key: cord-257244-gryp0khc authors: Edwards, M. R.; Walton, R. P.; Jackson, D. J.; Feleszko, W.; Skevaki, C.; Jartti, T.; Makrinoti, H.; Nikonova, A.; Shilovskiy, I. P.; Schwarze, J.; Johnston, S. L.; Khaitov, M. R. title: The potential of anti‐infectives and immunomodulators as therapies for asthma and asthma exacerbations date: 2017-08-10 journal: Allergy DOI: 10.1111/all.13257 sha: doc_id: 257244 cord_uid: gryp0khc Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning >20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy & Clinical Immunology Task Force on Anti‐infectives in Asthma was initiated to investigate the potential of anti‐infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti‐infectives and both microbe‐ and host‐based immunomodulators and their feasibility for use in asthma. Research in asthma over the last 20 years or more repeatedly shows an overwhelming link between the actions of microorganisms and asthma. 1, 2 From acting as direct pathogens, to educating the immune system and preventing opportunistic pathogen colonization through occupying specific niches, it is now well accepted that viruses, bacteria and fungi are positively associated with asthma onset, 3,4 asthma severity, 5,6 asthma exacerbation (AE) 7, 8 and asthma management 9 and even secondary prevention strategies of asthma (summarized in Table 1 ). Despite these important associations, the use of antiinfectives (antibiotics, antivirals, antifungals, vaccines) that specifically target known pathogens, or drugs that are based on or exploit microbe-host receptor interactions (toll-like receptor agonists, bacterial lysates) or are immunomodulators (vitamin D), and/or may work in part by altering our associated microbiology (probiotics) are, with the exception of severe asthma, seldom considered in asthma treatment, prevention and guidelines. These treatment options are summarized in Figure 1 . Task Force on Anti-infectives in Asthma was initiated in 2014 to ask open questions about the potential use of anti-infectives and immunomodulators as treatments for asthma and AE. We thus provide a thorough review of the field ( Table 2 for search methods and terms), and specifically, have considered several important points in relation to the use and implementation of anti-infectives in asthma, thus identifying important challenges for the field. In our investigation, we chose to include any such studies of treatment that is based on microorganisms or host molecules, or exploits microbe-host interactions and thus alters the host response or microbiome. In this review, we offer our findings on the above points and consider the role of anti-infectives, immunomodulators and alteration of host microbiology in both asthma development and AE. We include findings from recent clinical trials and discuss the relative merits of these approaches in the light of the many challenges facing asthma research and the state of the art of the field. This review thus provides important insights aimed at young researchers and clinicians and also experienced researchers in the field to inform and stimulate scientific discussion of this important topic. Overall, antibiotic use is associated with asthma risk rather than protection at most stages of human development, including pregnancy, 10, 11 early life 12 and childhood, 13 although why this is so is a subject widely debated. In Denmark, antibiotic use in pregnancy use was shown to increase risk of AE in five-year-old children by twofold if used in the third trimester. 10 Antibiotic exposure in foetal life was associated with an increased risk of asthma in cohort analyses, and this association more than tripled if antibiotics were used to treat respiratory tract infections rather than antibiotics used for either urinary tract or skin infections. These associations decreased, however, when sibling analysis was included (when nonaffected siblings are used as controls). 11 Early antibiotic use is also believed to increase asthma risk by two-to threefold in seven-to eight-year-olds. 13 T A B L E 1 Common respiratory tract pathogens linked with asthma and AE. This aspect of the field has been thoroughly reviewed elsewhere 2 Can produce aerosolized allergen common in asthma epidemics associated with thunder storms, involved in severe asthma with fungal sensitization (SAFS) The potential negative impact of antibiotics was explored in a birth-cohort study at age 11 from Manchester, United Kingdom. 12 There was a significantly higher risk of physician-confirmed wheezing after antibiotic prescription and a twofold increase in severe wheeze or AE after antibiotic prescription. In children who wheezed, the risk of AE and admissions to hospital were also significantly increased in the 2 years after the first antibiotic prescription. Children who received antibiotics in infancy had significantly lower induction of cytokines from PBMCs (taken at age 11) stimulated ex vivo with viruses, but surprisingly, not bacteria. The authors concluded that an increased susceptibility to viral infections is associ- The microbiome describes the bacteria, fungi and other microorganisms that are present in the environment and co-exist within our bodies. The respiratory microbiome can now be studied by 16S rRNA sequencing, and certain microbial phyla or genera are thought to be harmful or protective. 