MINI REVIEW published: 07 May 2019 doi: 10.3389/fimmu.2019.01013 Impact of Host Genetics and Biological Response Modifiers on Respiratory Tract Infections Alicia Lacoma 1 , Lourdes Mateo 2 , Ignacio Blanco 3 , Maria J. Méndez 4 , Carlos Rodrigo 5 , Irene Latorre 1 , Raquel Villar-Hernandez 1 , Jose Domínguez 1† and Cristina Prat 1*† 1 Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, CIBER Enfermedades Respiratorias, Barcelona, Spain, 2 Servei de Reumatologia, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain, 3 Clinical Genetics and Genetic Counseling Program, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Barcelona, Spain, 4 Servei de Pediatria, Hospital Universitari Germans Trias i Pujol, Edited by: Institut d’Investigació GermansTrias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain, 5 Servei de Pediatria, Ian Marriott, Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca, Facultat de Medicina, Unitat Docent Germans Trias i University of North Carolina at Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain Charlotte, United States Reviewed by: András N. Spaan, Host susceptibility to respiratory tract infections (RTI) is dependent on both genetic University Medical Center Utrecht, and acquired risk factors. Repeated bacterial and viral RTI, such as pneumonia from Netherlands Jesús Gonzalo-Asensio, encapsulated microorganisms, respiratory tract infections related to respiratory syncytial University of Zaragoza, Spain virus or influenza, and even the development of bronchiectasis and asthma, are *Correspondence: often reported as the first symptom of primary immunodeficiencies. In the same way, Cristina Prat cprat.germanstrias@gencat.cat neutropenia is a well-known risk factor for invasive aspergillosis, as well as lymphopenia for Pneumocystis, and mycobacterial infections. However, in the last decades a better † These authors are co-senior authors of this study knowledge of immune signaling networks and the introduction of next generation sequencing have increased the number and diversity of known inborn errors of immunity. Specialty section: On the other hand, the use of monoclonal antibodies targeting cytokines, such as This article was submitted to tumor necrosis factor alpha has revealed new risk groups for infections, such as Microbial Immunology, a section of the journal tuberculosis. The use of biological response modifiers has spread to almost all medical Frontiers in Immunology specialties, including inflammatory diseases and neoplasia, and are being used to target Received: 16 July 2018 different signaling networks that may mirror some of the known immune deficiencies. Accepted: 23 April 2019 Published: 07 May 2019 From a clinical perspective, the individual contribution of genetics, and/or targeted Citation: treatments, to immune dysregulation is difficult to assess. The aim of this article is to Lacoma A, Mateo L, Blanco I, review the known and newly described mechanisms of impaired immune signaling that Méndez MJ, Rodrigo C, Latorre I, predispose to RTI, including new insights into host genetics and the impact of biological Villar-Hernandez R, Domínguez J and Prat C (2019) Impact of Host Genetics response modifiers, and to summarize clinical recommendations regarding vaccines and and Biological Response Modifiers on prophylactic treatments in order to prevent infections. Respiratory Tract Infections. Front. Immunol. 10:1013. Keywords: immunogenetics, biological response modifiers, respiratory tract infections, primary doi: 10.3389/fimmu.2019.01013 immunodeficiencies, inborn errors Frontiers in Immunology | www.frontiersin.org 1 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections EPIDEMIOLOGY AND PATHOGENESIS OF Recently, changes in gut and lung microbiome composition RESPIRATORY TRACT INFECTIONS (dysbiosis) have also been related to dysfunctional immune modulation (22). Acute and chronic respiratory tract infections (RTI) are one of the most frequent causes of infections and antimicrobial prescription, and the leading cause of death in developing IMMUNE RESPONSE TO RESPIRATORY countries (1, 2). Pneumonia accounts for 1.3 million deaths TRACT INFECTIONS annually in children <5 years of age (3). In 2017, 1.6 million people died of tuberculosis (TB). Children (aged <15 Respiratory immune responses are complex, and inborn errors years) accounted for 15% of total deaths, higher than their can be present at any level. Essential pathways can be share of estimated cases, suggesting poorer access to diagnosis summarized as follows: Firstly, the pathogen has to be detected and treatment. About 1.7 billion people, 23% of the world’s by host cells. This identification relies on a set of pathogen population, are estimated to have a latent TB infection (4). associated molecular profiles that bind to pattern recognition The control of latent TB, a stage in which a person is receptors (PRR). PRR can be found as transmembrane, infected with Mycobacterium tuberculosis plays an important cytosolic or extracellular components. Among PRRs, it is role in disease control, since dormant bacilli are a reservoir important to mention toll-like receptors (TLR), nucleotide- of potential TB cases (5). Viral acute RTI are estimated to binding oligomerization domain-containing (NOD) receptor, cause 75% of acute diseases in children, and is the main NOD-like receptors (NLR), RIG-I-Like Receptors (RLR), and reason for hospitalization worldwide (6). The annual prevalence receptor CD14 because of their importance during respiratory in an otherwise healthy child is from 3 to 10 infections infections (23). Depending on the PRR, different intracellular (7). Early and recurrent lower RTI are linked to a higher signaling pathways are activated (24). Most of the signaling risk to develop asthma or bronchiectasis (8–10). However, pathways converge on signaling hubs, such as transcription bronchiectasis secondary to recurrent and severe infections alone nuclear factor κβ (NF-κβ), interferon regulatory factor families have declined, with an increasing proportion of patients being (IRF3, IRF7), and mitogen-activated protein kinase, leading to recognized as having underlying conditions predisposing to its the induction of gene expression encoding adhesion molecules, development (11). pro-inflammatory