Dr. Hahn's Research Section

Research linking Chlamydia pneumoniae to Asthma

This annotated bibliography area

contains asthma research reports, reviews, and correspondence relating to C. pneumoniae infection, asthma, chronic bronchitis, and COPD. Taken together, these data support the Chlamydia-Asthma Theory: that a significant proportion of asthma is caused by infection, and is treatable with antibiotics (article #57).

The bibliography includes the first published report(s) on the following topics:

Dr. Hahn's Asthma cure Research related to Chlamydia pneumoniae

Dr. David Hahn, MD, MS
Director, Wisconsin Research and Education Network (WREN)

Epidemiological

  • C. pneumoniae infection, asthmatic bronchitis and asthma (#1).
  • C. pneumoniae and smoking (#3).
  • C. pneumoniae and the “infectious asthma” syndrome (#18).
  • C. pneumoniae heat shock protein 60 antibodies, asthma and decreased lung function (#40#45, #62).
  • C. pneumoniae as a common denominator in asthma, chronic bronchitis and COPD (#48, #53).

Clinical

  • C. pneumoniae PCR in primary care clinical practice (#54).
  • C. pneumoniae initiation of chronic asthma (#30) and its “cure” (#19).
  • Microbiological eradication of C. pneumoniae from lung fluid and asthma improvement (#36).
  • Antibiotic effectiveness in “brittle” asthma (#31).
  • Randomized clinical trial (RCT) evidence for lasting symptom improvement after antibiotic treatment of persistent asthma (#60).

Miscellaneous

  • Definition for adult acute asthmatic bronchitis (#14).
  • Prevalence of adult-onset asthma in practice-based research network (primary care) settings (#13).
  • Hypothesis that C. pneumoniae infection causes atopy (#55).
  • Persistence of C. pneumoniae in vascular tissues after 4 to 6 weeks treatment (#42).
  • Suggestion to study C. pneumoniae and regional variations in heart disease (#7).

In 1890 the

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 (such as the one that causes leprosy) cannot be “grown in pure culture” in the laboratory.
  • There is no animal model of infection with that particular bacteria.

It is debatable whether or to what extent Koch’s postulates are relevant to multifactorial chronic disease syndromes such as asthma, that may include a component of bacterial causation:

  • Different types of asthma may have different “causes.”
  • The form of the bacteria (in this case, chlamydia) that causes disease may not be cultivable.
  • Not all infected individuals may demonstrate the disease (i.e., disease expression may depend on a specific host response not shared by a majority of those who are infected).

Despite such limitations, Koch’s postulates are still a useful benchmark in judging whether there is a cause-and-effect relationship between a bacteria (or any other type of microorganism) 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, indirectly by serology and directly by PCR testing, in around 50% of asthma, not in all asthma. C. pneumoniae has been associated with more severe forms of asthma, suggesting a disproportionate contribution to morbidity and mortality

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

Several investigators have reported isolation of C. pneumoniae from children and adults with asthma. The isolation techniques include culture, polymerase chain reaction (PCR) testing, and intracellular staining.

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

After accidental exposure, a laboratory worker developed pneumonia with wheezing. Non-asthmatic patients have developed asthma or chronic bronchitis after naturally acquired acute C. pneumoniae infections. Experimental inoculation of mice produces sustained bronchial hyperresponsiveness (Blasi et al. 2007), allergic airways sensitization (Horvat et al. 2007 and Schroder et al. 2008), and lung remodeling (Chen et al. 2009), three hallmarks of asthma.

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

C pneumoniae has been recovered by culture of the sputum from one of the patients who developed chronic bronchitis after naturally acquired infection.

Hill’s Criteria

Hill’s 9 criteria for causal association represent a more comprehensive set of characteristics that can be applied to the question about C. pneumoniae and asthma:

1. Strength of Association: What is the relative risk? The magnitude of the association between C. pneumoniae antibodies and asthma is large (#1) and unlikely to be explained by confounding.

