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ORIGINAL ARTICLE
Year : 2018  |  Volume : 8  |  Issue : 2  |  Page : 83-88  

Correlation of severity of functional gastrointestinal disease symptoms with that of asthma and chronic obstructive pulmonary disease: A multicenter study


1 Department of Pulmonary Medicine, ESI Post Graduate Institute of Medical Sciences and Research, New Delhi, India
2 Department of TB and Respiratory Diseases, Hind Institute of Medical Sciences, Barabanki, Uttar Pradesh, India
3 Department of Obstetrics and Gynecology, Hind Institute of Medical Sciences, Barabanki, Uttar Pradesh, India

Date of Submission24-Jul-2017
Date of Acceptance19-Feb-2018
Date of Web Publication19-Apr-2018

Correspondence Address:
Dr. Devesh Pratap Singh
House No-232, Manas Garden Colony, Behind BBD University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijabmr.IJABMR_258_17

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   Abstract 


Introduction: There is a growing clinical awareness about the influence of gut–lung axis on lung injury and coexisting manifestations of disease processes in both the intestine and lungs. Patients of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma very often present with coexistent gut symptoms. In the present study, we have tried to establish the correlation of severity of pulmonary pathology of COPD and asthma patients with functional gastrointestinal (GI) symptoms of the patients. Materials and Methods: This is a prospective, questionnaire-based study comprising patients with asthma and COPD. After following strict inclusion and exclusion criteria, a total of 200 patients (100 patients of bronchial asthma and 100 patients of COPD) were included in the study. Functional GI symptom questionnaire [Annexure 1-Bowel Disease Questionnaire] is based on ROME III diagnostic criteria. On the basis of GOLD (Global Initiative for Obstructive Lung Disease) guidelines, COPD patients were divided into 4 categories (mild - GOLD 1, moderate – GOLD2, severe – GOLD3 and very severe – GOLD4). Asthma patients were divided into three categories (well controlled, partly controlled, uncontrolled) on the basis of GINA (Global Initiative for Asthma) guidelines. Results: Highest percentage of patients with maximum GI symptoms was found in “GOLD-4” group among COPD patients and “uncontrolled” group among asthma patients. Highest percentage of patients with least GI symptoms was found in “GOLD-1” group among COPD patients and “well controlled” group among asthma patients. Conclusion: We can conclude from our study that the phenomenon of gut–lung axis not only exists but also the severity of symptoms of one system (gut) carries a high degree of concordance with severity of other (lung).

Keywords: Asthma, chronic obstructive pulmonary disease, functional gastrointestinal disease, gut microbiota, gut–lung axis


How to cite this article:
Ojha UC, Singh DP, Choudhari OK, Gothi D, Singh S. Correlation of severity of functional gastrointestinal disease symptoms with that of asthma and chronic obstructive pulmonary disease: A multicenter study. Int J App Basic Med Res 2018;8:83-8

How to cite this URL:
Ojha UC, Singh DP, Choudhari OK, Gothi D, Singh S. Correlation of severity of functional gastrointestinal disease symptoms with that of asthma and chronic obstructive pulmonary disease: A multicenter study. Int J App Basic Med Res [serial online] 2018 [cited 2018 Jul 22];8:83-8. Available from: http://www.ijabmr.org/text.asp?2018/8/2/83/230520




   Introduction Top


There is a growing clinical awareness about the influence of gut–lung axis on lung injury and coexisting manifestations of disease processes in both the intestine and lungs.[1],[2],[3],[4] Intestinal manifestations are commonly known to occur in viral respiratory infections.[4],[5],[6] Patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD) and bronchial asthma very often present with coexistent gut symptoms.[1],[2],[3],[4] However, the underlying mechanism of this gut–lung vital cross talk is not well defined yet.[7] Several studies have already linked asthma with functional gastrointestinal (GI) diseases.[8],[9] Functional GI diseases have been explained as “gut functioning abnormalities” defined on the basis of symptoms of patients without any demonstrable anatomical or biochemical disorders.[10],[11]

In the present study, we have tried to assess these intestinal symptoms of asthma and COPD patients on the basis of a preset questionnaire. We have also tried to further establish the correlation of severity of pulmonary pathology with GI symptoms score of the patients.


