Asthma Research

• Asthma improvement after antibiotic treatment

Evidence Review

New-Onset Asthma

Severe Asthma - Case Series

Severe Asthma - Controlled Trial

Overlap Syndrome (Asthma & COPD)

• Infectious Asthma

What is Infectious Asthma?

First Report

Re-emerging Entity

New-Onset Asthma

Serologic Markers

Koch’s Postulates

In 1890 German physician and bacteriologist Robert Koch set out his celebrated criteria for judging whether a given bacteria is the cause of a given disease as follows:

• The bacteria must be present in every case of the disease.

• The bacteria must be isolated from the host with the disease and grown in pure culture.

• The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.

• The bacteria must be recoverable from the experimentally infected host.

However, Koch’s postulates have their limitations and so may not always be the last word. They may not hold if:

• The particular bacteria cannot be “grown in pure culture” in the laboratory.

• Not all infected individuals demonstrate the disease (i.e., disease expression may depend on a specific host response not shared by a majority of those who are infected).

• What appears to be one disease is actually several diseases with different causes.

Despite such limitations, Koch’s postulates are still a useful benchmark in judging whether there is a cause-and-effect relationship between a bacteria and a clinical disease. How well does C. pneumoniae fulfill Koch’s postulates for asthma?

1. The bacteria must be present in every case of the disease.

• C. pneumoniae has been implicated, directly and indirectly, in around 50% of asthma, especially severe asthma.

2. The bacteria must be isolated from the host with the disease and grown in pure culture.

• C. pneumoniae has been cultured from children and adults with asthma.

3. The specific disease must be reproduced when a pure culture of the bacteria is inoculated into a healthy susceptible host.

• New-onset asthma and chronic bronchitis have happened after naturally acquired acute C. pneumoniae infections.

• C. pneumoniae infection of animals produces inflammation, bronchial hyper-responsiveness, reversible airflow limitation, allergic airways sensitization and lung remodeling - all hallmarks of asthma.

4. The bacteria must be recoverable from the experimentally infected host.

• C pneumoniae has been recovered from infected animals who developed the hallmarks of asthma. Transfer of lung cells from infected animals to uninfected animals causes asthma in the recipients.

Hill’s Criteria

Epidemiologic associations alone cannot prove causation. Hill’s 9 criteria make a causal association more likely:

1. Strength of Association: What is the relative risk?

• The magnitude of the association between C. pneumoniae-specific IgE and asthma is very large.

2. Consistency: Agreement over time, space and method?

• Associations between C. pneumoniae and asthma have been demonstrated in more than a dozen countries on 4 continents; over 30 years; using culture, PCR, intracellular staining, MIF, slgA and lgE immunoblotting; in primary and specialty medical care settings; and in population-based epidemiological studies.

3. Specificity: Is the outcome unique to the exposure?

• No. Most people worldwide are infected at some time, meaning that unique host response to infection is required to produce disease.

4. Temporality: Does exposure precede the outcome?

• Yes. C. pneumoniae infections can cause new-onset asthma.

5. Biologic-gradient: Is there a dose-response relationship?

• Yes

6. Plausibility: Does the association make biological sense?

• Yes. C. pneumoniae causes lung inflammation. Asthma is a chronic inflammatory disease of the lung.

7. Coherence: Compatible with knowledge of the disease?

• Yes. The role of infections in asthma is becoming more acknowledged over time..

8. Experimentation: Does treatment improve the disease?

• Yes. Macrolide antibiotics such as azithromycin are now a recommended treatment option for severe asthma. More research is required to understand how macrolides work, however.

9. Analogy: Does the association conform to a previously described related disease?

• Yes. There are compelling analogies with other chronic human chlamydial infections: trachoma and pelvic inflammatory disease.

References:

AB Hill. Environment and disease: association or causation? 1965

Fredericks & Relman. Reconsideration of Koch’s Postulates. 1996.

***Key article | **Of interest | *Worth a look

Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis and adult-onset asthma. JAMA 1991; 266:225-230 *** The seminal article associating acute and chronic C. pneumoniae respiratory infection with wheezing, acute asthma attacks, and chronic asthma.