2. Consistency: Agreement over time, space and method? Associations between C. pneumoniae and asthma have been demonstrated in 11 countries on 4 continents; over 15 years; using culture, PCR, intracellular staining, MIF, slgA and lgE immunoblotting; in primary and specialty medical care settings and in population-based epidemiological studies (#35 and Johnston & Martin 2005)

3. Specificity: Is the outcome unique to the exposure? C. pneumoniae , not C. trachomatis, is specifically associated with adult asthma (#1, #62); the majority of the adult population has been exposed to this infection and many asymptomatic individuals may be chronically infected, implying that a gene-environment interaction is needed to express disease.

4. Temporality: Does exposure precede the outcome? Yes. Systematic clinical studies document that acute infection is followed by new-onset asthma, not the reverse (#30, #49).

5. Biologic-gradient: Is there a dose-response relationship? Yes (#1)

6. Plausibility: Does the association make biological sense? Yes. Chlamydial infections are known to cause chronic inflammation in target organs. C. pneumoniae infects the lung; asthma is a chronic inflammatory disease of the lung (#53).

7. Coherence: Compatible with knowlege of the disease? Yes. Older models saw asthma as a non-infectious allergic disease; newer models acknowledge a major contribution from various infections, including chlamydiae (#53).

8. Experimentation: Does treatment improve the disease? Case reports (#11, #36), a case-series (#31), a before-after study (#19) and a randomized controlled trial (#60) consistently suggest important clinical benefits from prolonged antibiotic treatment directed against C. pneumoniae. More research is required (#38).

9. Analogy: Does the association conform to a previously described related disease? Yes. There are compelling analogies with other chronic human chlamydial infections such as trachoma and pelvic inflammatory disease (#61). References: AB Hill. The environment and disease: association or causation? 1965 Proc. R. Soc. Med; Fredericks & Relman 1996.

 

Index of key asthma research articles

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

1. Hahn DL, Dodge R, Golubjatnikov R. 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 infection with wheezing, acute asthma attacks, and chronic asthma. The association (odds ratio) of antibody and asthma was as strong or stronger than the association between cigarette smoking and lung cancer, motivating further study into whether C. pneumoniae infection is a “root cause” of asthma. This article also illustrates the importance of serendipity in research: asthma was not the focus of the study, and had these “extraneous” results been ignored and not published, it is likely that the field of “chlamydial asthma” research would not have developed as rapidly, or at all.

2. Hahn DL, Dodge RW. Detection of Chlamydia pneumoniae. Lancet 1991; 337:849 (letter) * A brief foray into the laboratory to investigate the clinical utility of rapid detection methods for C. pneumoniae throat and nasal infections.A reply from a prominent chlamydial researcher initiated a discussion regarding the complementary roles of basic and clinical science in solving health problems.

3. Hahn DL, Golubjatnikov R. Smoking is a potential confounder of the Chlamydia pneumoniae-coronary artery disease association. Arteriosclerosis & Thrombosis 1992; 12:945-947 *** The first study showing an association of smoking and C. pneumoniae antibody, suggesting that smoking might increase the likelihood of infection and/or the development of persistence in lung tissue.

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

5. Hahn DL. Chlamydia pneumoniae infection and asthma. Lancet 1992;339:1173-1174 ** Additional epidemiological evidence suggesting that C. pneumoniae infection could be related to worldwide incidence and prevalence of asthma, as first suggested by Dr. Roger Bone in an editorial.

6. Hahn DL. Another possible risk factor for airway disease. Chest 1993; 104:649 * Preliminary data implicating C. pneumoniae infection not only with asthma beginning after acute respiratory illness, but also with acute exacerbations of COPD.

7. Hahn DL, Garg R. Regional variation in ischemic heart disease: a possible missing risk factor? J Clin Epidemiol 1993; 46:668-669 ** To my knowledge, the first suggestion that C. pneumoniae infection might be responsible for regional variation in ischemic heart disease: a possibility that remains largely unexplored.

8. Hahn DL, Kerstjens HAM, Brand PLP, et al. Bronchodilator therapy with or without inhaled corticosteroid therapy for obstructive airways disease. NEJM 1993; 328:1044-1045 * Asthma specialists have been known to tell their patients that inhaled steroid treatments for asthma will prevent irreversible loss of lung function, but in fact the evidence does not support such an assertion. This letter discusses evidence from one of the best studies in adults.

