. MABSC infections are difficult to treat due to intrinsic and acquired resistance patterns, limited oral antibiotic options, and medication toxicity.2 Optimal treatment duration is not known and people who do not convert their cultures may require continued treatment to prevent decline in health.1 Case: 16-year-old male with cystic fibrosis (genotype N1303K/Y1092X) and NTM-pulmonary disease (NTM-PD). First positive culture appeared at age 8 and he has persistent positive AFB smear for M. abscessus massilinese. Comorbidities include pancreatic insufficiency, liver disease with portal hypertension and esophageal varices, splenomegaly, gastrostomy tube dependence, and oxygen dependence. He has never been treated with elexacaftor-tezacaftor-ivacaftor (Trikafta®). Figure 1 depicts NTM medication regimen and lung function over time. Treatment was initiated 3 months after first positive culture. Induction phase consisted of a 7-month course of azithromycin, imipenem, and tigecycline. Maintenance phase consisted of azithromycin, clofazimine, and nebulized amikacin. Cultures remained positive and lung function continued to decline, so treatment was re-escalated. Several attempts of de-escalation to oral and nebulized treatment regimens failed. Drug toxicities prompted changes to antimicrobial regimen, including drug fever with tigecycline, thrombocytopenia with imipenem and ceftaroline, and infusion reaction with ceftaroline. Oral omadacycline was initiated in early 2020; however, this was switched to IV per patient request as oral omadacycline must be given on an empty stomach and he has continuous nightly tube feeds. As shown in Figure 1, lung function persistently declined. As salvage therapy to attempt to preserve lung function, nebulized granulocyte macrophage-colony stimulating factor (GM-CSF) and nebulized meropenem were initiated. Doses are GM-CSF 240 mcg twice daily 1 week on, 1 week off, and meropenem 500 mg twice daily nebulized continuously. The three oral agents (azithromycin, clofazimine, and bedaquiline), IV omadacycline, and nebulized GM-CSF and meropenem has been a successful maintenance regimen with lung function stabilization (Figure 1). Nebulized therapy increases pulmonary exposure of the agent and reduces extrapulmonary effects. It is often utilized in the continuation phase of NTM-PD due to a lack of oral antibiotics with retained efficacy.1 GM-CSF has been identified as an important factor in immune clearance of MABSC.3, 4 Nebulized GM-CSF may be an effective treatment as persons with CF (pWCF) have reduced endogenous GM-CSF.3 GM-CSF activates the T-helper 1 (Th1) immune response which activates macrophages and neutrophils to clear infection.3, 4 Scientists developed a GM-CSF knockout (KO) mouse model to test antimicrobial agents for NTM infection.4 MABSC was cleared in the acute infection phase in mice by host defenses before development of this KO model. In GM-CSF KO mice, respiratory exposure to MABSC led to acute and chronic pulmonary MABSC infection, indicating the crucial role of cytokine GM-CSF in immune clearance of M. abscessus by the host.4 In CF, low GM-CSF favors the T-helper 2 (Th2) immune response pathway. The Th2 response leads to release of polymorphonuclear neutrophils in the lungs, resulting in inflammation and lung tissue damage.3 In a study of pwCF with chronic Pseudomonas aeruginosa infection, low GM-CSF was correlated with lower lung function, higher inflammation, and dominance of Th2 immune response.3 GM-CSF production is required for and stimulates the Th1 response, which is a more favorable response to clear infection.3 Nebulized GM-CSF has been safe and effective in two pwCF and MABSC disease.5 Nebulized GM-CSF has stabilized decline in lung function in this adolescent with NTM-PD and CF. In pwCF who have progressively declining lung function with NTM-PD, we encourage a trial of nebulized GM-CSF ± meropenem to attempt to preserve lung function. Colette Biro: Writing—original draft; investigation. Corinne Muirhead: Writing—review & editing; conceptualization. We would like to thank Dr. Kevin Winthrop, MD, MPH for the excellent care of this person and for his support in publishing this case report. The authors declare no conflict of interest. Informed parental consent was obtained for publication of this case report. This case report was exempt from IRB review per Oregon Health & Science University policy. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.