   Material and Methods Top


This is a questionnaire-based study comprising of patients with asthma and COPD. All patients were taken from the outpatient department of pulmonary medicine at two tertiary care institutes from October 2016 to June 2017. Patients with other respiratory diseases (except bronchial asthma and COPD), active or old history of tuberculosis, diabetes mellitus, pregnant females and HIV, and other immunocompromised states have been excluded from the study. A screening ultrasound (USG) abdomen was performed for all patients and patients with only normal screening USG were included in the study. On the basis of ROME III diagnostic criteria for common “Functional GI Disorders,” a questionnaire was formulated [Annexure 1-Bowel Disease Questionnaire].



For tests of association using “Bivariate correlations,” a “Moderate correlation” between “Severity of Asthma and COPD” and “GI symptom scores” (based on ROME III diagnostic criteria) was considered meaningful. To detect a moderate correlation (r = 0.25), a sample of 98 analyzable participants in each group of asthma and COPD provided 80% power, one sided to discover that the correlation was significantly different from there then being no correlation (i.e., that the correlation would be zero) at the 0.05 level. We have taken 100 analyzable participants in each group of asthma and COPD in our study.

After taking informed consent from every patient, the questionnaire [Annexure 1-Bowel Disease Questionnaire-based on various abdominal symptoms] was filled up by the investigators. Different questions in questionnaire have grades ranging from 0 to 1 (Grade “0” for answer 1 and Grade “1” for answer 2). GI symptom scores of patients have been divided into three categories (severe >10, moderate 5–10, and mild <5) reflecting severity of functional GI disorders. After following strict inclusion and exclusion criteria, a total of 200 patients (100 patients of bronchial asthma and 100 patients of COPD) were included in the study. A total of 56 males and 44 females were included in bronchial asthma group. A total of 65 males and 35 females were included in COPD group. Patients of <15 years and >80 years were excluded from the study. All patients were subjected to spirometry. COPD patients were divided into 4 categories (mild – GOLD1, moderate – GOLD2, severe – GOLD3, and very severe – GOLD4) as per the GOLD guidelines, depending on their airflow limitation severity (defined on the basis of postbronchodilator FEV1 on spirometry). Asthma patients were divided into three categories (well controlled, partly controlled, and uncontrolled) on the basis of their “level of asthma symptom control” as defined on the basis of GINA assessment of asthma control in adults, adolescents, and children. GI symptom score of every asthma and COPD patient was measured on the basis of questionnaire.

Statistical analysis was performed using the SPSS statistical package (version 17.0; SPSS Inc., Chicago, IL, USA). Categorical variables are expressed as frequencies and percentages. Pearson's Chi-square test was used to determine the relationship between disease (COPD or asthma) stage and GI symptom score.


   Results Top


All COPD patients were categorized into GOLD 4 (30 patients), GOLD 3 (32 patients), GOLD 2 (26 patients), and GOLD 1 (12 patients) groups. [Table 1] shows the distribution of numbers of COPD patients of varying severity (depending on COPD stage), according to their GI symptom scores. Numbers of patients with GI symptom scores >10 were 21 (42%), 20 (40%), 7 (14%), and 2 (4%) in GOLD 4, 3, 2, and 1 groups, respectively [Table 1]. Highest percentage of patients with least GI symptoms was found in “GOLD-1” COPD group.
Table 1: Distribution of numbers of chronic obstructive pulmonary disease patients of varying severity as per their gastrointestinal symptom score