When guideline treatment of asthma fails, consider a macrolide antibiotic. J Fam Pract 2019;68:536-45. ***
Evidence Review for macrolide treatment for asthma.

Azithromycin for bronchial asthma in adults: An effectiveness trial. J Am Bd Fam Med 2012; 25:442-459. *** Patients judged most likely to benefit from treatment were most reluctant to be randomized, so were treated “open label” : an example of selection bias by patients. This group exhibited an “all or none” response to azithromycin: individuals either had large benefit, or none. For those with improvement, benefit persisted after finishing antibiotics.

Outcomes of Antibiotics in Adults with “Difficult to Treat” Asthma or the Overlap Syndrome, *** Case series of antibiotic treatment resulting in important improvements in over half the patients with severely uncontrolled asthma. A subgroup who stopped antibiotics had persisting improvement.

Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials 2006;1:e11 DOI: 10.1371/journal.pctr0010011 *** An earlier randomized clinical trial (RCT) showing lasting improvement in asthma symptoms after antibiotic treatment for persistent asthma. C. pneumoniae IgA antibodies predicted worsening of asthma symptoms. A weak signal that IgA antibody might be associated with treatment response was also present.

Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial. J Fam Pract 1995; 41:345-351 *** The first report of a dramatic effect of antibiotic treatment of adult asthma, using patients as their own controls. Improvement in asthma symtoms appeared to be “all or none”, i.e., it was either dramatic or did not occur at all. This impression was confirmed in a later controlled trial.

Antichlamydial antimicrobial therapy for asthma. Arch Pediatr Adolesc Med 1995; 149:219-220 * Some doctors treat only culture proven respirstory infection. Others consider treating severe asthma patients empirically, especially if conventional treatments are ineffective.

Timely diagnosis of acute Chlamydia pneumoniae infection using “real-time” polymerase chain reaction (PCR) testing. In: Deák J, ed. Proceedings of the Fifth Meeting of the European Society for Chlamydia Research. Budapest, Hungary: Pauker, ISBN 963 482 666 0, 2004; 93 ** A report on rapid diagnosis of acute respiratory infection by polymerase chain reaction (PCR) testing of a family outbreak of acute C. pneumoniae infections. Acute C. pneumoniae infections are under-recognized and under-treated due to lack of availability of rapid and reliable tests. Unfortunately, testing respiratory secretions is not helpful for detecting chronic deep lung infections.

Hahn DL, Dodge RW. Detection of Chlamydia pneumoniae. Lancet 1991; 337:849 * Lab investigation of the clinical utility of other rapid detection methods for C. pneumoniae throat and nasal infections.

Intracellular Chlamydia pneumoniae infection demonstrated in alveolar epithelial and and Langhans giant cells in human lung. Eur Respir J 2000; 16, Suppl 31:334s (Abstract 2349) (pdf currently unavailable.) * Human lung alveolar epithelial cells and giant cells (macrophages) are targets for C. pneumoniae respiratory infection.

Failure of four and six weeks of treatment to eradicate evidence of Chlamydia pneumoniae from human lung and vascular tissue: pathology case reports. In: Saikku P, ed. Proceedings: Fourth Meeting of the European Society for Chlamydia Research. Helsinki, Finland: Esculapio, Bologna Italy, 2000; 395 * Case reports suggesting the difficulty of eradicating chronic and persistent deep tissue C. pneumoniae infections.

Chlamydia pneumoniae antibodies and adult-onset asthma. J All Clin Immunol 2000; 106:404 ** Serologic criteria for diagnosing acute C. pneumoniae respiratory infections are well established. Criteria for diagnosing chronic infection are not. Other than taking pieces of lung, we currently lack sensitive methods to diagnose deep lung infection.

Is there a role for antibiotics in the treatment of asthma? Involvement of atypical organisms. Biodrugs 2000; 14:349-354 ** Review and discussion of evidence for antibiotic effectiveness in asthma, circa 2000.

Eradication of Chlamydia pneumoniae from bronchoalveolar lavage (BAL) fluid associated with asthma improvement: case report. Ann Allergy Asthma Immunol 1999; 84:115 *** The first case report of post-antibiotic treatment eradication of C. pneumoniae from bronchoalveolar lavage fluid associated with lasting improvement in asthma symptoms, medication use and quality-of-life.