cytokines, chemokines, and type I interferon, Improvements in immunization programs and the wide among others. NLRs directly trigger inflammasome assembly availability of antimicrobials, have led to optimism for most of and caspase-1 activation, leading to interleukin (IL)-1β and IL- the devastating infectious diseases. Always without forgetting 18 processing (25). Type III interferons, also termed IFN-λ, that alleviation of poverty is crucial, the combination of genetic have been recently identified as regulators of immunity and versatility and ecological opportunism of the microbial world homeostasis in the respiratory tract (26) during infections, appears to have been under-estimated (12). Some emerging as well as during chronic lung diseases, such as asthma and pathogens, such as Legionella, avian influenza, and coronavirus chronic obstructive pulmonary disease (COPD) (27). Alveolar species were described in the past decades (13). Ethnic variations macrophages and dendritic cells (DC) have an important role in the incidence of RTI have also been reported, suggesting sensing microbes and thus activating lung epithelial cells and genetic susceptibility to disease (14). Most children, on reaching neutrophils. These are essential for the defense against bacteria, 2 years of age, have been in contact with the most common viruses, and Aspergillus (28, 29), as well as in the pathogenesis respiratory viruses, such as respiratory syncytial virus (RSV), of acute lung injury. In a recent study, patterns of differentially but while some develop a mild disease, others develop severe expressed cellular genes shared by several respiratory pathogens bronchiolitis (15). Influenza viruses cause mild to moderate were searched using transcriptomics (30). Most of the commonly respiratory illness in most people, but some develop fatal up-regulated host genes were related to the innate immune infections. The virulence factors encoded by viral genes can response and/or apoptosis, with Toll-like, RIG-I-like, and NLR explain seasonal or geographical differences at a population level, among the top 10 signalers. Some of the genes showed a high but are unlikely to account for inter-individual clinical variability degree of interconnection and possible redundancy to respiratory (16). TB outcome depends on the pathogen and extrinsic viral and bacterial infections. The adaptive immune response elements, as well as on host factors that are still unclear (17). requires the activation of antigen-specific T and B lymphocytes As regards bacteria, focusing on those species whose normal to trigger protective cellular and humoral responses. Most ecological niche is the airways, therapeutic decisions are a of the T lymphocyte subsets, along with B lymphocytes and daily clinical challenge (18). The shift from commensalism DC, are essential for immune defense and/or regulation (31). to infection is shaped by host intrinsic (genetics) and In particular, the protective immunity against M. tuberculosis extrinsic factors (for example, diet and exposure to depends on CD4+ T-helper1 lymphocytes that mainly secrete cigarette smoke and environmental pollution) and by interferon-gamma (IFN-γ), IL-2, and tumor necrosis factor bacterial features that also contribute to inter-individual alpha (TNF-α), which leads to macrophage activation, cytokine variability (19). Bacteria develop adaptive mechanisms production, and bacterial control (32). HIV-revealed T-cell (at genetic/phenotypic level) in order to survive in a lymphopenia as a well-defined risk group for Pneumocystis hostile environment, such as the respiratory tract (20, 21). jirovecii pneumonia (PJP), but also in other situations where Whether pathogen virulence generates clinical symptoms CD4 lymphocyte count is lower, such as renal transplant depends on how well the immune system limits its impact. recipients (33). Frontiers in Immunology | www.frontiersin.org 2 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections GENETIC SUSCEPTIBILITY TO (31), thus most of the defects can be potentially counterbalanced. RESPIRATORY TRACT INFECTIONS According to the literature, there is another view suggesting that while patients with broad immunodeficiencies may present The study of susceptibility to lower respiratory tract infections is with one of their many infections, the phenotype of particular complex, and requires different approaches. There are three main inborn errors of immunity is very narrow, with susceptibility to elements playing a role: host genetic background (in relation only one specific infection (36, 41, 42). A set of inborn errors to lung tissue functionality and immune response), pathogen affecting “primarily” innate immunity, exercise their effect on virulence determinants, and environmental factors. the adaptive immune response (41). The range and nature of Early life (children under 5 years of age) is a challenging infections depend on several factors. The improving recognition period because pulmonary tissue and the immune system of immune dysregulation diseases, autoinflammatory disorders, are still in a maturation process while being continuously and interferonopathies leads to changes in terminology. The exposed to airborne antigens (34). However, the occurrence annual report of the authoritative International Union of of life-threatening bacterial/viral/fungal infection in an Immunological Societies (43) has categorized and listed (as of otherwise healthy individual deserves further immunological February 2017) 354 inborn errors of immunity, and those with and genetic studies (35, 36). Complications during upper a predominant RTI phenotype have been included in Table 1. RTI include sinusitis and otitis media, and in the lower Despite the limitations of molecular genetic studies in airways, pneumonia, bronchitis, as well as the development pulmonary infections, several associations have been described of bronchiectasis, interstitial lung diseases, organizing between SNPs and bacterial pneumonia and mycobacterial pneumonia, and hyperreactive airway diseases (37). Indeed, infections (14, 45). Polymorphisms affecting community- genetic susceptibility for the concomitant illnesses that acquired pneumonia including, among others, those related predispose to RTI