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Asthma patients were categorized into uncontrolled (31 patients), partly controlled (25 patients), and well controlled (44 patients) groups. [Table 2] shows distribution of numbers of asthma patients of varying severity (depending on their asthma control level), according to their GI symptom scores. Number of patients with GI symptom score >10 were 21 (60%), 8 (22.9%), and 6 (17.1%) in uncontrolled, partly controlled, and well controlled groups, respectively [Table 2]. Highest percentage of patients with least GI symptoms was found in “well-controlled” asthma group.
Table 2: Distribution of numbers of asthma patients of varying severity as per their gastrointestinal symptom score

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The results of our study clearly showed that majority of COPD and asthma patients presenting with maximum severity (GOLD 4 and uncontrolled, respectively), also presented with worst GI symptom scores. On the contrary, majority of stable COPD and asthma patients (GOLD 1 and well controlled, respectively) presented with mild GI symptom scores.


   Discussion Top


In recent years, multiple theories and animal experimental models have been proposed to explain this phenomenon of gut–lung cross talk.

Effect of gut microbiota-Few studies have pointed toward qualitative or quantitative changes in gut microbiota, playing a possible role in variety of chronic lung diseases like asthma. Recent studies have described that both humans and animals are susceptible to develop allergic disorders later in life due to disturbances in microbiota in early life.[12] Russel et al. have proved in their experimental study on mice that there is a crucial window period during early developmental stage of life, during which suppression of microbial load and diversity by antibiotics administration will lead to airway inflammation on exposure to aeroallergens during later stages of life.[13] Similar findings were confirmed by Gollwitzer et al. in their study.[14] Another study by Abrahamsson et al. has revealed that infants with reduced diversity of gut microbiota during 1st month of their life, were more likely to be affected from asthma at 7 years of their age.[15] Babies born after cesarean section are said to have lower diversity of microbiota in their gut,[16] and these babies were found to have high likelihood of developing asthma in the future.[17] Bruzzese et al., in their study, have shown that restoration of gut microbiota (through administration of probiotics) is helpful in reducing both intestinal inflammation and pulmonary exacerbations in cystic fibrosis patients.[18]

Food habits-According to another theory, food habits can also significantly contribute to this gut–lung axis phenomenon by affecting microbiota of gut. Trompette et al. have revealed in their experimental study conducted on animal model that a high fermentable fiber diet could protect the mice from allergic inflammation of the lung.[19] Possible explanation to this is, a diet rich in fermentable fiber can result in the production of short-chain fatty acids which can, in turn, suppress allergic reactions through a gut–bone axis by enhancing hematopoiesis of macrophages and dendritic cell precursors.[20] This will bring about increased phagocytic activity in lungs with reduced ability to drive helper T-cell type 2 (Th2) cell effector functions.[19] This is a well-known fact that Th2 overactivation brings about type-1 IgE-mediated allergy and hypersensitivity reactions.[19] According to another hypothesis, regular diets enriched with high-fiber content are considered to be beneficial for lung function and helpful in reducing COPD risk.[21]

Secondary organ involvement in COPD patients-Secondary organ damage in COPD patients is another area of growing clinical interest nowadays. A study conducted by Ekbom et al. showed a significantly higher risk of both ulcerative colitis (hazards ratio: 1.83) and Crohn's disease (hazards: 2.72) among COPD patients.[20] It is commonly believed nowadays that both COPD and inflammatory bowel diseases may share common inflammatory pathways.[20],[22] Another possible mechanism among COPD patients was proposed in the study of Rutten et al.[23] According to this study, a possible mechanism may be compromised intestinal perfusion leading to ischemia, owing to high metabolic demands among COPD patients.[23]

Smoking-Smoking is considered to be an independent risk factor for both COPD and a variety of GI pathologies like Crohn's disease.[24] Multiple studies have suggested till date that smoking may increase risk of developing Crohn's disease by as much as 3 folds.[24],[25],[26],[27],[28] Another school of thought says that smoke antigens are capable of initiating an immune response which in turn may cause secretion of elastases (MMP-9,12 and neutrophil elastase) from neutrophils and macrophages.[29] These elastases are capable of degrading elastin proteins.[30] Since elastin is an integral protein in intestinal mucosa as well, we can easily elucidate the mechanism involved in intestinal pathology in relation to smoking. In a recent study, smoking has been found to be associated with several functional GI diseases and functional symptoms such as functional bloating, functional abdominal pain, functional diarrhea, and functional constipation.[31]

