According to the U.S. CDC in 2015, there were 18.4 million people over the age of 18 suffering from asthma, and another 6.2 million children < age 18, translating to a total of 16% of the U.S. population. 185 children and 3,262 adults died from asthma in 2007 for a total of 9 people dying each day that year. Loss of life and QUALITY of life aren’t the only associated costs of this disease. Our country spent $56 billion (2007) in medical fees, forgone school and work days, and early deaths.
To date, the recommended guidelines for treating asthma neglect the body of research linking asthma to infection. Rescue inhalers are prescribed for mild or intermittent asthma. Inhaled corticosteroids (ICS) are the next step for poorly controlled, more frequent symptoms. Patients who do not respond adequately to ICS then typically receive an added inhaled long-acting bronchodilator (LABA), and or a variety of other medications (oral and/or injectable biologic therapy). In spite of these interventions, many patients remain poorly controlled, severely impacting quality of life.
Regardless of peer-reviewed, published research and articles on the role that infection plays in asthma, the medical community at large has yet to integrate this knowledge into clinical practice. Antimicrobials have been found to be effective for a statistically significant number of patients suffering from asthma. There is an urgent need for larger studies to determine the ideal antimicrobial regimen (single versus combination therapy) and duration of treatment. Since the implicated intracellular pathogens are notoriously difficult to identify through currently available testing methods, a consensus is needed to define a clinical endpoint that would be indicative of a cure. Dr. David Hahn has been pioneering the antimicrobial approach to treating asthma for decades and authored a large research study. A recent trial (2017) AMAZES, published by Dr. Gibson and colleagues in Lancet, confirmed the suspicion that patients with asthma could benefit from Azithromycin treatment.
NEW – Does maintenance azithromycin reduce asthma exacerbations? An individual participant data meta-analysis.
Meta-analysis of 3 parallel-group, double-blind, randomized controlled trials in adults, n= 604, European Respiratory Journal, 2019
Background- “Preventing exacerbations is an important goal of asthma treatment. Long-term treatment with azithromycin may help achieve this. Our aim was to conduct a systematic review and individual participant data (IPD) meta-analysis to examine the efficacy of azithromycin in reducing exacerbations in asthma, and in the sub-phenotypes of non-eosinophilic asthma, eosinophilic asthma and severe asthma.”
Method- “We completed a systematic search of Embase, MEDLINE, PubMed, Cochrane Library, ClinicalTrials.gov and reference lists of previous systematic reviews in February 2019. We included parallel-group, double-blind, randomized controlled trials in adults comparing at least 8 weeks of azithromycin treatment with placebo, where the outcome of exacerbations was assessed over at least 6 months. Data were extracted from published sources, Cochrane Risk of Bias Tool was applied and IPD were sought from authors. Reviews were undertaken in duplicate. We conducted an IPD meta-analysis on the primary outcome of exacerbations and a random effects meta-analysis for secondary outcomes.”
Results- “Three studies were identified (n=604). In the IPD meta-analysis, treatment with azithromycin was associated with a reduced rate of exacerbations (oral corticosteroid course due to worsening asthma, antibiotic use for lower respiratory tract infection, hospitalization and/or emergency department visits) in asthma as well as in the non-eosinophilic, eosinophilic and severe asthma subgroups. Examining each exacerbation type separately, patients with eosinophilic asthma reported fewer oral corticosteroid courses, and patients with non-eosinophilic and severe asthma reported fewer antibiotic courses. Azithromycin was well tolerated.”
Conclusion- “Maintenance use of azithromycin reduces exacerbations in patients with eosinophilic, non-eosinophilic and severe asthma.”
Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial.
Randomized, double-blind, placebo-controlled parallel group trial, n = 420, Lancet, 2017
Methods- Azithromycin 500 mg or placebo three times per week for 48 weeks in adult patients (18 years or older) whose asthma remained poorly controlled in spite of inhaled corticosteroids with a LABA.
