Ntm in CF: Update on this challenging infection

Abstract

The role of nontuberculous mycobacteria (NTM) in cystic fibrosis (CF) has received significant attention in recent years due to its association with deterioration in lung health (1-4). NTM are obligate aerobes, which are ubiquitous in soil and water. NTM are categorized as “slow growing” species, the most common being Mycobacterium avium complex (MAC) or “rapid growing” species the most prevalent being Mycobacterium abscessus species (MABS). The proportion of NTM subtypes varies by geographical region with MABS appearing more commonly in Europe and Israel and MAC more common in North America (5-8). Steady increases in the prevalence of NTM-positive cultures in CF patients have been reported internationally (4,7,9). Person-to-person NTM transmission has been demonstrated in CF centers (10-13), whilst whole genome sequencing (WGS) has identified multiple international clusters of near-identical MABS isolates suggesting possible international transmission or dominant environmental strains (13). Malnutrition, low BMI (14), and vitamin D deficiency (15) have been associated with NTM acquisition in CF, underlining the importance of good nutritional support in CF care. Sputum acid-fast bacilli (AFB) smear and culture is the benchmark screening method (7,16,17). Serological screening using IgG titres to Mycobacterium antigen A60 (18) and anti-MABSC (19) has demonstrated significantly elevated levels in patients with MABS pulmonary disease (MABS-PD). These serological tests are potentially useful adjuncts to guide mycobacterial culture frequency and could thus help facilitate early diagnosis (19). The role of NTM in CF lung transplant is contentious with a wide variation in practice internationally (20). The International Society for Heart and Lung Transplantation (ISHLT) guidelines classify colonization with NTM as a relative contraindication for listing (21), whilst the CF Foundation/European CF Society considers persistent infection should not be an absolute contraindication (17). The presence of MABS has been shown to hasten lung function decline more rapidly than any other organism in CF with elevated rates of transplant and death (22). However, management is hampered by a paucity of CF-specific trial data for NTM treatment (23). Despite arduous multi-agent therapy the rates of sustained culture conversion are dissatisfying being reported as 45% for MABS and 60% for MAC (1). Although eradication may not be achievable in a significant proportion of patients there may be treatment benefits such as symptom reduction and stabilization of lung function (1,24). The necessity for the development of more effective treatment strategies has never been greater with promising data that clearance of MABS results in the rate of lung function decline returning to baseline levels (3). Several novel potential therapeutic targets have been identified. Blocking MgtC, a known MABS virulence factor involved in bacterial survival within macrophages, was protective against aerosolized MABS in the CF mouse model (25). Gallium-based compounds have been shown to effectively inhibit MABS growth by impairing iron uptake (26). Avibactam, a β-lactamase inhibitor, has been demonstrated during in vitro studies to enhance the efficacy of antibiotics against MABS (27). Intravenous phage treatment has also been successfully used to treat disseminated MABS infection following lung transplantation (28). International collaboration is required to undertake clinical trials to evaluate current and future treatments for NTM in CF patients.L6293888122019-09-26 <br />