can also play a role, including congenital to mannose-binding lectin and the IgG2 Fc gamma receptor defects of the airways, familial congenital bronchiectasis or II, and are discussed extensively elsewhere (14). The genetic tracheobronchomegaly (11). As regards impaired mucociliary contribution for the propensity to develop severe RSV infection clearance, cystic fibrosis is the most common autosomal recessive was estimated to account for ∼20% of the variance in RSV disease disorder and primary cause of bronchiectasis in the developed severity. Several studies have attempted to link candidate host world. Mutations are well-defined, but its severity is influenced SNPs to disease severity, mostly in chemokine receptors and by genes involving inflammatory and anti-inflammatory PRRs (46, 47). mediators (38, 39). Other disorders include ciliopathies and As regards TB, SNPs are frequently found in loci involving disorders of humoral immunity. Alpha 1-antitrypsin is a TLR-2, TNF-α, IL-12, and IFN-γ, and their corresponding circulating serine protease inhibitor (serpin) made in the receptors (45). Genetic variations in dendritic cell-specific liver that plays an important role in modulating immunity, ICAM-3 grabbing non-integrin have been linked with inflammation, apoptosis, and possibly cellular senescence reduced risk of developing TB (48). Mendelian susceptibility programs and its deficiency is considered the genetic cause to mycobacterial disease is a syndrome characterized by of COPD, but there are other genetic factors that may affect susceptibility to weakly virulent mycobacteria, including the disease activity and outcomes, even in patients without this attenuated vaccine Bacillus Calmette-Guerin (BCG) strain deficiency (27). and non-tuberculous mycobacteria (NTM). Different gene High-throughput whole genome sequencing technologies mutations have been identified, most of which are related and novel bioinformatics tools are revealing the sequence to IFN-γ-mediated immunity (49–51). Using exome and and annotation of the complete human genome, as well as transcriptome sequencing, three rare loss-of-function variants genome-wide maps of polymorphic microsatellite markers and have been recently characterized in theIFIH1 gene. These encode single nucleotide polymorphisms (SNP). In order to characterize a RIG-I-like receptor involved in the sensing of viral RNA (52). genetic susceptibility, two complementary approaches can be The deficiency causes a primary immunodeficiency manifested envisaged: whole genome association studies (WGAS) for the in extreme susceptibility to common respiratory RNA viruses. identification of variants with high population frequency but low Interestingly, human primary immunodeficiency disorders (PID) impact at individual level in terms of risk of infection (although affecting T and B cells were not found to predispose to severe SNP identification can potentially be later included in healthcare influenza. However, human IRF7 was shown to be essential for planning protocols); and mechanistic studies for identifying IFN-α/β- and IFN-λ-dependent protective immunity against disease-causing mutations with deleterious effects, related to a primary influenza in vivo (53). high risk of infection at individual level, although its frequency in general population is low. Many genetic variants have been associated with complex human diseases and traits, but often IMPACT OF BIOLOGICAL RESPONSE confer relatively small increases in risk (40). According to a recent MODIFIERS IN RESPIRATORY TRACT review, there are more than 300 primary immunodeficiency INFECTIONS AND TUBERCULOSIS disorders (PIDs), most of them monogenic conditions with Mendelian inheritance, that are mainly associated with crucial Biological response modifiers (BRM) are substances that interact defects in adaptive immunity (31). Innate immune responses are with and modify the host immune system by acting on largely redundant, with pleiotropic nature of some gene products a therapeutic target considered important in the pathogenic Frontiers in Immunology | www.frontiersin.org 3 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections TABLE 1 | Reported risk of infection and recommended prophylaxis according to functional classification of biologicals-based on ESCMID consensus document (44) and to categorization of inborn errors of immunity-based on International Union of Immunological Societies annual report (43). Reported risk of infection Recommendations TB Pneumocystis Pneumococcal/ Influenza screening prophylaxis capsulated vaccination and bacteria prophylaxis vaccination TARGETED AGENT Anti-tumor necrosis factor-α Two to four increase in the risk of active TB compared to Yes No Yes Yes agents healthy patients and other granulomatous conditions Rate of Legionella 37-fold higher. Histoplasmosis and coccidioidomycosis Interleukins, immunoglobulins IL-1 family, moderate risk of infection, Yes No Yes Yes and complement factors IL-6 and IL-6 receptor (JAK), similar to TNF. Neutropenia in some cases C5 targeted, Aspergillus encapsulated bacteria, specially Neisseria, IL-17 upper respiratory tract infections and Candida IgE helminth infection, Strongyloides Cell surface Drug induced neutropenia Optional No Age Yes receptors/associated signaling Skin and soft tissue infections and sometimes pneumonia appropriate pathways Overall risk of infection low for epidermal growth factor Intracellular signaling pathways Increased overall risk of infection, cytomegalovirus and Yes Yes Age Yes hepatitis B reactivation appropriate Difficult to distinguish from the risk of the underlying disease Cases of Pneumocystis, invasive fungal infection nocardiosis, mainly JAK Lymphoid cells surface antigens Can cause IgG hypogammaglobulinaemia and neutropenia Yes Yes Age Yes (CD19, CD20, CD52) Evidence of catheter related bacteremia, severe respiratory appropriate tract infection, hepatitis B reactivation and varicella zoster Lymphoid/Myeloid cells surface Similar to anti CD20 Optional Yes Age Yes antigens (CD22, CD30, CD33, appropriate CD38, CD40, SLAMF-7, CCR4) Immune checkpoint inhibitors, Associated T cell lymphopenia but no opportunistic infections Yes Yes Yes Yes cell adhesion inhibitors, reported sphingosine-1-phosphate Risk of varicella zoster