Evidence for Chlamydia pneumoniae infection in steroid-dependent asthma. Ann Allergy Asthma Immunol 1998; 80:45-49 *** The first case series documenting persisting improvement in steroid-dependent severe asthma after anti-chlamydial antibiotic treatment.

Can acute Chlamydia pneumoniae infection initiate chronic asthma? Ann Allergy Asthma Immunol 1998; 81:339-344 *** This ten-year prospective clinical and microbiologic study in primary care is the first to document that acute C. pneumoniae infections can cause acute wheezing illnesses (asthmatic bronchitis, pneumonia) that develop into chronic asthma or chronic bronchitis: The Infectious Asthma (IA) syndrome.

Incident wheezing and prevalent asthma have different serologic patterns of “acute” Chlamydia pneumoniae antibodies in adults. In: Stary A, ed. Proceedings of the Third Meeting of the European Society for Chlamydia Research. Vienna, Austria: Società Editrice Esculapio, Bologna, 1996; 226 ** People with an acute C. pneumoniae respiratory infection and wheezing can be diagnosed by serologic criteria. If they go on to develop chronic asthma they will have high persisting antibody levels but these levels are not diagnostic of chronic infection because they could also represent a past infection that is no longer present.

Chlamydia pneumoniae. Chest 1994; 105:1914-1915 * The microimmunofluorescence (MIF) test remains the “gold standard” to measure C. pneumoniae antibodies.

Hahn DL. How to use what we know about Chlamydia pneumoniae. Internal Medicine 1992; 13:35-38 * A brief clinical review of current knowledge about C. pneumoniae respiratory illnesses, circa 1992.

***Key article | **Of interest | *Worth a look

Asthma and chlamydial infection: a case series. J Fam Pract 1994; 38:589-595 *** Infectious Asthma (IA) in association with acute Chlamydia pneumonae and Mycoplasma pneumoniae infections.

Infectious asthma: A reemerging clinical entity? J Fam Pract 1995; 41:153-157 *** IA is surprisingly common, and IA is associated with more loss of lung function than non-IA. Could C. pneumoniae infection be responsible?

Association of Chlamydia pneumoniae IgA antibodies with recently symptomatic asthma. Epidemiol Infect 1996; 117:513-517 *** New-onset adult asthma associated with IgA but not with IgG antibodies against C. pneumoniae. IgA is thought to be better than IgG as an indicator of chronic infection. IgA has a stronger association with asthma than IgG. IgE is even stronger. See next article.

Chlamydia pneumoniae and chronic asthma: Updated systematic review and meta-analysis of population attributable risk. *** Meta-analysis combines all available studies on a subject. Allergy to C. pneumoniae – measured by specific IgE (allergic) antibody – was present in almost half of all asthma patients studied. Allergy to C. pneumoniae was even higher in patients with severe asthma (see next article).

Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity. PLoS ONE 2012; 7(4):1-9. *** Half of community-based asthma patients had allergic antibodies (IgE) directed against C. pneumoniae. Of those with IgE, half also had C. pneumoniae bacteria circulating in their blood. Being allergic to C. pneumoniae was strongly associated with having more severe asthma.

Airflow limitation, asthma, and Chlamydia pneumoniae-specific heat shock protein 60. Ann Allergy Asthma Immunol 2008;101:614-618. ** A small but growing body of evidence suggests that C. pneumoniae infection contributes to asthma lung damage (scarring) to produce COPD. The implication is that early detection and treatment might prevent the development of COPD from asthma.

Does most asthma really begin during the pre-school years? Am J Respir Crit Care Med. 2006, 173: 575-576 * Contrary to popular and expert opinion, most asthma does not begin - defined as first becoming symptomatic - in childhood.

Diagnosed and possible undiagnosed asthma: a Wisconsin Research Network (WReN) study. J Fam Pract 1994; 38:373-379 *** Adult-onset asthma was as common as childhood-onset asthma.