9. Hahn DL, van Schayck CP, Dompeling E, et al. Effect of inhaled steroids on the course of asthma. Ann Int Med 1993; 119:1051-1052 * Another discussion of the lack of effect of inhaled corticosteroids on halting lung function decline in asthma. In this study of more severe asthma, steroid treatment actually tended to accelerate the loss of lung function, raising a concern that immunosuppression in potential chlamydial asthma might have long term detrimental effects, in contrast to the well established immediate beneficial effects on symptom suppression.

10. Hahn DL, Ichikawa T, Ninomiyo H, et al. 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 * Experts believe that macrolide effects on asthma are explained by anti-inflammatory rather than antibacterial mechanisms. This letter was an early plea to design studies to distinguish between these two possible mechanisms.

11. Hahn DL. Infection as a cause of asthma. Ann Allergy 1994; 73:276 ** A case report documenting asthma improvement in a persistently C. pneumoniae culture positive patient who also had persistent blood eosinophilia. After antibiotic treatment the patient described in this report also had disappearance of eosinophilia which is usually caused by allergy, not infection. However, eosinophilia is a characteristic of some chlamydial infections.

12. Hahn DL, Kern DG, Neill MA. Chlamydia pneumoniae. Chest 1994; 105:1914-1915 * The microimmunofluorescence (MIF) test remains the “gold standard” to measure C. pneumoniae antibodies. Nevertheless, there has been controversy about the accuracy of MIF serodiagnostic criteria for diagnosing acute infection (including incomplete recognition of the possibility of persistent infection unaccompanied by an acute antibody response), and debate about appropriate methods to measure population seroprevalence. This letter highlights some of the issues.

13. Hahn DL, Beasley JW. Diagnosed and possible undiagnosed asthma: a Wisconsin Research Network (WReN) study. J Fam Pract 1994; 38:373-379 *** In 1994 the asthma referral specialist literature contained statements such as “…asthma begins in childhood.” The experience of primary care physicians was quite different but had never been published. This practice-based study measured the prevalence of adult-onset asthma and, consistent with population-based epidemiological studies, found that adult-onset asthma was as common as childhood-onset asthma.

14. Hahn DL. Acute asthmatic bronchitis: A new twist to an old problem. J Fam Pract 1994; 39:431-435 *** Another article presenting a primary care perspective on asthma and its relation to acute lower respiratory tract illnesses such as acute bronchitis.

15. Hahn DL, Golubjatnikov R. Asthma and chlamydial infection: a case series. J Fam Pract 1994; 38:589-595 *** Shortcomings of Reference article 1 were its non-systematic use of pulmonary function, and asthma was not a primary question. This follow up study used pulmonary function to address wheezing and asthma as the primary questions, and confirmed the original findings. Although the editor requested the title, this study is better described as a case-control study.

16. Hahn DL. Asthma management. J Fam Pract 1994; 39:16-17 * A letter documenting that almost half of Wisconsin Research Network physicians had access to spirometry, circa 1994.

17.  Hahn DL, Emre U, Hammerschlag M. Antichlamydial antimicrobial therapy for asthma. Arch Pediatr Adolesc Med 1995; 149:219-220 * A letter and response illustrating the debate, circa 1995, over interpretation of serological and culture results, and the relative importance of patient-oriented (e.g., symptoms) and disease-oriented (e.g. microbiology) outcomes.

18. Hahn DL. Infectious asthma: A reemerging clinical entity? J Fam Pract 1995; 41:153-157 *** The first report documenting the high frequency with which asthma began after a remembered acute respiratory illness, and the apparent dramatic loss of lung function in patients with this “infectious asthma” syndrome. Reference #39 documents that “infectious asthma” is also associated with C. pneumoniae antibodies, suggesting that chlamydial infection in asthma can cause lung remodelling (i.e., permanent lung damage via scarring, also called COPD). Others have confirmed the association of C. pneumoniae antibodies and accelerated loss of lung function in non-atopic adult-onset asthma: ten Brinke et al.; Pasternaket al.

