ASSOCIATION OF CHLAMJ DIA PNEUMONIAE IGA ANTIBODIES WITH RECENTLY SYMPTOMATIC ASTHMA
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E / J I ~ / P I 111fccr I I I O ~(1996). 117, 513-517 C o p y r ~ g h t0 1996 Cambridge Unlvers~tyPress Association of Chlamj~diapneumoniae IgA antibodies with recently symptomatic asthma Dc2trri Mcrlical Cc~titcvunrl the. Drari E',,~rn(I(~tion , f i r Health, Research an(/ Educ,atiot~,!lftrrli.son, Wi.rc,on.sin, ['.PA ?Y(~tio/~al Plrhlic Hc~althInstitutc, D ~ p a r t n l r t ~int Olrlu. Firllarzd 01' Mic.rohio/og~,,Clniversitl. c?f Oulu. Fir~lnnrl :' D(~/~(~r.tri~c?it SUMMARY T o determine whether recently diagnosed adult-onset asthma is associated with serologic evidence of chronic Clilan~j~diu pt~eumoniueinfection, we performed a case-control study in a primary care clinic of cases with asthma (25 adults reporting first symptoms of asthma within 2 years of enrollment) and 45 concurrently enrolled sex and age (f10 years) matched non- asthmatic controls with normal pulmonary function. C. pneumoniur-specific IgA, IgG and IgG4 antibodies, and circulating immune conlplexes (CIC) were measured by microin~n~unofluorescence testing. Results showed that frequencies of IgG titres 2 16 (9270). IgG4 titres 2 16 (20%) and CIC 2 4 (60%) in asthma patients were not significantly different from those of controls. However, asthmatics had a significantly higher prevalence of C. prlc~allnt7iclr-specificIgA titres >, 10 (72 O/O of cases vs 44 O/O of controls, P < 0.05). After adjustment for the effects of age. sex and smoking, the odds ratio for a n association of IgA and asthma was 3.7 (95 O/b confidence interval 1.2-1 1.5). We conclude that recently symptomatic reversible airway obstruction in adults is associated with the presence of C. pneunzaniue-specific IgA antibodies, a proposed indicator of chronic respiratory C. pneunfoniar infection. Although several viral and atypical pathogens have INTRODCCTION been linked with possible asthma initiation and Asthma is an important cause of respiratory morbidity promotion, the association of C. pneunzoniae infection afrecting approximately 5-10 % of children and adults with asthma is most extensively documented . in industrialized countries [I]. Prevalence and mor- Evidence on the role of C. pneumoniar in the tality, especially in older individuals, are increasing aetiopathogenesis of asthma has been achieved by for unexplained reasons . Currently. most experts culture isolation. polymerase chain reaction, serolo- favour the view that asthma is a non-infectious gically and by preliminary treatment trials . The inflammatory lung disease. Recently. however, there majority of evidence for C. pnrumoniae infection in has been a resurgence of interest in the possibility that adult-onset asthma has been based on serology, since chronic pulmonary infection may be an initiator and successful culture isolation of C. pneun~otliaefrom the promoter of asthma in addition to an acknowledged upper airway of adults with stable chronic asthma has role for acute viral infection in precipitating asthma been only infrequently reported. exacerbations. Most serologic evidence for C. l~neumoniueinfection in adult asthma has been based on the measurement * Corresportdence and request for reprints: D r . Hahn, Arcand of IgG or total (IgG, 1gM and IgA) antibodies which Park Clinic. 3431 East Washington Avenue.. Madison. WI 53704. USA. cannot clearly distinguish previous exposure from
514 D. L. Hahn et al. ongoing (chronic) infection . It has been suggested 15 cases were also matched with a non-asthmatic that presence of serum IgA antibodies may be a useful control patient diagnosed with acute bronchitis who marker in the diagnosis of some chronic bacterial (I) denied wheezing and dyspnoea and (2) had normal infections, since half life of serum IgA is less than 1 pulmonary function. An interim analysis indicated week  and its continuous presence may indicate that bronchitis controls were intermediate in sero- persistent antigenic stimulation of the immune system. positivity between cases and asymptomatic controls In support of IgA antibodies as a marker for chronic . This finding led to cessation