A theory explaining time trends in asthma prevalence. Eur Respir J. 2006, 27: 434-435. *** Unrecognized C. pneumoniae pandemics may be responsible for worldwide increases in asthma during the latter half of the 20th century.

Chlamydia pneumoniae infection and asthma. Lancet 1992;339:1173-1174 ** C. pneumoniae infection could be related to worldwide incidence and prevalence of asthma, as suggested in a JAMA editorial.

Chlamydia pneumoniae and the “Dutch Hypothesis”. Chest 2002; 122:1510-1512 *** Is C. pneumoniae a common denominator in asthma and COPD?

Host immune response to Chlamydia pneumoniae heat shock protein 60 is associated with asthma. Eur Resp J 2001; 17:1078-1082 *** A mechanism to explain how COPD can develop from C. pneumoniae infection in people with asthma. The same mechanism is associated with scarring damage in tubal infertility and in the eyes of trachoma sufferers.

Serologic markers for Chlamydia pneumoniae in asthma. Ann Allergy Asthma Immunol 2000; 84:227-233 *** C. pneumoniae associated with Infectious Asthma (IA) . And also with acute bronchitis. Is acute bronchitis a risk factor for getting asthma?

Smoking is a potential confounder of the Chlamydia pneumoniae-coronary artery disease association. Arteriosclerosis & Thrombosis 1992; 12:945-947 *** Are smokers more susceptible to C. pneumoniae infections?

***Key article | **Of interest | *Worth a look

Chlamydia pneumoniae and chronic asthma: Updated systematic review and meta-analysis of population attributable risk. PLoS One 2021;16:e0250034. *** This meta-analysis (combined results of all available studies) found that allergy to C. pneumoniae – as evidenced by specific IgE (allergic) antibody – was present in almost half of all asthma patients studied. Allergy to C. pneumoniae was even higher in patients with severe asthma.

When guideline treatment of asthma fails, consider a macrolide antibiotic. J Fam Pract 2019;68:536-45. *** Evidence graded review of antibiotic treatment of new-onset asthma and severe asthma.

Infection-mediated asthma: Etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides. Respiratory Research 2017;18. *** Basic science, epidemiologic and clinical review. Asthma research has been plagued by selection bias (most people with asthma are excluded). Broad-based, pragmatic treatment trials are needed.

Role of Chlamydia pneumoniae as an inducer of asthma. In: Friedman H, Yamamoto Y, Bendinelli M, eds. Chlamydia pneumoniae Infection and Disease. New York: Kluwer Academic/Plenum Publishers, 2004; 239-262 *** The role of C. pneumoniae in asthma, lung remodeling and COPD. Disease burden and societal costs of asthma and COPD are conventionally calculated as separate entities. Could early treatment of C. pneumoniae (and/or other pathogens) benefit both asthma and COPD?

Chlamydia/Mycoplasma: Do they cause new-onset asthma in adults? In: Johnston SL, Papadopoulos NG, eds. Respiratory Infections in Allergy and Asthma. New York, Basel: Marcel Dekker, Inc., 2003; 645-662 *** C. pneumoniae and M. pneumoniae as causes of new-onset asthma in people without previous symptoms of asthma. Advantages and disadvantages of performing prospective microbiological and clinical studies in practice-based research networks (PBRNs), compared to classical population-based epidemiological studies.

Acute asthmatic bronchitis: A new twist to an old problem. J Fam Pract 1994; 39:431-435 *** Primary care perspective on the links between acute bronchitis and asthma.

Chlamydia pneumoniae as a respiratory pathogen. Frontiers Biosci 2002; 7:E66-76 *** Review, aimed at the microbiology community, of the role of C. pneumoniae in acute and chronic respiratory illnesses.

Evaluation and management of acute bronchitis. In: Hueston WJ, ed. 20 Common Problems in Respiratory Disorders. New York: McGraw-Hill, 2002; 141-153 ** Acute bronchitis and its potential role as a precursor to chronic respiratory illnesses such as asthma and COPD, for practicing clinicians.

Is there a role for antibiotics in the treatment of asthma? Involvement of atypical organisms. Biodrugs 2000; 14:349-354. ** Evidence for antibiotic effectiveness in asthma, circa 2000.