virus receptor modulators and proteasome inhibitors INBORN ERRORS OF IMMUNITY Severe combined immune Severe opportunistic disseminated infections in early Non- Yes No No deficiency: childhood applicable (cohabitants) Less severe combined immune Some related to recurrent respiratory tract infections Optional Yes Yes Yes deficiency Combined immune deficiencies Recurrent infections Optional No Yes Yes with syndromic features e.g., Wiscot Aldrich and those altering DNA reparation Humoral immune deficiencies Repeated respiratory tract infections (pneumonia, sinusitis, Optional No Yes Yes Antibody deficiencies otitis, …) Defects of phagocyte number or Fungal and bacterial infections, pulmonary abscesses, No No Yes Yes function aspergillosis Defects in intrinsic and innate Pyogenic bacterial infections In No (*) Yes Yes immunity selected cases Autoinflammatory diseases No clear predisposition to infection No No Yes Yes Complement deficiencies Disseminated infections (meningitis/sepsis) by capsulated No No (*) Yes Yes microorganisms and Neisseria *Antibiotic prophylaxis to prevent bacterial infections. Frontiers in Immunology | www.frontiersin.org 4 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections process of the disease. Monoclonal antibodies (mAbs) are the risk of serious infections is highest during the first 6 now established as therapies for malignancies, transplant months of therapy (62) (up to 4.5-fold risk), although, after rejection, several immune disorders from most organ systems, 1 year this risk is no different from conventional DMARDs. and even infectious diseases (54). Safety problems related to Recurrent infections in RA are common. In a prospective immunomodulation and infection have been identified in some observational cohort study, the baseline annual rate of a first cases (55). The use of mAb indirectly provides insights into serious infection was 4.6%. Additionally, 14% of this cohort the function of the molecule to combat particular pathogens, experienced a recurrent episode/year during their follow-up, increasing our knowledge of the immune system (56). A with the highest risk being within the first year (29%), and recent consensus document has reviewed the groups of drugs with respiratory infections being the most common (44% of according to the targeted site of action, the expected impact all episodes) (63). Factors that have shown to be predictive of on susceptibility to infection, the evidence of risk, and the infection include, age, functional status, specific comorbidities recommendation of prevention strategies. It is also important (chronic renal/lung disease), corticosteroid treatment, number to mention the influence of previous or concomitant therapies, of previous DMARD, treatment failures, previous serious underlying conditions, and the accumulative exposure to the infections, and current treatment with anti-TNF-α inhibitors or agent (44). As regards lower RTI, treatment with BRM results non-biological DMARDs (64). Nevertheless, recent data suggest in an increased risk is reported for pneumonia, influenza- that patients having a serious infection and exposed to biological related complications, TB and NTM, Pneumocystis, and fungal treatment have a significantly lower risk of sepsis and fatal infections, such as histoplasmosis, taking into account the impact outcome than patients treated with conventional DMARDs of geographical variations on incidence rates (57). The knowledge (62, 65). British and French national biological registries have obtained from experience with the prescription of BRM may reported OI rates of 200–270/100,000 in patients using anti- be particularly valuable for the understanding of some genetic TNF-α therapies (66, 67). In particular, there is evidence of inborn errors, as the type of infections acquired as a side effect an increased risk of M. tuberculosis, herpes zoster, and Listeria may help to identify which genetic defects favors a similar infections. The overall incidence of OI is not significantly infectious phenotype. With the current knowledge and because of different considering drug classes; however, the rate of PJP pleiotropic effects, it is not feasible to show how biological agents is significantly higher in those patients using rituximab in actually mimic some inborn errors of immunity, but several comparison to anti-TNF-α therapy. The absolute risk of PJP parallelisms can be inferred. We provide a Table containing is low, although corticosteroid exposure is a strong predictor. the list of BRM according to their functional classification, Current data do not support PJP prophylaxis for all rituximab and inborn errors categorized according to common infectious users. However, it may be appropriate in certain high-risk phenotypes (Table 1). Data presented are extracted from the individuals. Furthermore, rituximab-associated neutropenia and respective consensus documents, and lists the main RTI and impaired antibody response is also well-described. preventive recommendations. Pre-clinical and clinical evidence indicate that anti-TNF- Current recommendations should be focused on rheumatic α therapy (infliximab, adalimumab, golimumab, certolizumab diseases because of the greater experience in follow-up time pegol, and etanercept) is associated with a 2- to 4-fold increase (more than 15 years) and number of patients treated. Biological in the risk of active tuberculosis and other granulomatous therapies targeting TNF-α, T cells, B cells, and various conditions. Risk seems to be lower for etanercept (68). Risk cytokines (including IL-6 and IL-1) have become essential also depends on local TB prevalence: in the year 2000, for the treatment of rheumatic diseases [mainly rheumatoid Spanish investigators reported an estimated TB incidence of arthritis (RA), ankylosing spondylitis, and psoriatic arthritis], as 1,893/100,000 person-years in patients with RA treated with well as other immune-mediated diseases. Moreover, additional infliximab (69). This rate is ∼10- to 20-fold higher than the drugs with novel targets, including those that inhibit IL-12– observed rate in naïve patients. These rates have decreased IL-23, IL-17α, or the Janus activating kinase system have dramatically since the establishment of latent tuberculosis been