19. Hahn DL. 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 antimicrobial treatment of adult asthma, using patients as their own controls. The effect appeared to be “bimodel”, i.e., it was either dramatic or did not occur. Follow up clinical experience suggests that clinical relapses in some patients tend to occur after about two years, but they often respond to re-treatment.

20. Verheij T, Zermansky A, Hahn DL. Antibiotics in acute bronchitis. Lancet 1995; * A discussion of the microbiology and treatment of acute bronchitis, emphasizing the limited extent of our knowledge about this extremely common condition.

21. Hahn DL. Evidence for Chlamydia pneumoniae infection in asthma. In: Allegra L, Blasi F, eds. Chlamydia Pneumoniae Infection. Milan, Italy: Springer-Verlag, 1995; 65-75 ** The first of several reviews of current knowledge of C. pneumoniae and asthma. See also References #24#33 , #35 , #47 , and especially #54  for more recent updates. This was the first to discuss the possible role of C. pneumoniae as a causal factor in the spectrum of obstructive airways diseases including asthma and COPD.

22. Hahn D. 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 ** Addresses an important methodological issue surrounding interpretation of C. pneumoniae serologic patterns. In retrospect, one of the serological criteria associated with acute infection in young adults with acute respiratory illness did not accurately indicate acute infection in older adults with chronic asthma. This appears to be the first discussion of a conundrum that is now widely accepted (see Dowell-CDC).

23. Hahn DL, Anttila T, Saikku P. Association of Chlamydia pneumoniae IgA antibodies with recently symptomatic asthma. Epidemiol Infect 1996; 117:513-517 *** Due to use of a polyvalent (mixed) antibody, the initial studies could not distinguish whether asthma was associated with C. pneumoniae IgG antibodies, IgA antibodies, or both. This study found that new-onset adult asthma was associated with IgA but not with IgG. Since IgA is thought to be an indicator of chronic infection in other bacterial diseases, this appears to be the first evidence that IgA might be a marker for chronic infection in asthma.

24. Hahn DL. Intracellular pathogens and their role in asthma: Chlamydia pneumoniae in adult patients. Eur Respir Rev 1996; 6:224-230 ** A second review of C. pneumoniae and asthma in adults.

25. Hahn DL. Role of Chlamydia pneumoniae in acute respiratory tract infections, excluding pneumonias. Antibiotics for Clinicians 1998; 2 (Supplement 3):9-18 ** Review of C. pneumoniae as a cause of acute non-pneumonic respiratory tract illnesses.

26. Pasternak A, Hahn D, McBride P, et al. 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 * Pilot study of C. pneumoniae antibodies and severity of coronary artery disease (CAD), which found that several types of antibody including IgA were associated with the extent and severity of CAD. If the source of the IgA antibodies was the lung, then this suggests that persistent seeding of the coronary arteries from the lung could produce more disease.

27. Hahn DL, Werner NL. 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 ** To investigate whether antibiotics are associated with protection against heart attacks, several observational studies have been undertaken. This one hypothesized that antibiotics might in some cases precipitate acute vascular events, and found some evidence for this possibility in patients younger than 60 years of age. However, all the observational studies are significantly limited, as discussed in this report. One interesting finding was the huge difference in antibiotic usage by young adults, compared to older adults.

28. Hahn DL, Chang CK, Kuo C-C, et al. 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 *** Evidence for C. pneumoniae organism detection in abdominal aortic aneurysms of patients, some of whom also had obstructive lung disease, accompanied by a review of epidemiological studies associating asthma and chronic bronchitis with atherosclerosis. To my knowledge this is the first publication to suggest the hypothesis that chronic C. pneumoniae lung infection may be a risk factor for vascular diseases such as heart attacks, and aortic aneurysms. See also Reference #26 for more data supporting this hypothesis.

29. Blasi F, Allegra L, Tarsia P, et al. Chlamydia pneumoniae and asthma. Thorax 1998; 53:1095-1096 * Discussion about a report of C. pneumoniae association with severe “brittle” asthma, but not with “ordinary” acute asthma exacerbations. A methodological concern was poor matching (by age and sex) of cases and controls. Another issue not mentioned here is the inadvisability of choosing hospital controls instead of outpatient controls.