5, 16 Antibiotics may negatively affect bacterial ecology in early life and this in turn affects asthma development. 10 In retrospective studies, the association between antibiotic use and increased risk of asthma or wheezing in children is further confused due to the potential of reverse causation. 12, 17 In experimental animals, the negative impact of antibiotics has already been shown, and long-term oral antibiotic treatment affects the gut microbiome, which in turn affects lung immunity to influenza virus. 18 Indeed, how diet and the gut microbiome affect mucosal immunity including respiratory immunology is now a subject of wide interest; 19, 20 hence antibiotics through regulating the gut microbiota thus directly affect F I G U R E 1 Summary of anti-infectives, immunomodulators and microbiome modulators and their methods of action. Anti-infectives (such as antibiotics, antifungals and antivirals) directly act on the pathogen or its receptor limiting infection or replication. Vaccines work by boosting both innate and importantly, adaptive immune responses (provided by dendritic cells, T and B lymphocytes) to the pathogen providing longlasting protection. Immunomodulators including TLR agonists, BL, vitamin D act on the immune system, boosting innate immune responses providing short-term protection. Vitamin D may act on underlying immune responses, such as inflammatory responses or allergic inflammation, reducing pathogen-driven inflammation or pathogen-driven enhanced allergic inflammation. Microbiome modulators such as probiotics may alter the microbiome of the gut. This may have important downstream effects on the immune system, such as those that affect respiratory immunology and asthma the development of the immune system. The potential of antibiotic-induced changes in the developing microbiome to be directly responsible for asthma or AE risk is yet to be formally proven, however. Macrolide antibiotics are a class of antibiotic commonly prescribed for respiratory tract infections or inflammatory respiratory disorders. Macrolides may have additional properties to their bacteriostatic function, such as anti-inflammatory 21 and even antiviral activity. 22, 23 Despite their ability to inhibit both bacteria and virus infections, only a few studies have tested macrolides as therapies for asthma or AE. Guidelines state very little on macrolide use in asthma, and studies have shown positive effects on severe and neutrophilic asthma, yet the evidence supporting this is conflicting. These studies in both stable asthma and AE have been recently reviewed, 24 and the data suggest macrolide-responsive subgroups (eg neutrophilic asthma) may exist. 25, 26 Additionally, recent studies also report a reduction in severe LRTI rates 27 and asthma-like symptoms 28 Antibiotics are associated with asthma risk and their use should be discouraged for asthma or wheeze-like illnesses. A possible explanation for this association is that antibiotics affect the microbiome in a negative way and thus increase susceptibility to disease. With the realization that the microbiome is key in controlling host immunity early in life, and the design of supportive animal studies that have modelled this association and identified protective genera, 31 this idea has merit but the overall hypothesis remains to be thoroughly tested in human clinical models. Antibiotics may also be associated with asthma via other, as yet to be identified mechanisms, and likely involve reverse causation. The narrower antibacterial spectrum of some macrolide antibiotics, combined with their other advantageous properties, suggests that these may have use in AE but their use remains controversial. The prophylaxis with intramuscular/intravenous antibody palivizumab has been shown to effectively decrease respiratory syncytial virus (RSV)-induced bronchiolitis-related hospitalization, need for mechanical ventilation and recurrent wheezing. 32 Interestingly, it has also decreased recurrent wheezing induced by other viruses postbronchiolitis. The second-generation monoclonal antibody motavizumab has also markedly reduced hospitalization with RSV. 33 but the development programme has been discontinued. 38 Only a few patients benefit from the M2 ion channel inhibitors, amantadine and rimantadine, drug resistance is high, and they have significant adverse events. 39 Neutralizing antibodies against RSV, coronaviruses and influenza viruses are being developed. Inhibiting virus replication through interfering with viral enzymes active within cells poses additional problems in drug discovery; however, several useful inhibitors for respiratory tract viruses have found their way into phase I/II clinical trials. Few, however, have been specifically tested in asthma. Favipiravir is a novel antiviral compound that selectively and potently inhibits the RNA-dependent RNA polymerase of many RNA viruses including influenza virus, enteroviruses and paramyxoviruses. 