introduced more recently. Immunomodulation offered infection (LTBI) screening prior to biological therapy (67, by biological and non-biological disease-modifying therapies 70). It is essential to rule out LTBI in such individuals in and prednisone contributes greatly to the increased risks of order to reduce the risk of active TB reactivation. Interferon- opportunistic infections (OI) (58, 59). In Figure 1 we present gamma release assays (IGRAs) are useful tools for LTBI the sites of action and associated risks of the most frequently diagnosis. They are more specific than the tuberculin skin test prescribed BRM. (TST) because they do not show cross-reactivity with BCG- Two recent meta-analysis have calculated the relative risk vaccination or NTM sensitization (71–73). Moreover, these in- of infection for rheumatic patients under biological treatment, vitro assays incorporate a mitogen control that can detect the with an odds ratio (OR) of 1.31–1.41 (60, 61). The absolute presence of anergy, common in patients on immunosuppressive increase in the number of serious infections per 1,000 patients therapy (74). However, the clinical performance of IGRAs treated/year is six times higher than that observed with synthetic is still controversial due to the variety of concomitant disease-modifying anti-rheumatic drugs (DMARDs). Different immunosuppressive drug-regimens used at the time of LTBI meta-analyses and national registries have confirmed the increase screening, population heterogeneity, and the severity of the on the impact of any infections (20%), serious infections (40%), disease itself (75). Therefore, the clinical accuracy of IGRAs and TB (250%), associated with anti-TNF-α use (60). In addition, seems to be differentially affected depending on the specific type Frontiers in Immunology | www.frontiersin.org 5 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections FIGURE 1 | Mode of action of biological response modifiers (BRM) according to cell type, cytokine and/or receptor targeted. Risk of developing infections according to the BRM considered is also shown. List of BRM. Anti-tumor necrosis factor-α (TNF-α) agents. ADA, adalimumab; CTZ, certolizumab; GLM, golimumab; IFX, infliximab; ETN, etanercept. Anti-interleukins, immunoglobulins, and complement factors. Anti IL-1, anakinra ANK; Anti IL-6: TCZ, tocilizumab; Anti IL-17: SCK, secukinumab; IXE, ixekizumab; BRD, brodalumab. Anti-IL12/23: USK, ustekinumab. Cell surface receptors/associated signaling pathways agents. Anti-CD28: ABT, abatacept; B-cell activating factor (BAFF): BLM, belimumab. Lymphoid cells surface antigens. Anti-CD20: RTX, rituximab. mAb, monoclonal antibody; PEG, polyethylene glycol; TB, tuberculosis; LTBI, latent tuberculosis infection. of immune disorder. Crohn’s disease and/or its concomitant NTM infection (78), mostly Mycobacterium avium. In some drug-profile (such as azathioprine or high-dose corticosteroids) countries, NTM infections are more common than TB after could negatively affect the clinical performance of IGRAs anti-TNF-α treatment. However, there are still no established when compared with other immune-mediated diseases, such recommendations as regards screening and prophylaxis (79). A as psoriasis or inflammatory rheumatic diseases (76). Thus, it baseline chest x-ray should be recommended prior to starting seems prudent and convenient to perform dual LTBI testing therapy, and in patients with chronic unexplained cough, further with TST and IGRAs (77). Patients with RA and underlying work-up should include chest computed tomography scans and structural lung diseases are at increased risk of developing culture of respiratory specimens. Frontiers in Immunology | www.frontiersin.org 6 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections Immunization strategies are recommended for all cases, experience are mandatory in order to prevent re-emerging regardless of whether the patient has PID or is receiving severe infections. immunosuppressive treatment, and it is of importance to be vaccinated according to the national immunization AUTHOR CONTRIBUTIONS routine schedules. For patients with anti-TNF-α treatment, pneumococcal and age-appropriate anti-viral vaccinations CP organized the structure and supervised the manuscript (i.e., influenza) should be administered (68). Immunization elaboration, revised literature and wrote a part of every chapter. before and after BRM is well-established as regards AL revised literature, wrote the sections related to the immune inactivated vaccines, and precautions should be taken for response to infection and part of genetics, and edited the live vaccines (57). However, even if response to vaccines is manuscript. IL, RV-H, and JD revised and wrote the aspects impaired in patients with PID (80), it may have an effect related to tuberculosis, and JD also supervised the manuscript in patients receiving some BRM. This may be partially elaboration. LM revised and wrote the section regarding the explained by the concept of trained immunity-based impact of biological response modifiers specially related to vaccines (81). rheumatologic diseases. LM, AL, and RV-H prepared the figure. In conclusion, RTIs belong to the most common causes MM and CR revised aspects related to immunodeficiencies, and of infections in humans worldwide. The genetic contribution impact of BRM in children. IB revised host genetic factors. All to severe RTIs may have been masked by other interventions authors revised and approved the final version of the manuscript. (82). The inborn errors of innate immunity show us that the absence of a measurable immunological defect does FUNDING not exclude an immunodeficiency (41). Further functional genetic studies are necessary in order to fully validate This research was supported by two grants from the Instituto the impact of host genetics during lung infections. The de Salud Carlos III (PI 16/01912, PI 17/01139, and PI18/00411), knowledge obtained from experience with the prescription integrated in the Plan Nacional de I + D + I and funded jointly of BRM may be particularly valuable, as the infections by the ISCIII Subdirección General de Evaluación and the Fondo acquired as a side effect may help to identify genetic Europeo de Desarrollo Regional (FEDER). JD is a researcher defects with a similar infectious phenotype. In the meantime, from the Miguel Servet programme. CP was awarded by recommendations based on biological rationale and clinical programa Germans Trias Sapiens Fundació Catalunya la Pedrera. REFERENCES 11. Gould CM, Freeman AF, Olivier KN. Genetic causes of bronchiectasis. Clin Chest Med. (2012) 33:249–63. doi: 10.1016/j.ccm.2012.03.002 1. Ferkol T, Schraufnagel D. The global burden of respiratory disease. Ann Am 12. McMichael A. Environmental and social influences on infectious diseases. In: Thorac Soc. (2014) 11:404–6. doi: 10.1513/AnnalsATS.201311-405PS Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J, editors. Evolutionary 2. Mizgerd JP. Lung infection–a public health priority. PLoS Med. (2006) Biology of Bacterial and Fungal Pathogens. Washington: American Society for 3:e76. doi: 10.1371/journal.pmed.0030076 Microbiology Press (2008). p. 31–8. 3. Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA, et al. Global 13. Morens DM, Folkers GK, Fauci AS. The challenge of emerging burden of childhood pneumonia and diarrhoea. Lancet. (2013) 381:1405– and re-emerging infectious diseases. Nature. (2004) 430:242– 16. doi: 10.1016/S0140-6736(13)60222-6 9. doi: 10.1038/nature02759 4. World Health Organization. Global Tuberculosis Report 14. Affandi JS, Price P, Waterer G. Can immunogenetics illuminate the diverse 2018 (WHO/CDS/TB/2018.20). Geneva: World Health Organization. manifestations of respiratory infections? Ther Adv Respir Dis. (2010) 4:161– 5. Rustad TR, Sherrid AM, Minch KJ, Sherman DR. Hypoxia: a window 76. doi: 10.1177/1753465810371484 into Mycobacterium tuberculosis latency. Cell Microbiol. (2009) 11:1151– 15. Lambert L, Sagfors AM, Openshaw PJ, Culley FJ. Immunity to RSV in 9. doi: 10.1111/j.1462-5822.2009.01325.x early-Life. Front Immunol. (2014) 5:466. doi: 10.3389/fimmu.2014.00466 6. Nair H, Simoes EA, Rudan I, Gessner BD, Azziz-Baumgartner E, Zhang JS, 16. Ciancanelli MJ, Abel L, Zhang SY, Casanova JL. Host genetics of severe et al. Global and regional burden of hospital admissions for severe acute lower influenza: from mouse Mx1 to human IRF7. Curr Opin Immunol. (2016) respiratory infections in young children in 2010: a systematic analysis. Lancet. 38:109–20. doi: 10.1016/j.coi.2015.12.002 (2013) 381:1380–90. doi: 10.1016/S0140-6736(12)61901-1 17. Bastos HN, Osorio NS, Gagneux S, Comas I, Saraiva M. The 7. Regamey N, Kaiser L, Roiha HL, Deffernez C, Kuehni CE, Latzin P, et al. Troika host-pathogen-extrinsic factors in tuberculosis: modulating Viral etiology of acute respiratory infections with cough in infancy: a inflammation and clinical outcomes. Front Immunol. (2017) community-based birth cohort study. Pediatr Infect Dis J. (2008) 27:100– 8:1948. doi: 10.3389/fimmu.2017.01948 5. doi: 10.1097/INF.0b013e31815922c8 18. Cookson W, Cox MJ, Moffatt MF. New opportunities for managing 8. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, acute and chronic lung infections. Nat Rev Microbiol. (2018) 16:111– Meijer A, Kimpen JL, et al. Respiratory syncytial virus and 20. doi: 10.1038/nrmicro.2017.122 recurrent wheeze in healthy preterm infants. N Engl J Med. (2013) 19. Sen R, Nayak L, De RK. A review on host-pathogen interactions: 368:1791–9. doi: 10.1056/NEJMoa1211917 classification and prediction. Eur J Clin Microbiol Infect Dis. (2016) 35:1581– 9. Henderson J, Hilliard TN, Sherriff A, Stalker D, Al Shammari N, Thomas HM. 99. doi: 10.1007/s10096-016-2716-7 Hospitalization for RSV bronchiolitis before 12 months of age and subsequent 20. Cullen L, McClean S. Bacterial adaptation during chronic respiratory asthma, atopy and wheeze: a longitudinal birth cohort study. Pediatr Allergy infections. Pathogens. (2015) 4:66–89. doi: 10.3390/pathogens4010066 Immunol. (2005) 16:386–92. doi: 10.1111/j.1399-3038.2005.00298.x 21. Prat C, Lacoma A. Bacteria in the respiratory tract-how to treat? Or 10. Gern JE. Viral respiratory infection and the link to asthma. Pediatr Infect Dis do not treat? Int J Infect Dis. (2016) 51:113–22. doi: 10.1016/j.ijid.20 J. (2008) 27(10 Suppl.):S97–103. doi: 10.1097/INF.0b013e318168b718 16.09.005 Frontiers in Immunology | www.frontiersin.org 7 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections 22. Budden KF, Gellatly SL, Wood DL, Cooper MA, Morrison M, Hugenholtz Immunodeficiency Diseases Committee report on inborn errors of immunity. P, et al. Emerging pathogenic links between microbiota and the gut- J Clin Immunol. (2018) 38:96–128. doi: 10.1007/s10875-017-0464-9 lung axis. Nat Rev Microbiol. (2017) 15:55–63. doi: 10.1038/nrmicro. 44. Fernandez-Ruiz M, Meije Y, Manuel O, Akan H, Carratala J, Aguado JM, 2016.142 et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) 23. Mizgerd JP. Acute lower respiratory tract infection. N Engl J Med. (2008) Consensus document on the safety of targeted and biological therapies: an 358:716–27. doi: 10.1056/NEJMra074111 infectious diseases perspective (Introduction). Clin Microbiol Infect. (2018) 24 24. Hancock RE, Nijnik A, Philpott DJ. Modulating immunity as Suppl. 2:S2–9. doi: 10.1016/j.cmi.2018.01.029 a therapy for bacterial infections. Nat Rev Microbiol. (2012) 45. van Tong H, Velavan TP, Thye T, Meyer CG. Human genetic factors 10:243–54. doi: 10.1038/nrmicro2745 in tuberculosis: an update. Trop Med Int Health. (2017) 22:1063– 25. Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting 71. doi: 10.1111/tmi.12923 to microbes through the inflammasomes. Nat Immunol. (2012) 46. Amanatidou V, Apostolakis S, Spandidos DA. Genetic diversity of the host and 13:325–32. doi: 10.1038/ni.2231 severe respiratory syncytial virus-induced lower respiratory tract infection. 26. Andreakos E, Salagianni M, Galani IE, Koltsida O. Interferon-lambdas: front- Pediatr Infect Dis J. (2009) 28:135–40. doi: 10.1097/INF.0b013e31818c8d17 line guardians of immunity and homeostasis in the respiratory tract. Front 47. Janssen R, Bont L, Siezen CL, Hodemaekers HM, Ermers MJ, Doornbos Immunol. (2017) 8:1232. doi: 10.3389/fimmu.2017.01232 G, et al. Genetic susceptibility to respiratory syncytial virus bronchiolitis is 27. Egli A, Mandal J, Schumann DM, Roth M, Thomas B, Lorne Tyrrell D, et al. predominantly associated with innate immune genes. J Infect Dis. (2007) IFNLambda3/4 locus polymorphisms and IFNLambda3 circulating levels 196:826–34. doi: 10.1086/520886 are associated with COPD severity and outcomes. BMC Pulm Med. (2018) 48. Barreiro LB, Neyrolles O, Babb CL, Tailleux L, Quach H, McElreavey K, et al. 18:51. doi: 10.1186/s12890-018-0616-6 Promoter variation in the DC-SIGN-encoding gene CD209 is associated with 28. Dagenais TR, Keller NP. Pathogenesis of Aspergillus fumigatus tuberculosis. PLoS Med. (2006) 3:e20. doi: 10.1371/journal.pmed.0030020 in invasive aspergillosis. Clin Microbiol Rev. (2009) 22:447– 49. Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, et al. 65. doi: 10.1128/CMR.00055-08 Germline CYBB mutations that selectively affect macrophages in kindreds 29. Camp JV, Jonsson CB. A role for neutrophils in viral respiratory disease. Front with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol. (2017) 8:550. doi: 10.3389/fimmu.2017.00550 Immunol. (2011) 12:213–21. doi: 10.1038/ni.1992 30. Martinez I, Oliveros JC, Cuesta I, de la Barrera J, Ausina V, Casals C, et al. 50. Schurr E. The contribution of host genetics to tuberculosis pathogenesis. Apoptosis, toll-like, RIG-I-like and NOD-like receptors are pathways jointly Kekkaku. (2011) 86:17–28. induced by diverse respiratory bacterial and viral pathogens. Front Microbiol. 51. Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, (2017) 8:276. doi: 10.3389/fmicb.2017.00276 et al. Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in 31. Fischer A, Rausell A. What do primary immunodeficiencies tell us about humans homozygous for a common TYK2 missense variant. Sci Immunol. the essentiality/redundancy of immune responses? Semin Immunol. (2018) (2018) 3:eaau8714. doi: 10.1126/sciimmunol.aau8714 36:13–6. doi: 10.1016/j.smim.2017.12.001 52. Asgari S, Schlapbach LJ, Anchisi S, Hammer C, Bartha I, Junier T, et al. Severe 32. O’Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP. viral respiratory infections in children with IFIH1 loss-of-function mutations. The immune response in tuberculosis. Annu Rev Immunol. (2013) 31:475– Proc Natl Acad Sci USA. (2017) 114:8342–7. doi: 10.1073/pnas.1704259114 527. doi: 10.1146/annurev-immunol-032712-095939 53. Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y, Volpi S, et al. Life- 33. Brunot V, Pernin V, Chartier C, Garrigue V, Vetromile F, Szwarc I, et al. threatening influenza and impaired interferon amplification in human IRF7 An epidemic of Pneumocystis jiroveci pneumonia in a renal transplantation deficiency. Science. (2015) 348:448–53. doi: 10.1126/science.aaa1578 center: role of T-cell lymphopenia. Transplant Proc. (2012) 44:2818– 54. Kaplon H, Reichert JM. Antibodies to watch in 2018. MAbs. (2018) 10:183– 20. doi: 10.1016/j.transproceed.2012.09.089 203. doi: 10.1080/19420862.2018.1415671 34. Lambert L, Culley FJ. Innate immunity to respiratory infection in early life. 55. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and Front Immunol. (2017) 8:1570. doi: 10.3389/fimmu.2017.01570 side effects of monoclonal antibodies. Nat Rev Drug Discov. (2010) 9:325– 35. Casanova JL, Abel L. The human model: a genetic dissection of immunity 38. doi: 10.1038/nrd3003 to infection in natural conditions. Nat Rev Immunol. (2004) 4:55– 56. Davis BP, Ballas ZK. Biologic response modifiers: Indications, 66. doi: 10.1038/nri1264 implications, and insights. J Allergy Clin Immunol. (2017) 36. Casanova JL, Abel L. Human genetics of infectious diseases: Unique 139:1445–56. doi: 10.1016/j.jaci.2017.02.013 insights into immunological redundancy. Semin Immunol. (2018) 36:1– 57. Davies HD, Committee On Infectious D. Infectious complications with the 12. doi: 10.1016/j.smim.2017.12.008 use of biologic response modifiers in infants and children. Pediatrics. (2016) 37. Yazdani R, Abolhassani H, Asgardoon M, Shaghaghi M, Modaresi M, Azizi G, 138:e2016120. doi: 10.1542/peds.2016-1209 et al. Infectious and noninfectious pulmonary complications in patients with 58. Fisher MC, Greenberg JD. Assessing infection risk with biologic agents primary immunodeficiency disorders. J Investig Allergol Clin Immunol. (2017) in RA: methodological challenges. Nat Rev Rheumatol. (2009) 5:288– 27:213–24. doi: 10.18176/jiaci.0166 91. doi: 10.1038/nrrheum.2009.51 38. Cutting GR. Modifier genes in Mendelian disorders: the 59. Woodrick RS, Ruderman EM. Safety of biologic therapy example of cystic fibrosis. Ann N Y Acad Sci. (2010) 1214:57– in rheumatoid arthritis. Nat Rev Rheumatol. (2011) 7:639– 69. doi: 10.1111/j.1749-6632.2010.05879.x 52. doi: 10.1038/nrrheum.2011.145 39. Corvol H, Blackman SM, Boelle PY, Gallins PJ, Pace RG, Stonebraker 60. Minozzi S, Bonovas S, Lytras T, Pecoraro V, Gonzalez-Lorenzo M, JR, et al. Genome-wide association meta-analysis identifies five modifier Bastiampillai AJ, et al. Risk of infections using anti-TNF agents in rheumatoid loci of lung disease severity in cystic fibrosis. Nat Commun. (2015) arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic 6:8382. doi: 10.1038/ncomms9382 review and meta-analysis. Expert Opin Drug Saf. (2016) 15(sup1):11– 40. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, 34. doi: 10.1080/14740338.2016.1240783 et al. Finding the missing heritability of complex diseases. Nature. (2009) 61. Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen 461:747–53. doi: 10.1038/nature08494 R, et al. Risk of serious infection in biological treatment of patients with 41. Bucciol G, Moens L, Bosch B, Bossuyt X, Casanova JL, Puel A, et al. Lessons rheumatoid arthritis: a systematic review and meta-analysis. Lancet. (2015) learned from the study of human inborn errors of innate immunity. J Allergy 386:258–65. doi: 10.1016/S0140-6736(14)61704-9 Clin Immunol. (2019) 143:507–27. doi: 10.1016/j.jaci.2018.07.013 62. Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, et al. 42. Casanova JL. Severe infectious diseases of childhood as monogenic Anti-TNF therapy is associated with an increased risk of serious infections in inborn errors of immunity. Proc Natl Acad Sci USA. (2015) 112:E7128– patients with rheumatoid arthritis especially in the first 6 months of treatment: 37. doi: 10.1073/pnas.1521651112 updated results from the British Society for Rheumatology Biologics Register 43. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila with special emphasis on risks in the elderly. Rheumatology (Oxford). (2011) T, et al. International Union of Immunological Societies: 2017 Primary 50:124–31. doi: 10.1093/rheumatology/keq242 Frontiers in Immunology | www.frontiersin.org 8 May 2019 | Volume 10 | Article 1013 Lacoma et al. Susceptibility to Respiratory Tract Infections 63. Subesinghe S, Rutherford AI, Byng-Maddick R, Leanne Hyrich K, Benjamin 74. Dominguez J, Latorre I. Role of the T-cell interferon-gamma release assays in Galloway J. Recurrent serious infections in patients with rheumatoid preventing reactivation of latent tuberculosis infection in immunosuppressed arthritis-results from the British Society for Rheumatology Biologics Register. patients in treatment with anti-TNF agents. J Crohns Colitis. (2008) 2:250– Rheumatology (Oxford). (2018) 57:651–5. doi: 10.1093/rheumatology/kex469 4. doi: 10.1016/j.crohns.2008.05.007 64. Zink A, Manger B, Kaufmann J, Eisterhues C, Krause A, Listing J, et al. 75. Sester M, van Leth F, Bruchfeld J, Bumbacea D, Cirillo DM, Dilektasli Evaluation of the RABBIT Risk Score for serious infections. Ann Rheum Dis. AG, et al. Risk assessment of tuberculosis in immunocompromised (2014) 73:1673–6. doi: 10.1136/annrheumdis-2013-203341 patients. A TBNET study. Am J Respir Crit Care Med. (2014) 190:1168– 65. Richter A, Listing J, Schneider M, Klopsch T, Kapelle A, Kaufmann J, et al. 76. doi: 10.1164/rccm.201405-0967OC Impact of treatment with biologic DMARDs on the risk of sepsis or mortality 76. Latorre I, Minguez S, Carrascosa JM, Naves J, Villar-Hernandez R, Muriel after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. B, et al. Immune-mediated inflammatory diseases differently affect IGRAs’ (2016) 75:1667–73. doi: 10.1136/annrheumdis-2015-207838 accuracy for latent tuberculosis infection diagnosis in clinical practice. PLoS 66. Mariette X, Gottenberg JE, Ravaud P, Combe B. Registries in rheumatoid One. (2017) 12:e0189202. doi: 10.1371/journal.pone.0189202 arthritis and autoimmune diseases: data from the French registries. 77. Santin M, Garcia-Garcia JM, Rigau D, Altet N, Anibarro L, Casas I, et al. Rheumatology (Oxford). (2011) 50:222–9. doi: 10.1093/rheumatology/keq368 Executive summary of the guidelines for the use of interferon-gamma release 67. Rutherford AI, Patarata E, Subesinghe S, Hyrich KL, Galloway JB. assays in the diagnosis of tuberculosis infection. Enferm Infecc Microbiol Clin. Opportunistic infections in rheumatoid arthritis patients exposed to biologic (2016) 34:304–8. doi: 10.1016/j.eimc.2015.11.021 therapy: results from the British Society for Rheumatology Biologics 78. Winthrop KL, Chang E, Yamashita S, Iademarco MF, LoBue Register for Rheumatoid Arthritis. Rheumatology (Oxford). (2018) 57:997– PA. Nontuberculous mycobacteria infections and anti-tumor 1001. doi: 10.1093/rheumatology/key023 necrosis factor-alpha therapy. Emerg Infect Dis. (2009) 15:1556– 68. Baddley JW, Cantini F, Goletti D, Gomez-Reino JJ, Mylonakis E, San-Juan R, 61. doi: 10.3201/eid1510.090310 et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) 79. Winthrop KL, Iseman M. Bedfellows: mycobacteria and rheumatoid Consensus Document on the safety of targeted and biological therapies: an arthritis in the era of biologic therapy. Nat Rev Rheumatol. (2013) 9:524– infectious diseases perspective (Soluble immune effector molecules [I]: anti- 31. doi: 10.1038/nrrheum.2013.82 tumor necrosis factor-alpha agents). Clin Microbiol Infect. (2018) 24 Suppl. 80. Mieves JF, Wittke K, Freitag H, Volk HD, Scheibenbogen C, 2:S10–20. doi: 10.1016/j.cmi.2017.12.025 Hanitsch LG. Influenza vaccination in patients with common 69. Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, Montero MD, Group B. variable immunodeficiency (CVID). Curr Allergy Asthma Rep. (2017) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may 17:78. doi: 10.1007/s11882-017-0749-3 predispose to significant increase in tuberculosis risk: a multicenter active- 81. Sanchez-Ramon S, Conejero L, Netea MG, Sancho D, Palomares O, Subiza surveillance report. Arthritis Rheum. (2003) 48:2122–7. doi: 10.1002/art.11137 JL. Trained immunity-based vaccines: a new paradigm for the development 70. Carmona L, Gomez-Reino JJ, Rodriguez-Valverde V, Montero D, Pascual- of broad-spectrum anti-infectious formulations. Front Immunol. (2018) Gomez E, Mola EM, et al. Effectiveness of recommendations to prevent 9:2936. doi: 10.3389/fimmu.2018.02936 reactivation of latent tuberculosis infection in patients treated with 82. Casanova JL. Human genetic basis of interindividual variability in tumor necrosis factor antagonists. Arthritis Rheum. (2005) 52:1766– the course of infection. Proc Natl Acad Sci USA. (2015) 112:E7118– 72. doi: 10.1002/art.21043 27. doi: 10.1073/pnas.1521644112 71. Dominguez J, Ruiz-Manzano J, De Souza-Galvao M, Latorre I, Mila C, Blanco S, et al. Comparison of two commercially available gamma interferon blood Conflict of Interest Statement: The authors declare that the research was tests for immunodiagnosis of tuberculosis. Clin Vaccine Immunol. (2008) conducted in the absence of any commercial or financial relationships that could 15:168–71. doi: 10.1128/CVI.00364-07 be construed as a potential conflict of interest. 72. Ferrara G, Losi M, D’Amico R, Roversi P, Piro R, Meacci M, et al. Use in routine clinical practice of two commercial blood tests for diagnosis Copyright © 2019 Lacoma, Mateo, Blanco, Méndez, Rodrigo, Latorre, Villar- of infection with Mycobacterium tuberculosis: a prospective study. Lancet. Hernandez, Domínguez and Prat. This is an open-access article distributed under the (2006) 367:1328–34. doi: 10.1016/S0140-6736(06)68579-6 terms of the Creative Commons Attribution License (CC BY). The use, distribution 73. Latorre I, De Souza-Galvao M, Ruiz-Manzano J, Lacoma A, Prat or reproduction in other forums is permitted, provided the original author(s) and C, Altet N, et al. Evaluating the non-tuberculous mycobacteria effect the copyright owner(s) are credited and that the original publication in this journal in the tuberculosis infection diagnosis. Eur Respir J. (2010) 35:338– is cited, in accordance with accepted academic practice. No use, distribution or 42. doi: 10.1183/09031936.00196608 reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 9 May 2019 | Volume 10 | Article 1013