Results- Azithromycin reduced asthma exacerbations (1·07 per patient-year [95% CI 0·85-1·29]) compared with placebo (1·86 per patient-year [1·54-2·18]; incidence rate ratio [IRR] 0·59 [95% CI 0·47-0·74]; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 [61%] patients in the placebo group vs 94 [44%] patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 [95% CI 0·21-0·52]; p=0·001). Diarrhea was more common in azithromycin-treated patients (72 [34%] vs 39 [19%]; p=0·001).
Conclusions- Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma.
Azithromycin for Bronchial Asthma in Adults: An Effectiveness Trial
Randomized, placebo-controlled, double-blinded trial, n = 97, JABFM, 2012
Methods- 12 weekly doses of adjunctive azithromycin, with follow-up to 1 year after randomization, in adults with persistent asthma.
Results- At 1 year, compared with the placebo arm, subjects randomized to azithromycin were more likely to have an AQL score ≥1 unit increase compared with baseline, but this difference was not statistically significant (36% vs 21% for placebo; P = .335). Compared with placebo, OL subjects had significant improvements in overall asthma symptoms from baseline (P = .0196), AQL (P = .0006), and asthma control (P = .0148).
Conclusions- Adults with asthma who were randomized to azithromycin did not show statistically significant improvement in asthma outcomes, although the study was underpowered to detect clinical improvement in 15% (number needed to treat = 7). Adults with severe persistent asthma who elected OL treatment documented clinical improvements in asthma symptoms, AQL, and asthma control that persisted after completion of OL azithromycin (number needed to treat = 2).
Long term effect of doxycycline in asthma: a real world observation
Prospective Observational Cohort Study, n=145, European Respiratory Journal, 2017.
Methods- “In a prospective, real-world observation, a cohort of asthmatic patients were treated with standard therapy with or without long term use of oral add-on doxycycline. The changes in spirometric variables in terms of post bronchodilator FEV1, FEV1/FVC, and FEF25–75 were noted.”
Results- “A group of patients in add-on doxycycline (n=73) and COPD therapy only (n=72) groups with similar age (p<0.05) and BMI but different baseline post bronchodilator FEV<1 (1.25±0.50 and 1.66±0.73 Litres) were treated for similar length of time (346.89±269.61 and 335.82±274.51 days) respectively. The mean absolute change in post-bronchodilator FEV1 has been +130 ml (p=.0000) in add-on doxycycline group while it was -70 ml (p= 0.027) in those receiving COPD therapy alone. There were parallel changes in FEV1/FVC (p<0.005) and FEF<25-75 (p<0.00001) in the doxycycline treated patients former signifying overall improvement in lung function.”
Conclusion- “Add-on doxycycline appears to be well tolerated and results in significant improvement in the lung function in asthmatic patients on long term use. The observation deserves further validation.”
Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity
Two case-control studies, n= 66, PLoS One 2012.
Methods- (1) Prevalence of Cp IgE (measured by immunoblotting) and Cp DNA (by polymerase chain reaction) in peripheral blood, and biomarker associations with asthma severity. (2) Case-control studies of Cp IgE association with asthma using healthy blood donor (study 1) and non-asthmatic clinic patient (study 2) controls.
Results- Of 66 asthma subjects 33 (50%) were Cp IgE positive and 16 (24%) were Cp DNA positive (P = 0.001 for association of Cp IgE and DNA). Cp IgE was detected in 21% of mild intermittent asthma v 79% of severe persistent asthma (test for trend over severity categories, P = 0.002). Cp IgE detection was significantly (P = 0.001) associated with asthma when compared to healthy blood donor controls but not when compared to clinic controls.
Conclusions- Half of this sample of community asthma patients had detectable IgE against C. pneumoniae. Cp IgE was strongly and positively associated with asthma severity and with asthma when healthy blood donor controls were used. These results support the inclusion of Cp IgE as a biomarker in future studies of infectious contributions to asthma pathogenesis.