Chlamydia pneumoniae, asthma and COPD: what is the evidence? Ann Allergy Asthma Immunol 1999; 83:271-292 *** Review of the evidence for links between asthma and COPD, circa 1999,

Chlamydia pneumoniae: a new possible cause of asthma. In: Allegra L, Blasi F, eds. Chlamydia pneumoniae: the lung and the heart. Milano: Springer-Verlag, Italia, 1999; 114-123 ** Review, circa 1999. Notably broad clinical spectrum of presentations of reactive airways caused by documented C. pneumoniae infections: acute asthmatic bronchitis, pneumonia with bronchospasm, new-onset asthma, cough-variant asthma with eosinophilia, chronic adult asthma with eosinophilia, and chronic asthmatic bronchitis.

Chlamydia infection and pneumonia. In: Paradise LJ, Friedman H, Bendinelli M, eds. Opportunistic Intracellular Bacteria and Immunity. New York: Plenum Press, 1999; 233-253 * A review of C. pneumoniae infection as a cause for pneumonia.

Role of Chlamydia pneumoniae in acute respiratory tract infections, excluding pneumonias. Antibiotics for Clinicians 1998; 2 (Supplement 3):9-18 ** C. pneumoniae can cause a wide variety of respiratory illnesses, not just pneumonia.

Intracellular pathogens and their role in asthma: Chlamydia pneumoniae in adult patients. Eur Respir Rev 1996; 6:224-230 ** An early review of C. pneumoniae and asthma in adults.

Evidence for Chlamydia pneumoniae infection in asthma. In: Allegra L, Blasi F, eds. Chlamydia Pneumoniae Infection. Milan, Italy: Springer-Verlag, 1995; 65-75 ** Another early review of C. pneumoniae and asthma. The first to discuss the possible role of C. pneumoniae in the spectrum of obstructive airways diseases including asthma and COPD.

***Key article | **Of interest | *Worth a look

Macrolide treatment for "chlamydial asthma": Evidence for enrollment bias in an effectiveness trial. Wisconsin Primary Care Research & Quality Improvement Forum. Middleton, Wisconsin 2010. ** Selection bias means not studying a representative sample of patients with the disease. The most egregious examples of selection bias in asthma and COPD studies are perpetrated by researchers. Another source is clinician behavior. This report documents that patients can also self-select themselves out of randomized clinical trials to create selection bias

Beyond the Dutch Hypothesis. American Journal of Respiratory and Critical Care Medicine. 2006; 174:1056-1057. * Analogy between asthma and established chlamydial diseases such as trachoma, the world’s leading cause of preventable blindness, and pelvic inflammatory disease that can cause infertility via scarring of the fallopian tubes.

Chlamydia pneumoniae and airway remodelling. J Allergy Clin Immunol 2006;117:1193-1194 * In prospective (forward-looking) asthma research studies, testing patients at the time of first asthma symptoms is better to detect acute infection than testing at unrelated times. A hybrid clinical-epidemiologic approach may be the best answer.

Chlamydophila pneumoniae in asthma. Eur Respir J 2005; 25:392-395 * Finding C. pneumoniae does not distinguish acute from chronic infection. Antibody patterns can help make the distinction.

Origins of atopy in pediatric asthma. J Allergy Clin Immunol 2005; 115:425-426 * Contrary to popular belief, allergies are not a root cause for asthma. Animal studies show that C. pneumoniae infection causes allergy, not only to C. pneumoniae but also to other allergens. Could an infection be causing both asthma and allergy?

Feasibility of a practical clinical trial for asthma conducted in primary care. J Am Board Fam Pract 2004; 17:190-195 ** Need for patient-oriented research that studies a generalizable population and measures patient-important outcomes.

Ethics of placebo controlled studies of inhaled steroids for COPD. Thorax 2004;59 :538 –543 * Importance of patient-oriented (e.g., quality of life) versus disease-oriented (e.g. lab tests) outcomes.