30. Hahn DL, McDonald R. Can acute Chlamydia pneumoniae infection initiate chronic asthma? Ann Allergy Asthma Immunol 1998; 81:339-344 *** This ten-year prospective primary care study 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 evidence also strongly suggests the presence of ongoing infection as shown by sputum culture positivity and/or long-lasting symptom improvement following antibiotic treatments (see Reference #19 ).

31. Hahn D, Bukstein D, Luskin A, et al. Evidence for Chlamydia pneumoniae infection in steroid-dependent asthma. Ann Allergy Asthma Immunol 1998; 80:45-49 *** The first case series documenting long-lasting improvement in steroid-dependent (“brittle”) asthma after anti-chlamydial antibiotic treatment.

32. Kalayoglu MV, Hahn DL, Byrne GI. 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. See complementary review of C. pneumoniae in non-pneumonic respiratory illnesses Reference #25

33. Hahn DL, Allegra L. 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. Highlights of this review include case reports of documented C. pneumoniae infection associated with acute asthmatic bronchitis, pneumonia with bronchospasm, new-onset asthma, cough-variant asthma with eosinophilia, chronic adult asthma with eosinophilia, and chronic asthmatic bronchitis.

34. Haider AW, Luna M, Gaziano JM, et al. Antibiotic use and risk of myocardial infarction. JAMA 1999; 282:1997-1999 * Further discussion of the limitations of observational studies of antibiotic treatment of coronary heart disease, with the caution that the evidence was insufficient to warrant antibiotics in heart disease.

35.  Hahn DL. Chlamydia pneumoniae, asthma and COPD: what is the evidence? Ann Allergy Asthma Immunol 1999; 83:271-292 *** The most comprehensive review of the subject to date, introducing the concept that asthma and COPD may be related by development of lung remodeling caused by chronic C. pneumoniae infection. See Reference #54 for a more complete development of the concept of chlamydial lung remodeling.

36. Hahn DL, Middleton KM, Campbell LA, et al. 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.

37. Hahn DL, McBride PE, Pasternak AV. The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study. Am J Med 2000; 108:179 * Further discussion of the relationship between respiratory diseases (chronic cough, asthma, chronic bronchitis, and accelerated decline in lung function), heart disease, and C. pneumoniae infections.

38. Hahn DL. 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.

39. Hahn DL, Routes JM, Nelson HS. Chlamydia pneumoniae antibodies and adult-onset asthma. J All Clin Immunol 2000; 106:404 ** Both diagnosis (via microbiologic isolation) and association (via epidemiological methods) have been used to study the role of infections in asthma. Diagnosis is appropriate in the study of individual patients suffering disease; association studies are appropriate when studying populations. Despite some dissent, serological criteria for diagnosing acute C. pneumoniae infection are well established; criteria for diagnosing chronic infection are not. Other than taking pieces of lung, we currently lack sensitive methods to diagnose chronic lung infection in asthma.

40. Hahn DL, Peeling RW, Dillon E, et al. Serologic markers for Chlamydia pneumoniae in asthma. Ann Allergy Asthma Immunol 2000; 84:227-233 *** An example of an epidemiological association study of the association of C. pneumoniae antibodies with the “infectious asthma” syndrome (called AAWI in this study). An interesting sidelight was the association with acute bronchitis (see Reference #46 , Evaluation and management of acute bronchitis). This is the first report of an association with heat shock protein 60 (hsp60), an important chlamydial antigen. More on hsp60 in Reference #45

41. Hahn D, Pasternak A, McBride P, et al. Chlamydia pneumoniae serology at the time of initial percutaneous transluminal angioplasty does not predict early recurrent ischemic events including restenosis. In: Saikku P, ed. Proceedings: Fourth Meeting of the European Society for Chlamydia Research. Helsiki, Finland: Esculapio, Bologna Italy, 2000; 264 * One of several studies finding no association of restenosis and C. pneumoniae infection.

42.  Hahn D, Campbell LA, Kuo C-C. 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 persistent deep tissue C. pneumoniae infections.

43. Hahn DL, Kuo CC, Campbell LA. 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.)* As shown in animal models, this report documents that human lung alveolar epithelial cells and giant cells (macrophages) are targets for C. pneumoniae infection.