Secondary Outcomes of a Pilot Randomized Trial of Azithromycin Treatment for Asthma
Randomized, placebo-controlled, blinded, allocation-concealed parallel group trial, PLoS Clinical Trials, 2006.
Methods- Adults with stable, persistent asthma given azithromycin (six weekly doses) or identical matching placebo, plus usual community care.
Results- Juniper AQLQ improved by 0.25 (95% confidence interval; -0.3, 0.8) units, overall asthma symptoms improved by 0.68 (0.1, 1.3) units, and rescue inhaler use decreased by 0.59 (-0.5, 1.6) daily administrations in azithromycin-treated compared to placebo-treated participants. Baseline IgA antibodies were positively associated with worsening overall asthma symptoms at follow-up (p = 0.04), but IgG was not (p = 0.63). Overall asthma symptom improvement attributable to azithromycin was 28% in high IgA participants versus 12% in low IgA participants (p for interaction = 0.27).
Conclusions- Azithromycin did not improve Juniper AQLQ but appeared to improve overall asthma symptoms. Larger community-based trials of antichlamydial antibiotics for asthma are warranted.
Airflow limitation, asthma, and Chlamydia pneumoniae–specific heat shock protein 60
Case-control study, n = 138, Annals of Allergy Asthma and Immunology, 2008.
Methods- analyzed C pneumoniae– exposed primary care patients (86 adult asthmatic cases and 52 nonasthmatic controls) for seroreactivity against a C pneumoniae–specific hsp60 fragment and against the C trachomatis hsp60 molecule. Analyzed associations with asthma and irreversible lung remodeling as measured by means of postbronchodilator FEV-1.
Results- 27% of asthmatic patients were C pneumoniae hsp60 seropositive vs 8% of controls (P < .01). Controlling for age, sex, and smoking, C pneumoniae hsp60 seropositivity was associated with lower postbronchodilator FEV-1 in asthmatic patients (P < .05). No comparable associations were present for C trachomatis hsp60.
Conclusions- In individuals with evidence of previous exposure to C pneumoniae infection, a host antibody response against a C pneumoniae hsp60 fragment but not against C trachomatis hsp60 was associated with airflow limitation in adults with asthma.
The Effect of Telithromycin in Acute Exacerbations of Asthma
Double-blind, randomized, placebo-controlled study, n = 278, New England Journal of Medicine, 2006.
Methods- Adults enrolled within 24 hours after an acute exacerbation of asthma requiring short-term medical care. Administered 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care.
Results- Of the two outcomes, only asthma symptoms showed a significantly greater reduction among patients receiving telithromycin than among those receiving placebo. Mean (±SD) scores on a test of asthma symptoms (on a 7-point scale, with 0 denoting no symptoms and 6 denoting severe symptoms) were 3.0±1.4 at baseline and 1.7±1.1 at the end of treatment for the telithromycin group and 2.8±1.3 at baseline and 2.0±1.0 at the end of treatment for the placebo group. The mean decrease in symptom scores during the treatment period was 1.3 for telithromycin and 1.0 for placebo (mean difference, −0.3; 95 percent confidence interval, −0.5 to −0.1; P=0.004). There was no significant treatment effect on the other primary outcome measure, a change in morning peak expiratory flow. Nausea was more common among patients in the telithromycin group than in the placebo group (P=0.01).
Conclusions- This study provides evidence of the benefit of telithromycin in patients with acute exacerbations of asthma; the mechanisms of benefit remain unclear.
Effect of Prolonged Treatment with Azithromycin, Clarithromycin, or Levofloxacin on Chlamydia pneumoniae in a Continuous-Infection Model
Antibiotic activity assay of continuous C. pneumoniae infection in vitro, Antimicrobial Agents and Chemotherapy, 2002.