of further bronchitis infection, microbe-specific serum IgA has been asso- control accrual. Only results from asymptomatic ciated with a variety of chronic illnesses caused by controls are reported here. bacterial pathogens including C. trachomatis . In Spirometric testing was performed according to particular, C. pneumoniae-specific IgA has been American Thoracic Society (ATS) guidelines , using associated with C. pneumoniae reinfection  and with a Gould spirometer (System 21, Gould Medical chronic obstructive pulmonary d~sease . These Products Inc., Dayton, Ohio). Baseline (pre- observations suggest that it would be worthwhile bronchodilator) testing was performed for all study investigating IgA as a potential marker for chronic patients. Post-bronchodilator testing was obtained infection in asthma. from asthma cases but not for asymptomatic controls. Most investigations using measurement of C. Blinded serologic testing was performed using the pneumoniae antibodies have focussed on established microimmunofluorescence (MIF) test developed by (prevalent) asthma and relatively little information is Wang and Grayston [lo]. A Finnish isolate of C. available regarding associations with incident asthma. pneumoniae, Kajaani-6 , was used as antigen with Associations with prevalent asthma cannot exclude C. traclzomatis L, and a pool of two C. psittaci strains the possibility that C. pneumoniae infection follows as controls. IgG4 antibodies were titrated using rather than precedes the development of asthma respective monoclonal mouse antibody in the indirect symptoms, and is a consequence of rather than a immunofluoresence test. IgG was neutralized potential cause for asthma. The study of incident (Gullsorb, Gull Laboratories, Salt Lake City, USA) asthma requires large, prospective studies which have before IgA titrations [I I]. C. pneumoniae-specific yet to be performed. This case-control study was immune complexes were measured as described earlier designed to determine whether serologic evidence of . Coded case and control sera were batched and C. pneumoniae infection would be found in patients tested together. with recently symptomatic asthma. Fisher's exact test was used to analyse 2 x 2 tables, and Student's t test was used to test for significant differences in the means of continuous variables. MATERIAL A N D M E T H O D S Unadjusted Mantel-Haenszel odds ratios were calcu- Between September 1991 and June 1994, study lated and logistic regression was used to adjust for the subjects were enrolled during the course of usual effects of age, sex and smoking. A two-sided P-value practice in a primary care ambulatory clinic located in less than 0.5 was considered significant. a medium sized midwestern city whose population was mainly white and middle-class. Case eligibility RESULTS included (1) recent onset (longer than 3 months but less than 2 years duration) of asthma symptoms which The study group (25 cases and 45 controls) averaged included intermittent wheezing and dyspnea triggered 46 years of age (range 27-80) and 66% were males. by a variety of stimuli, (2) reversible airway ob- Nineteen percent were current smokers, 37 % were ex- struction of at least 200 ml and 12 % demonstrated by smokers and 44% had never smoked. For ever- spirometry beforelafter bronchodilators and (3) no smokers, average pack-years consumed was 23.6. prior history of childhood asthma. Syndromes in the asthma case group were adult-onset Each case was matched concurrently from the asthma (I 5), asthma with chronic airways obstruction attending practice population with one or two sex and ( 9 , exercise-induced asthma (4) and cough variant age ( f 10 years)-matched non-asthmatic controls who asthma (1). The majority of cases had mild asthma, (1) were not experiencing an acute respiratory illness indicated by the finding that 15 (60 %) of 25 had a pre- and (2) had normal pulmonary function, including an bronchodilator FEVl of greater than 70 % predicted. FEVl (percent predicted) of 90 % or greater. The first Diagnoses in the control group included visits for