44. Hahn DL. Defining the relationship between C. pneumoniae and chronic asthma. J Respir Dis 2000; 21:536 * A brief commentary for practicing physicians, emphasizing the need for randomized, controlled treatment trials to further define the entity “chlamydial asthma”.

45. Huittinen T, Hahn D, Wahlstrom E, et al. Host immune response to Chlamydia pneumoniae heat shock protein 60 is associated with asthma. Eur Resp J 2001; 17:1078-1082 *** In collaboration with Finnish researchers, the second report of an association of asthma with C. pneumoniae hsp60 antibodies, and the first to find that hsp60 antibodies were also related to lower lung function. Chlamydial hsp60 is associated with scarring damage in tubal infertility and trachoma, suggesting the same process might be occurring in chronically infected human lung tissue to produce lung remodelling and COPD (see References #35 & #54 ).

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

47. Hahn DL, Azenabor AA, Beatty WL, et al. 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 lung diseases.

48. Hahn DL. Chlamydia pneumoniae and the “Dutch Hypothesis”. Chest 2002; 122:1510-1512 *** Discussion of C. pneumoniae as as “common denominator” in asthma and COPD.

49. Hahn DL. 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 *** Updated review on C. pneumoniae and M. pneumoniae as causes of asthma in previously non-asthmatic adults, with an updated discussion of potential pathogenesis mechanisms. This review also discusses the advantages and disadvantages of performing prospective microbiological and clinical studies in practice-based research networks (PBRNs), compared to classical population-based epidemiological studies. PBRNs are regional and national organizations comprising practicing primary care clinicians prepared to conceive, design and implement clinical research of interest and value to primary care practitioners and their patients

50. Hahn DL, Plane MB. 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 ** Preliminary evidence that C. pneumoniae may be a “common denominator” in acute bronchitis and asthma. We propose that chronic infection predisposes to lower airway symptoms in both non-asthmatic and asthmatic subjects, and that an additional factor(s) (e.g., marked by presence of anti-hsp60 antibodies, related to innate immunity genotypes) must be present to promote the development of reactive airways and/or lung remodeling.

51. Hahn DL, Burge PS, Lewis SA. Ethics of placebo controlled studies of inhaled steroids for COPD. Thorax 2004;59 :538 –543 * Further discussion of differences between the patient-oriented (e.g., quality of life) and disease-oriented (e.g. pulmonary function) approaches to interpreting the results of clinical studies. The importance to patients of making clear distinctions between these two perspectives cannot be overestimated.

52. Hahn DL, Plane MB. Feasibility of a practical clinical trial for asthma conducted in primary care. J Am Board Fam Pract 2004; 17:190-195 *** Important not only because it is the first attempt to conceive, design and implement a practice-based research network (PBRN) asthma clinical trial in primary care settings, but also because it contains a discussion of the need for patient-oriented research that(1) studies a generalizable population, (2) is internally valid, and (3) measures patient-oriented outcomes.

53. Hahn DL. 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 *** Most comprehensive review to date discussing 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. If early treatment of C. pneumoniae (and/or other pathogens) benefits both asthma (by symptom control) and COPD (by interrupting pathogenesis), then benefit/cost ratios increase, perhaps dramatically.

54. Hahn DL, Hester JD. 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 a family outbreak of acute C. pneumoniae infections by polymerase chain reaction (PCR) testing in a primary care setting. Acute C. pneumoniae infections are under-recognized and under-treated due to lack of availability of rapid and reliable tests. Fortunately, there is interest in developing such tests. Unfortunately, testing of respiratory secretions is probably not going to be very sensitive for detection of chronic lung infections.

55. Hahn DL. Origins of atopy in pediatric asthma. J Allergy Clin Immunol 2005; 115:425-426 * To my knowledge, this is the first time anyone suggested that C. pneumoniae infection might bias the immune system towards the “allergic phenotype” in asthma. Meta-analyses of epidemiological studies do not support the idea that allergies or atopy cause all or even most asthma. Alternatively, could an underlying cause for asthma also cause allergy as a byproduct, or “side-effect”?

