We searched PubMed for articles published from Feb 1, 1979, to March 31, 2015, with the terms “nontuberculous mycobacteria”, “MSMD”, “GATA2”, “NEMO”, “CYBB”, “ISG15“, “anti-interferon γ autoantibodies”, “cystic fibrosis”, “primary ciliary dyskinesia”, “pulmonary”, and “intrathoracic”. Only papers published in English were used.
ReviewHost susceptibility to non-tuberculous mycobacterial infections
Introduction
Non-tuberculous mycobacteria are ubiquitous in soil, water, and man-made environments.1, 2, 3 Infections caused by these largely non-pathogenic organisms seem to be increasing worldwide and are now more prevalent than those caused by Mycobacterium tuberculosis in developed countries.4, 5 Clinical diseases caused by non-tuberculous mycobacterial infections include lymphadenitis, skin and soft tissue infections, pulmonary disease, and disseminated infection (figure 1). Although disseminated non-tuberculous mycobacterial infections are opportunistic in patients with overt immunodeficiency, such as the late stages of HIV infection, hairy cell leukaemia, and individuals taking specific immunosuppressive therapies,6, 7, 8 refractory or recurrent non-tuberculous mycobacterial infections, especially of the airways, are also seen in otherwise healthy individuals.
Patients with immunodeficiencies, whether primary or acquired, often have poor responses to antimicrobial drugs alone. In some primary immunodeficiencies, adjunctive immunotherapy or cytokine replacement might be beneficial, and in some cases a cure might necessitate haemopoietic stem cell transplantation. An understanding of the distinct type of non-tuberculous mycobacterial infection directs the relevant testing for underlying causes, selection of optimum therapy, and long-term prophylaxis. Furthermore, definitive molecular diagnoses are essential for prognostic assessment and genetic counselling.
Natural immunity to mycobacteria relies on the interleukin 12–interferon γ pathway, connecting myeloid cells (monocytes, macrophages, and dendritic cells) to lymphoid cells (T cells and natural killer cells).9 Patients with severe combined immunodeficiencies, complete DiGeorge syndrome, X-linked hyper-IgM syndrome, and chronic granulomatous disease, have distinct immune defects affecting this pathway and are prone to other infections including Mycobacterium bovis BCG, but not non-tuberculous mycobacteria.10 Susceptibility to non-tuberculous mycobacteria infection is, therefore, not the result of generic susceptibility to mycobacterial infections. Susceptibility to infection varies according to organism and anatomic location. In this Review, we focus on the specific host immune deficiencies that predispose individuals to disseminated non-tuberculous mycobacterial and isolated pulmonary non-tuberculous mycobacterial infections.
Section snippets
Disseminated non-tuberculous mycobacterial diseases
Immunity to mycobacterial infection needs effective interplay between myeloid and lymphoid compartments (figure 2). After engulfing mycobacteria, mononuclear phagocytes produce interleukin 12, which stimulates T cells and natural killer cells through the interleukin-12 receptor, a heterodimer of IL12RB1 and IL12RB2. The interleukin-12 receptor signals via TYK2 and JAK2, leading to STAT4 phosphorylation, homodimerisation, and nuclear translocation to induce interferon γ production (figure 2).
Mendelian susceptibility to mycobacterial disease
Disseminated non-tuberculous mycobacterial infections in children are often caused by inborn errors in the interleukin 12–interferon γ pathway. These diseases are sometimes grouped together by syndrome and referred to as mendelian susceptibility to mycobacterial disease.16 Individuals with any of these genetic defects are characterised by a predisposition to infections with weakly virulent mycobacteria, such as BCG and non-tuberculous mycobacteria.17 This pathway also controls the response to
NEMO deficiency
NFκB is a transcription factor that plays a key part in immune and inflammatory responses.94, 95 Latent in the cytoplasm, NFκB is activated when its inhibitor (IκB) is degraded after phosphorylation by IκB kinase (IκK), which is a heterotrimer of α, β, and γ (also called NEMO) chains. The X-linked IKK-γ gene (IKBKG) that encodes NEMO is necessary for transducing signals from Toll-like receptors, interleukin 1, and TNFα in the immunological pathways, and signalling through the receptor
Anti-interferon γ autoantibodies
By contrast with the genetic diseases mentioned, anti-interferon γ autoantibodies cause an acquired susceptibility to non-tuberculous mycobacterial infections (especially rapidly growing mycobacteria) and other opportunistic infections. All cases are adult-onset with high titre, neutralising anti-interferon γ autoantibodies, which completely block interferon γ activation, negating the interferon γ–interleukin-12 pathway.109 The sex distribution of this syndrome in Asia is equal, but outside
Diagnosis
Although genotyping is the gold standard for the diagnosis of genetic defects, molecular assays are not available in all clinical settings. Nevertheless, some diagnostic clues, from age at onset, sex, pattern of inheritance, pathological features, concomitant infections, and complications can help to refine clinical decision making (table 1).
Isolated pulmonary non-tuberculous mycobacterial infection in adults
Pulmonary disease is the most common manifestation of non-tuberculous mycobacterial infection.120, 121 Despite the wealth of information regarding these infections, underlying immune defects have not been well characterised in patients with isolated pulmonary non-tuberculous mycobacterial infections (table 2).
Miscellaneous conditions
Job's syndrome (hyper-IgE recurrent infection syndrome) is due to dominant negative mutations in STAT3. Patients have recurrent staphylococcal skin abscesses, eczema, and pulmonary infections156 along with scoliosis, joint hypermobility, and a high arched palate.157 About a third of patients have non-tuberculous mycobacteria isolated from at least one sputum culture, and 16% of patients met American Thoracic Society criteria for pulmonary non-tuberculous mycobacterial infection,121 several of
Conclusions
Despite being ubiquitous in the environment, non-tuberculous mycobacteria can cause severe diseases in patients with immune or respiratory epithelial defects. Frequent treatment failures, the need for treatment with several drugs, prolonged treatment courses, drug toxicities, and drug interactions are signs that new and better treatment strategies are needed. Recognition of the underlying defects in the host defences against infection will not only facilitate the development of more effective
Search strategy and selection criteria
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Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome
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