C. pneumoniae IgA and asthma 5 15 Table 1. Palienl clzaracteristics Asthma cases Controls P-value Number 25 45 - Age, mean (s.D.) 46.7 (9.4) 45.7 (10.5) n.s. Sex, M / F (number) 1619 30115 n.s. Smoking status, number (%) Current 9 (36) 4 (9) Ex 10 (40) 16 (36) Never 6 (24) 25 (56) 0.01* Cumulative pack-years, eversmokers (s.D.) 29.9 (28.1) 17.6 (15.5) n.s. Pre-bronchodilator pulmonary function FEV 1, %predicted (s.D.) 69.5 (13.7) 102.0 (8.5) < 0.0001 FEF25 %-75 %, %predicted (s.D.) 39.4 (12.7) 91.9 (25.5) < 0.0001 Post-bronchodilator change in FEV 1, % (s.D.) 24.8 ( 1 5.4) n.d.t - * Ever-smokers v s . never-smokers. t Post-bronchodilator pulmonary function was not performed for controls. Table 2. Serologic resul~s,for Chlamydia 44%, P < 0.05). in titres of 10 or greater (Table 2). pneumoniae The unadjusted odds ratio for an association of IgA and asthma was 3.1 (95 % confidence interval 1.1- Asthma 9.0). After adjusting for the effects of age, sex and cases Controls P-value smoking the odds ratio did not change significantly Number 25 45 - (ad-justed odds ratio 3.7, 95% confidence interval Antibody findings, number (%) 1.2-1 1.5). Smoking status (ever- versus never-) was 1gA titre 3 10 18 (72) 20 (44) < 0.05 also associated with asthma in the multivariate IgG titre 3 16 23 (92) 38 (84) n.s. IgG4 titre 3 16 5 (20) 7 (16) n.s. analysis (odds ratio 4.5, 95% confidence interval 1C 3 4* 15 (60) 24 (53) n.s. 1.4-14.2). A logistic test for interaction between smoking and IgA antibody was not statistically * Chlamydia1immune complexes. There were no significant significant (P = 0.38). N~ other I ~ A titre cutoff, nor associations for any IC cutpoint. any titre combination of IgG/IgA differentiated cases from controls. physical examinations (23), musculoskeletal com- plaints (12) and miscellaneous conditions (3 skin disorders, 1 anxiety complaint, 1 urethritis, 1 asympto- DISCUSSION matic parent of a patient, 1 headache, 2 stomach disorders, 1 vertigo). The results of this case-control study suggest that Table 1 compares characteristics of asthma cases almost three-quarters of cases have chronic C. and asymptomatic controls. There were no significant pneumoniae infection, as indicated by the presence of differences between cases and controls in age or sex, C. pneumoniae-specific IgA, during the first few years but cases were significantly more likely than controls of symptomatic asthma. The relationship between to be categorized as current or past smokers. Cases recently reported symptoms (a study criteria) and pre- had also smoked more cigarettes than controls, but existing subclinical disease could not be explored, this difference in cumulative pack-years smoked did however, due to the retrospective nature of the study not achieve statistical significance. Consistent with design. Prospective studies (or study of stored sera study entry criteria, pre-bronchodilator FEVl and from historical cohorts) will be required to examine FEF25 %-75 % were significantly lower in asthma temporal relationships between infection and de- cases than in controls. velopment of de novo asthma. These studies will be There were no differences between cases and required to determine whether IgA antibodies are controls in frequencies of C. pnrumoniae-specific IgG detectable over time, as we measured IgA antibodies antibodies. IgG4 antibodies or immune complexes. in single specimens only. However, cases had significantly more often IgA Previous work associating C. pnrumoniae anti- antibodies present in the serum than controls (72 % vs bodies with asthma employed a measurement of total
516 D. L. Hal111 et al. antibodies (IgG, IgA and IgM) 1131. The MIF test, sclerotic plaques . IgA antibodies could better when properly interpreted (not accepting non-specific reflect chronic inflammation of mucous membranes in bright fluorescence), is specific, and moreover, can lung. differentiate immunoglobulin classes. Results of this Smoking and IgA antibodies were both associated case-control study, showing an association with IgA with asthma in this study. Current [19, 201 and ex- and no association with IgC antibodies, suggest that smokers  have more seropositivity and higher previously reported serological associations may have titres of C. pneumoniae antibodies than