56. Hahn DL, Biscione GL, Corne J, et al. Chlamydophila pneumoniae in asthma. Eur Respir J 2005; 25:392-395 * Comments on a study that detected C. pneumoniae in the throats of adults with asthma.

57. Hahn DL (2006) A theory explaining time trends in asthma prevalence. Eur Respir J 27: 434-435. *** The distillation of the current evidence into the theory that C. pneumoniae is an important cause of asthma, much as H. pylori was once theorized as an important cause for peptic ulcer disease.

58. Hahn DL (2006) Does most asthma really begin during the pre-school years? Am J Respir Crit Care Med 173: 575-576 * Further discussion about the controversy that “asthma begins in childhood.”

59. Hahn DL, Karjalainen J and Pasternak R. Chlamydia pneumoniae and airway remodelling. J Allergy Clin Immunol 2006;117:1193-1194 * Discussion about the best research design to identify whether infection causes new cases of asthma.

60. Hahn DL, Plane MB, Mahdi OS and Byrne GI. Secondary outcomes of a pilot randomized trial of azithromycin treatment for asthma. PLoS Clin Trials 2006;1:e11 DOI: 10.1371/journal.pctr0010011 *** The first randomized clinical trial (RCT) evidence for lasting symptom improvement after antibiotic treatment of persistent asthma. This trial is also the first to report that C. pneumoniae IgA antibodies predicted worsening of asthma symptoms. There was also a suggestion that high antibody levels might be associated with treatment response

61. Hahn DL. Beyond the Dutch Hypothesis. American Journal of Respiratory and Critical Care Medicine. 2006; 174:1056-1057.* This communication suggests an analogy between asthma and other established chlamydial diseases such as trachoma, the world’s leading cause of preventable blindness, and pelvic inflammatory disease.

62. Hahn, D. L., and R. W. Peeling. Airflow limitation, asthma, and Chlamydia pneumoniae-specific heat shock protein 60. Ann Allergy Asthma Immunol 2008;101:614-618. ** This study adds to a small but growing body of evidence suggesting that 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.

63. Macrolide treatment for “Chlamydial Asthma”: Evidence for enrollment bias in an effectiveness trial.

64. Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity. PLoS ONE 2012; 7(4):1-9. ***This study found that half of community-based asthma patients had “allergic antibodies” directed against C. pneumoniae, and of these “allergic” asthmatics, 50% also had evidence for an active infection circulating in their blood. Also, being “allergic” to the bacteria was strongly associated with having more severe asthma. This finding adds to the growing body of evidence that C. pneumoniae infection may be involved in causing more severe asthma symptoms.

65. Azithromycin for bronchial asthma in adults: An effectiveness trial. J Am Bd Fam Med 2012; 25:442-459. *** This clinical trial (called AZMATICS) found that azithromycin had significant benefits for the majority of subjects with severe, treatment resistant asthma who elected to take azithromycin. This trial was “approved” but not funded by the National Institutes of Health (NIH), therefore it was not able to enroll the 600+ subjects originally planned, nor were tests for infection possible. Among the stated reasons for declining to fund AZMATICS, the NIH review summary stated “it remained the opinion of the committee that current and former smokers should be excluded from the study” and “The committee felt that the need for a “real world” setting for this trial was overemphasized…”

66. A Cure for Asthma? What Your Doctor Isn’t Telling You, and Why *** This book summarizes the evidence for infection as a treatable cause for asthma that has been published over more than 20 years. It also attempts to answer the question, Why are the experts ignoring it? A remarkable juxtaposition of events occurred recently that illustrates this yawning gap between the positive evidence and the negative expert opinion. In late 2013 a meta-analysis (combined results of all the studies) of randomized trials of macrolides (azithromycin is a macrolide) for the long term management of asthma in adults was published. The results showed positive benefits for symptoms, quality of life, hyper reactivity (“twitchy airways”) and peak flow (a measure of lung function) (Reiter et al. 2013). In early 2014 the European Respiratory Society and the American Thoracic Society released a guideline on severe asthma. They recommended AGAINST macrolides for asthma without referencing any evidence (Chung-2014, page 365 ).

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