Methods- investigating the effect of higher concentrations and a longer duration of treatment with azithromycin, clarithromycin, or levofloxacin on the growth of C. pneumoniae ( 4 μg of azithromycin/ml, 16 μg of levofloxacin/ml, or 64 μg of clarithromycin/ml.
Results- The results of this study demonstrated that prolonged treatment with azithromycin, clarithromycin, and levofloxacin at concentrations achieved in the epithelial lining fluid reduced but did not eliminate C. pneumoniae from continuously infected host cells.
Conclusions- 1) The dosages of azithromycin being used in coronary artery disease secondary prevention are 500 or 600 mg/day for 3 and 6 days followed by weekly doses of 500 to 600 mg for periods of 3 months to 1 year. Based on the data presented here, it would appear unlikely that these dosage regimens would eliminate C. pneumoniae from an intravascular focus. 2) Existence of persistence also raises a separate important issue for the treatment of C. pneumoniae-associated diseases. Persistent forms generally do not replicate or have reduced activity and therefore may not be susceptible to antibiotics. It is quite possible that the 20 to 30% rate of microbiologic failures in reported C. pneumoniae treatment studies and the ability of C. pneumoniae to survive antibiotic treatment in our experiments may be directly related to the persistent state.
Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.
Prospective clinical, bacteriologic, and serologic study, also a matched comparison of patients with and without evidence of CpN infection. , n = 365, JAMA, 1991.
Methods- adult male patients (serologic titers greater than or equal to 1:64 and less than 1:16, respectively). Association of acute C pneumoniae infection with signs and symptoms of respiratory illness and the relationship of C pneumoniae antibody titer with wheezing at the time of enrollment in the study, and with the diagnosis of asthmatic bronchitis.
Results- Nine (47%) of 19 patients with acute C pneumoniae infection had bronchospasm during respiratory illness, and there was a strong quantitative association of C pneumoniae titer with wheezing at the time of enrollment in the study (P = .01).
In the matched study, C pneumoniae antibody was significantly associated with asthmatic bronchitis after, but not before, respiratory illness (odds ratio, 7.2; 95% confidence interval, 2.2 to 23.4). Four infected patients had newly diagnosed asthma after illness, and four others had exacerbation of previously diagnosed asthma.
Conclusions- Some C pneumoniae antibody titers, although not diagnostic of chlamydial infection by present criteria, probably represent acute reinfection or ongoing chronic infection. Repeated or prolonged exposure to C pneumoniae may have a causal association with wheezing, asthmatic bronchitis, and asthma.
The Bronchial Lavage of Pediatric Patients with Asthma Contains Infectious Chlamydia
PCR analysis of blood and BAL samples, n=70, American Journal of Respiratory and Critical Care Medicine, 2005.
Methods- From July 2002 to July 2003, samples were obtained from 70 pediatric patients with chronic respiratory symptoms. This study used a combination of modified tissue culture media and macrophage cells to successfully isolate and culture viable Chlamydia from blood and bronchoalveolar lavage (BAL) samples.
Results- “Forty-two of these patients had asthma, whereas the remaining patients had various respiratory disorders. Fifty-four percent (38) of the BAL samples were PCR-positive for Chlamydia, and 31% (22) of the PCR-positive samples were positive when cultured on macrophages. Twenty-eight samples (40%) and 14 samples (20%) of the PCR- and culture-positive samples, respectively, were from patients with asthma. Culture of the blood samples revealed that 24 (34.3%) of 70 were positive for Chlamydia compared with 8 (11%) of 70 matched nonrespiratory control subjects (p < 0.01); 17 (24%) of the positive blood cultures from the respiratory group were from patients with asthma. Elevation of total IgE was strongly associated with lavage culture positivity for Chlamydia. ”
Conclusions- “We therefore conclude that viable Chlamydia pneumoniae organisms are frequently present in the lung lavage fluid from this cohort of predominantly asthmatic pediatric patients.”