non-smokers. actually been attributable to IgA antibodies. None of It has been suggested that the associations between the cases in this study had detectable IgM antibodies. smoking and chronic cardiopulrllonary disease may Secretory IgA (sIgA) is generated in response to be mediated by the promotion of C. pneumoniae mucosal infection and some of the sIgA may be infection . This small study was not designed to absorbed into the systemic circulation . Thus, address pathogenic pathways involving smoking, serum IgA antibody levels may be an indirect measure infection and asthma, nor was it powerful enough to of mucosal infection which might be more readily detect potentially significant interactions of smoking detectable by measurement of sIgA in respiratory and infection. secretions. C. pnc~ut71oniae-specificsIgA has been Interim analysis suggested that the bronchitis demonstrated in respiratory secretions from chronic control group had seropositivity intermediate between bronchitis patients  and has also been correlated cases and asymptomatic controls . Based on a with respiratory symptoms in a prospective cohort prevalence of C. pneumoniae infection in acute study of children with asthma . The present study bronchitis patients of between 5 % [I 31 and 25 YO[2 11. employed as antigen in the MIF test a European C. this result was not surprising. Thus, use of a bronchitis pnc~untotziac~strain which may be less sensitive in the control group would afford a more challenging test detection of antibodies from patients infected with a for association than the use of an asympton~atic North American strain [ I 51. Since serum is routinely control group. Another challenging design for as- obtained in clinical practice, whereas respiratory sociation in future case-control studies might be the washings or secretions are not, i t will be worthwhile to use of controls with classic atopic asthma or other perform further studies on serum IgA using hom- asthma syndromes not considered infectious in nature. ologous antigen to investigate the clinical utility of In conclusion, this case-control study is the first to serology in di;~pnosis of chronic C. priclrttloniae show a significant association of C. pneumonirrt7- infection. specific serum IgA antibodies with recently sympto- No associations were found in this study between matic reversible airway obstruction in adults. Future asthma and IgG antibodies. IgC4 antibodies and the larger studies are warranted to test the clinical presence of immune complexes. Frequency of IgG usefulness of IgA antibodies as a diagnostic tool in antibodies was 84% in controls, indicating an un- the detection of chronic C. pneumoniae infection in usually high level of previous exposure in this clinical asthma and perhaps also in other chronic cardio- population, since IgC antibody prevalence has usually pulmonary diseases of unknown or questionable been reported to be about 50 % in middle-aged adults aetiolopy. worldwide [I6]. The prevalence of IgC4 antibodies was 20% in asthmatics, not significantly different ACKNOWLEDGEMENTS from the 16% prevalence found in controls. This Supported by the Dean Foundation for Health, finding requires further investigations. as IgC4 anti- Research and Education, Madison, Wisconsin and bodies have been associated with acute reinfections the Academy of Finland. with C. pneumoniae (Antilla and colleagues, personal observation). The presence of circulating immune complexes has been proposed as a marker for chronic REFERENCES C. priclm7onirre infection in coronary artery disease 1. Cookson J B . Prevalence rates of asthma in developing , but it was not associated with asthma in this countries and their comparison with those of Europe study. The presence of immune complexes containing and North America. Chest 1987; 91: 97s-103s. chlamydial proteins points to free access of chlamydial 2. Burney P. Epidemiology of asthma. Allergy 1993; 48: 17-23. products into the circulation and could be a marker 3. Hahn DL. Evidence for Chlamydia pneumoniae in- for. as an example, chlamydial infection of arterio- fection in asthma. In; Allegra L, Blasi F, eds.
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