40 A phase III clinical trial of favipiravir for influenza therapy has been just completed in Japan and the United States. Rupintrivir is a potent, irreversible inhibitor of RV 3C protease. It has a broad antipicornaviral spectrum, but the development programme has been discontinued. 41 The nucleoside inhibitor ribavirin is a synthetic purine nucleoside analogue exhibiting antiviral activity against a broad range of both DNA and RNA viruses in vitro. 42 It is the only antiviral agent currently available against RSV infection, but its use has many concerns. ALS-008176 is an oral RSV replication inhibitor (a cytidine nucleoside analogue). In randomized, double-blind, clinical trial in healthy adults inoculated with RSV, more rapid RSV clearance and a greater reduction in viral load were observed in the groups of patients treated with ALS-008176 than in the placebo group. 43 Small interfering RNA (siRNA) 44 infected with wild-type RSV. 46 It was well tolerated, effective as well as decreased the incidence and progression of bronchiolitis obliterans syndrome in lung transplant recipients with naturally occurring RSV infection. 47 The development of cidofovir and its derivative, brincidofovir, broad-spectrum antivirals active against five families of dsDNA viruses (including adenoviruses), are currently in phase III clinical trials. 48 The neuraminidase inhibitors prevent influenza virus release from infected cells and infection of adjacent cells. Oral oseltamivir and inhaled zanamivir are recommended for the treatment and chemoprophylaxis of influenza in children and adults. 49 Inhaled laninamivir has shown good safety and efficacy profiles in the treatment for influenza in patients with chronic respiratory tract diseases and has been approved in Japan. 50 Single dose of intravenous peramivir has been shown to be noninferior to oseltamivir and to have good safety profile also in patients with chronic respiratory tract diseases. 51 Biologically, interferons (IFNs) are induced within hours of infection 52 and consequently induce the expression of hundreds of antiviral effecter molecules blocking virus replication. 53 The effectiveness of itraconazole in the treatment for ABPA has been confirmed in two randomized, placebo-controlled trials 60, 61 leading to the recommendation for azole use in asthma-ABPA by the Cochrane collaboration. 62 Pooled data from these studies suggest itraconazole is effective in around 60% of asthma-ABPA patients. 63 Newer triazoles including voriconazole and posaconazole have also been studied in ABPA with promising results. However, the greater incidence of drug toxicity with voriconazole, and substantial financial costs of both voriconazole and posaconazole limit their current widespread use. More recently, the use of azoles has also been studied in SAFS. In the first such study by Denning et al, 64 subjects with over half having to discontinue treatment due to bronchospasm. 66 Consequently, the prospect of amphotericin B use in asthma remains unlikely. The majority of reports to date have investigated the use of antifungal agents in adult asthmatics; however, the potential for their use in children has also been highlighted in a recent paediatric study describing sensitization to fungal allergens in 59% of severe asthmatic children. 67 Unfortunately, reports of azole use in asthmatic children are limited to a few subjects only leading to the current joint ERS/ATS guideline recommending the consideration of treatment only after detailed evaluation in a specialist severe asthma centre. 68 In summary, to date, there have only been a handful of placebo-con- heterogeneity of asthma continues to develop, it is possible that subgroups within ABPA/SAFS will emerge in whom treatment with antifungal therapy will be predictably beneficial. However, we still remain some distance away from this goal at present. Influenza infections can precipitate acute AEs and may be more severe among asthma patients 69 More studies are needed to validate these findings. A comparison of LAIV with TIV also failed to show significant differences in AE numbers in adults or children (>6 years). 70 Thus, the potential role of influenza vaccines in AE prevention requires further in-depth study, in virologically confirmed influenza and with improved definition and characterization of asthmatic subgroups. AEs. Three large cross-over trials show no evidence of increases in AEs in the two weeks following TIV in adults or children. 71 Concerns that LAIV could increase AEs, wheezing episodes and hospitalizations in children 70 were allayed the absence of an association of LAIV with AE in high-risk children. 