Chlamydia pneumoniae Induces Interferon Gamma Responses in Peripheral Blood Mononuclear Cells in Children with Allergic Asthma
Comparison of Interferon (IFN)-y responses in PCR positive pediatric asthma patients versus non-asthmatic controls, n=33, Scandinavian Journal of Immunology, 2017.
Methods- “Presence of C. pneumoniae was tested from asthma patients (N = 17) and non-asthmatic controls (N = 16) (PCR). PBMC were infected for 1 h ± C. pneumoniae AR-39 (MOI = 0.1) and cultured for 48 h. IFN-γ levels were measured in supernatants (ELISA). C. pneumoniae-IgG antibodies in serum were determined (MIF).”
Results- “All subjects tested negative for C. pneumoniae (PCR). C. pneumoniae-induced IFN-γ production in vitro was more prevalent in asthma compared with non-asthma; levels of IFN-γ were higher in asthma compared with non-asthma (P = 0.003). There was no association between recent respiratory infection and positive IFN-γ responses.”
Conclusions- “These data show that C. pneumoniae modulates IFN-γ responses in patients with asthma, even in absence of active infection.”
Respiratory Chlamydia Infection Induce Release of Hepoxilin A3 and Histamine Production by Airway Neutrophils
Prospective mouse model, Frontiers in Immunology, 2018.
Methods-AAD adult Balb/c mouse model to evaluate airway pathology and immune response by assaying bronchoalveolar lavage (BAL) fluid cytokine, cellularity, histidine decarboxylase (HDC) as well as histamine released in response to in-vivo chlamydial antigen stimulation of purified airway neutrophils
Results- Chlamydial infection induced increased production of IL-2, IL-12, TNF-α, and IFN-γ in BAL fluid compared to uninfected animals. When purified neutrophils from infected animals were challenged with chlamydial antigen in vitro there was significant histamine release.
Conclusions- These findings suggest that neutrophils, provoked by Chlamydia infection can synthesize and release histamine. This contributes directly to airway inflammation.
Chlamydia pneumoniae and asthma
Prospective serological study, n=169 asthmatics, and 1518 control subjects, Thorax BMJ, 1998.
Methods- “Antibodies to C pneumoniae were measured by microimmunofluorescence in 123 patients with acute asthma, 1518 control subjects admitted to the same hospital with various non-cardiovascular, non-pulmonary disorders, and 46 patients with severe chronic asthma, including some with “brittle” asthma. Acute infection or reinfection was defined by titres of IgG of ⩾512 or IgM ⩾8 or a fourfold rise in IgG, and previous infection by IgG 64–256 or IgA ⩾8. Logistic regression was used to control for likely confounders, including ethnic origin, age, sex, smoking habit, steroid medication, diabetes mellitus and social deprivation, on antibody levels.”
Results- “Antibody titres consistent with acute C pneumoniae infection were found in 5.7% of patients with acute asthma and 5.7% of control patients, while 14.6% of patients with acute asthma and 12.7% of control patients had titres suggesting previous infection. These two groups did not differ significantly. However, titres suggesting previous infection were found in 34.8% of patients with severe chronic asthma: the difference between this group and the control group was statistically significant with an adjusted odds ratio of 3.99 (95% confidence interval 1.60 to 9.97).”
Conclusion- “These data raise important questions about the previously demonstrated association of C pneumoniae infection with asthma, and suggest that future studies of this association should give particular attention to the presence or absence of a history of severe chronic asthma.”
Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides
Abstract (excerpt)- “Infections with atypical bacteria also appear to play a role in the induction and exacerbation of asthma in both children and adults. Recent studies confirm the existence of an infectious asthma etiology mediated by Chlamydia pneumoniae (CP) and possibly by other viral, bacterial and fungal microbes. It is also likely that early-life infections with microbes such as CP could lead to alterations in the lung microbiome that significantly affect asthma risk and treatment outcomes. These infectious microbes may exacerbate the symptoms of established chronic asthma and may even contribute to the initial development of the clinical onset of the disease. “
Chlamydia pneumoniae: possible association with asthma in children.