Is Chlamydia pneumoniae a missing link in the “Dutch Hypothesis” and chronic non-specific lung disease? In: Deák J, ed. Proceedings of the Fifth Meeting of the European Society for Chlamydia Research. Budapest, Hungary: Pauker, ISBN 963 482 666 0, 2004; 191 ** Is C. pneumoniae a “common denominator” in acute bronchitis and asthma.?

Defining the relationship between C. pneumoniae and chronic asthma. J Respir Dis 2000; 21:536 * The need for randomized, controlled treatment trials.

The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study. Am J Med 2000; 108:179 * Asthma, chronic bronchitis, accelerated decline in lung function and heart disease may all be related through C. pneumoniae infection.

Antibiotic use and risk of myocardial infarction. JAMA 1999; 282:1997-1999 * Without randomized trials evidence is insufficient to warrant antibiotics in heart disease even though there is an association with C. pneumoniae infection.

Chlamydia pneumoniae and asthma. Thorax 1998; 53:1095-1096 * Debate about the relative contributions of C. pneumoniae infection to asthma initiation, exacerbation and promotion (continued asthma symptoms and/or severity of asthma symptoms).

Detection of Chlamydia pneumoniae in abdominal aortic aneurysm specimens from patients with chronic obstructive pulmonary disease (COPD) and asthma: pilot results. In: Stephens RS, Byrne GI, Christiansen G, et al., eds. Proceedings of the Ninth International Symposium on Human Chlamydial Infection. Napa, California, USA: ISBN 0-9664383-0-2, 1998; 235-238 ** Animal studies show that C. pneumoniae disseminates from the lung to blood vessels. C. pneumoniae lung infection may be a risk factor for vascular diseases such as heart attacks, and aortic aneurysms.

Age-dependent associations of acute vascular events with prior antibiotic prescriptions: implications for treatment trials of chlamydia-associated atherosclerosis. In: Stephens RS, Byrne GI, Christiansen G, et al., eds. Proceedings of the Ninth International Symposium on Human Chlamydial Infection. Napa, California, USA: ISBN 0-9664383-0-2, 1998; 183-186 ** Possible adverse effect of antibiotics in younger patients with cardiovascular disease but uncertainty exists. Huge difference in antibiotic usage by young adults, compared to lower usage by older adults.

Prevalence and persistence of Chlamydia pneumoniae antibodies in patients undergoing percutaneous transluminal angioplasty (PTCA) and associations with clinical disease severity. In: Stephens RS, Byrne GI, Christiansen G, et al., eds. Proceedings of the Ninth International Symposium on Human Chlamydial Infection. Napa, California, USA: ISBN 0-9664383-0-2, 1998; 179-182 * C. pneumoniae antibodies including IgA were associated with the extent and severity of coronary artery disease (CAD). If the source of the IgA antibodies were the lung, then this would suggest that persistent seeding of the coronary arteries from the lung could produce more disease.

Antibiotics in acute bronchitis. Lancet 1995;345:1244-5. * We know very little about this extremely common condition.

Asthma management. J Fam Pract 1994; 39:16-17 * Almost half of Wisconsin Research Network physicians had access to spirometry (lung function testing apparatus), circa 1994.

Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients. Am Rev Respir Dis 1993; 147:1064-1065 * Macrolide effects in asthma are believed by many experts and clinicians to be related to anti-inflammatory rather than antibacterial mechanisms. Studies of macrolide mechanisms of action in human lung diseases need to include tests for Chlamydia.

Effect of inhaled steroids on the course of asthma. Ann Int Med 1993; 119:1051-1052 * Another study showing failure of inhaled corticosteroids (ICS) to halt lung function decline in asthma. In this study of severe asthma, ICS actually tended to accelerate the loss of lung function. Could ICS reactivate C. pneumoniae infection to create more lung scarring and damage?

Bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. NEJM 1993; 328:1044-1045 * Another study showing no effect of ICS on decreasing loss of lung function in asthma..

Regional variation in ischemic heart disease: a possible missing risk factor? J Clin Epidemiol 1993; 46:668-669 ** Could C. pneumoniae infection be responsible for regional variation in ischemic heart disease: in the US?

Another possible risk factor for airway disease. Chest 1993; 104:649 * C. pneumoniae infection as a risk factor for asthma and COPD.