72 F I G U R E 3 Challenges and unknowns facing new treatments for asthma exacerbations that target respiratory pathogens. Challenges facing the design and implementation of therapies that directly target pathogens or their biology (in blue) include site of infection and site of drug delivery, route of delivery, specific mechanism of action, the drug's pharmacodynamics (PD) and pharmacokinetics (PK) and also the patient demographic (Pt), subset or specific endophenotype of asthma concerned. These challenges can at least in part be addressed by preclinical studies and are often taken into account during drug design. Unknowns are also identified (in red) and can be model or pathogen specific. These include, but are not limited to, the window of therapeutic opportunity (Dt) for therapeutic treatments, which defines the time between infection and onset of clinical disease (LRTI symptoms for asthma), and importantly, this variable thus describes the window in which suppressing replication in theory will suppress symptoms and/or clinical disease. How pathogen load affects clinical disease is also controlled by a second variable (Dl), which defines the quantity of pathogen that has to be affected to observe a quantitative change in clinical disease or symptoms. The unknown c defines a comparison, between a new drug (eg antiviral) versus the standard treatment (eg GC). This unknown is important as regulatory authorities will not approve a new drug if does not show improvements or a better safety profile compared with the standard treatment already available. The unknown d represents duration of treatment; this takes into account other variables that are often difficult to predict and include the possible effects of secondary infections (eg bacterial co-infection), drug resistance (eg as seen with macrolides), plasticity of endophenotype treated and other complexities that can impact on clinical disease after pathogen load is decreased as defined by Dl. Theoretical relationships between pathogen and load and clinical disease are based on human challenge studies with RV, in asthmatic individuals 57,58 The presence of Streptococcus pneumoniae (pneumococcus) has been linked to AE, and in children, early-life pneumococcal colonization is associated with an increased risk of wheezing and asthma later in childhood. 4 Furthermore, asthma is a risk factor for invasive pneumococcal disease (IPD), 75 warranting pneumococcal vaccination, which is recommended for all people with asthma over 6 years of age if they did not receive routine childhood pneumococcal immunization. 76 The There has been concern over potential pro-allergic and pro-asthmatic effects of childhood immunizations, in particular regarding measles, mumps and rubella vaccine (MMR). However, the suspected association between MMR and asthma (since been discredited) was based on a small study comparing anthroposophic to nonanthroposophic children and was not confirmed in a subsequent multinational study in these populations. 82 A wealth of studies has also failed to show evidence of pro-asthmatic effects of vaccination against poliovirus, pertussis, tetanus, hepatitis B or Haemophilus influenzae. In contrast, significant evidence suggests antiasthmatic effects of childhood vaccinations. Inverse associations between childhood asthma prevalence and high cumulative vaccine doses, 83 pertussis vaccination 84 and MMR 85 have been found and reduced asthma hospitalization rates and medication use in MMR-vaccinated children. 86 The immunogenic potential of different vaccine formulations in asthma has been questioned, but normal antibody responses to pertussis, varicella, hepatitis B, measles and rubella vaccination have been reported. Mumps antibody titres after MMR were lower and measles antibodies waned more quickly from 9 years of age in asthmatics. Treatment with inhaled glucocorticoids (GCs) did not affect the antibody response to hepatitis B or varicella immunization, but these were impaired by oral GC therapy. The vaccinations discussed are safe and effective in asthma, may help prevent asthma development, and pneumococcal and annual influenza vaccination in particular should be offered to asthmatics. Future vaccines against RV and RSV, which are the main triggers for AEs and have been linked to asthma inception, should help reduce asthma morbidity and mortality. HOST RESPONSES Bacterial lysates (BL) have been extensively used in Europe to effectively reduce the number of seasonal acute respiratory illnesses (ARI). BL are microbial products that when given orally, may exhibit certain immunostimulatory and immunomodulatory effects. 87 Their effectiveness was confirmed in numerous interventional trials (reviewed in ref. 88) . BL have been successfully tested in preventing wheezing attacks provoked by ARIs in preschool children demonstrating a 38% reduction in symptomatic wheezing and a decrease in the number of URTI. 89 There is only one interventional clinical study to date, demonstrating a promising antiallergic potential of an orally applied BL. 90 Therefore, one may speculate that bacteria-derived preparations may become an interesting class of immune modulators for the future. Recognition of invading microbes is controlled by a range of innate pattern recognition receptors including TLRs which are directed at highly conserved molecular motifs expressed on the invading pathogen. This ancient surveillance network provides a form of first line of defence in the airway. 91 Signalling through TLRs produces a broad range of pro-inflammatory cytokines, chemokines and importantly, antimicrobial proteins. Therefore, precise targeting of individual TLR pathways could provide a mechanism of promoting specific immunity, allowing for tailored immunomodulation, an approach that is highly attractive in chronic diseases such as asthma where numerous immunological disparities are evident. withdrawal of inhaled GCs whilst asthma conditions remain stable or even improved. 