8 – patient Case Series, Clinical Infectious Diseases, 2014.
Excerpt- “In conclusion, this report supports the role of C. pneumoniae in asthma exacerbation. Whether C. pneumoniae-associated asthma may be cured with antibiotics or will also require steroids remains unknown and may vary from patient to patient. This case series underlines the importance of screening asthmatic children for C. pneumoniae. Moreover, our findings suggest that C. pneumoniae prevalence is likely underestimated and children with chronic cough, even in absence of fever, should be tested for C. pneumoniae.”
Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae
European Respiratory Journal, 2002.
Abstract- “Conventional risk factors have been unable to explain most of the substantial increase in the prevalence of asthma observed in many countries during the last few decades. Much attention has been directed at the “hygiene hypothesis”, the apparent inverse relationship between intense systemic childhood infections and the subsequent development of asthma and atopy. However, it is not only the absence or scarcity of infections, but the prolonged presence of certain microorganisms in the lungs that may be involved in the development of asthma. Accumulating evidence suggests that Chlamydia pneumoniae, an intracellular ubiquitous pathogen with an innate propensity to persist and cause chronic infections, may be associated with asthma. This microorganism can achieve a state of “latency” in which it is viable but dormant and does not multiply. During this state, however, chlamydia continues to synthesize the “stress” protein, a 60-kDa heat shock protein (hsp60). This protein is able to elicit a strong host inflammatory response at sites of its production and appears to be involved in tissue injury and scarring processes. As inflammation has been found to be present in almost all asthmatics, whatever the severity and aetiology of the disease, inhaled glucocorticoids now have an established position in the treatment of early stages. However, corticosteroids negatively affect many aspects of cell-mediated immunity and favour the shift from a T-helper-1-type response towards a T-helper-2-type response. Corticosteroids may thus severely deteriorate the host9s ability to eradicate an intracellular pathogen, such as Chlamydia pneumoniae, which requires a properly functioning cell-mediated (T-helper-1-type) immune response to be cleared. These drugs are also able to reactivate persistent Chlamydia to an active growth phase, which, by increasing the production of proinflammatory cytokines at the site of infection, can further amplify inflammation in the airways of patients with asthma.”
Chronic Chlamydia pneumoniae lung infection: a neglected explanation for macrolide effects in wheezing and asthma?
Excerpt- “C. pneumoniae is an established cause for acute lower respiratory tract infections in all age groups and is associated with a range of chronic lung diseases including asthma, chronic bronchitis, and COPD.3 The biological plausibility for C pneumoniae to dysregulate the lung immune system to produce acute and chronic asthma is supported by a large body of in-vitro and in-vivo laboratory data.4 In a study in which lower airways of children ranging in age from 3 months to 18 years were sampled directly, C pneumoniae was detected in between half and threequarters of cases.5 Positive detection was equally prevalent in cases of severe, refractory asthma, and in other forms of paediatric chronic lower respiratory tract illnesses for which bronchoscopies were indicated. This provides evidence that C pneumoniae plays a role in protean manifestations of severe chronic lower respiratory tract infections in children.”
“A Cure for Asthma? What your doctor isn’t telling you and why”, By David L. Hahn, MD, MS, Peoples Pharmacy Press, 2013.
For patients: www.asthmastory.com provides excellent context to the whole story, complete with patient accounts and a list of doctors across the US who treat asthma based on this body of research. It was created by Jim Quinlan, an asthma patient whose near-fatal asthma attack led to successful treatment with azithromycin.
If you are a physician and would like to refer patients for treatment based upon this literature Dr. Fred Wagshul, a Pulmonologist in Dayton, Ohio, has been treating Asthma utilizing a combination of antibiotics for over 25 years. The practice is called the Lung Center of America and the website contains videos highlighting various patient experiences.