101 The proposed mechanism is the restoration of the Th1/Th2 balance. However, supporting evidence is yet to be provided. A follow-up, double-blind, placebo-controlled study carried out in poorly controlled, moderate-to-severe asthmatics where CYT003A was administered as an add-on to current GCs and b 2agonist therapy showed no significant advantage over placebo in relation to the primary outcome of change from baseline in Asthma Control Questionnaire (ACQ) or in secondary outcomes of change from baseline in prebronchodilator forced expiratory volume (FEV 1 ). 102 These data suggest that whilst CYT003A may have a use in initial control of disease in GC-sensitive patients, it has no efficacy as an add-on therapy for more severe patients. In addition, more prolonged administration of the TLR9 agonist, assessing its ability to readdress the supposed Th2 skewing, was not conducted. Additional concerns stem from recent reports of potential impairment of TLR9 function in PBMCs in severe asthmatic patients. 103 Evidence is accumulating on the potential of vitamin D in immunoregulation, particularly in lymphocyte function and cytokine production, suggesting its potential in modifying asthma incidence and severity. 104 The association between low levels of vitamin D and asthma has been supported by many observational and epidemiologic studies. 105 A recent meta-analysis of epidemiological studies demonstrated a positive association of vitamin D deficiency and asthma (RR 1.68 95% CI 1.3-2.2). 106 Parallel-conducted, prospective, observational studies on vitamin D supplementation in infancy, however, showed rather conflicting data and do not support these implications. 107 Other studies in pregnant woman, including two large clinical trials, did not find protective effects on offspring wheeze. 108, 109 Interpretations of existing evidence argue an advantage of vitamin D supplementation. 107 115 However, interventional trials in infants receiving both pre-and probiotics in allergy and/or asthma prevention provided equivocal results. 116 Whilst moderate positive effects in infant eczema were found, a lack of evidence that probiotics prevent any other allergy including asthma in three other similar meta-analyses remains a matter of concern. [117] [118] [119] In view of two well-conducted meta-analyses, an opportunity of asthma/wheezing prevention with probiotics seemed to not be plausible. 118, 119 One may speculate, however, that the studies to date may not have used the right probiotic, the right dose, the right timing or duration and/or population. Therefore, more studies are still needed. Evidence to date suggested that modulation of the gut microbiome may represent an interesting therapeutic or preventative opportunity for the prevention of allergic asthma and AE, whilst clinical trials do not confirm initial enthusiastic expectations. In view of the recent systematic reviews, probiotics cannot be recommended as adjunctive therapy for asthma or asthma prevention. Though, recent technological developments that permit identification of the most promising microbial strains and their products that may exhibit more profound positive effects will keep this area active and interesting to follow. With the exception of antibiotics and antifungals, current guidelines do not take into account the potential of specific or broader-spectrum anti-infectives or immunomodulatory agents in asthma or AE. Despite wide interest and active research in this area, the basis for this is likely due to a lack of clinical studies that allow robust or clear conclusions to be made regarding efficacy. For the clinical studies that have been performed with available anti-infectives or immunomodulatory agents, conclusions are often contradictory or show a lack of robust evidence supporting an effect. Reasons for these outcomes include a small number of studies, differences in study design making direct comparisons difficult or studies that are underpowered for primary or secondary endpoints, or subgroup analysis. As shown in Table 3 There is also a substantial body of literature investigating preclinical development of anti-infectives and immunomodulatory drugs and preparations in animal models, with many studies endeavouring to better understand the scientific principles behind their mechanism (s) of action. This is an absolute necessity in the anti-infective drug discovery pipeline; however, there is some confusion regarding how best to progress these anti-infectives in these studies in clinical trials, or alternatively, how interpretations of preclinical work can best inform on future clinical trials is a subject of wide debate. Much consideration still needs to be given to how future drug targets related to anti-infectives are progressed, and how drug discovery programmes are best implemented to exploit these. 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The potential of anti-infectives and immunomodulators as therapies for asthma and asthma exacerbations interests in respect to this publication. All authors participated in the discussion and approved the final version of this position paper.