Genetic predisposition-Till date, multiple different genetic mutations have been defined which predispose the development of COPD and inflammatory bowel diseases separately. Among various genetic mutations identified till date which may predispose to the development of Crohn's disease, NOD 2 genetic mutation (nucleotide-binding oligomerization domain containing 2) is of particular importance.[32],[33],[34] Recently, Kinose et al. have identified NOD-2 genetic mutation in COPD patients as well.[35] This may further support the theory of genetic influence on gut–lung axis. Hedgehog-interacting protein (HHIP) is another gene among various other described genes, which has been shown to be a potentially susceptible locus for predisposition of COPD.[36],[37] Same HHIP gene locus was earlier found to be important in intestinal crypt axis development.[38]

Our study further endorses the phenomenon of gut–lung cross talk. Most of the participants in our study were found suffering from bowel symptoms. Their high GI symptom scores were significantly correlated with severity of their lung diseases (Low FEV1 in COPD patients and poor control in asthma patients).

It is worth noting that epithelia of both GI system and respiratory system develop from a common embryonic origin from primitive foregut.[39],[40] This may possibly explain the remarkable structural similarities between respiratory and GI tracts,[41],[42] and we can conclude that structural and immunological similarities may be the reason behind common and overlapping pathological presentations of both systems.


   Conclusion Top


We can conclude from our study that the phenomenon of gut–lung axis not only exists but also the severity of symptoms of one system (gut) carries a high degree of concordance with severity of other (lung). Our study clearly demonstrates that it is not mere a coincidence that patients of asthma and COPD, very frequently present with abdominal complaints. These findings are of vital importance, as a better understanding and further researches on this phenomenon can lead to opening of new dimensions for prevention, treatment, and rehabilitation of patients of chronic respiratory ailments as well as patients of multiple GI pathologies. One important limitation of our study is that we have taken into account only functional GI disorders; therefore, further studies are needed to study the correlation of demonstrable (anatomical and biochemical) GI diseases with obstructive airway diseases and other lung pathologies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Roussos A, Koursarakos P, Patsopoulos D, Gerogianni I, Philippou N. Increased prevalence of irritable bowel syndrome in patients with bronchial asthma. Respir Med 2003;97:75-9.  Back to cited text no. 1
[PUBMED]    
2.
Baral V, Connett G. Acute intestinal obstruction as a presentation of cystic fibrosis in infancy. J Cyst Fibros 2008;7:277-9.  Back to cited text no. 2
[PUBMED]    
3.
Keely S, Hansbro PM. Lung-gut cross talk: A potential mechanism for intestinal dysfunction in patients with COPD. Chest 2014;145:199-200.  Back to cited text no. 3
[PUBMED]    
4.
Marsland BJ, Trompette A, Gollwitzer ES. The gut-lung axis in respiratory disease. Ann Am Thorac Soc 2015;12 Suppl 2:S150-6.  Back to cited text no. 4
[PUBMED]    
5.
Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z, et al. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated th17 cell-dependent inflammation. J Exp Med 2014;211:2397-410.  Back to cited text no. 5
    
6.
Dilantika C, Sedyaningsih ER, Kasper MR, Agtini M, Listiyaningsih E, Uyeki TM, et al. Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness. BMC Infect Dis 2010;10:3.  Back to cited text no. 6
[PUBMED]    
7.
Cooke KR, Hill GR, Gerbitz A, Kobzik L, Martin TR, Crawford JM, et al. Hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental idiopathic pneumonia syndrome: Potential role for a gut-lung axis of inflammation. J Immunol 2000;165:6612-9.  Back to cited text no. 7
[PUBMED]    
8.
Jones MP, Walker MM, Ford AC, Talley NJ. The overlap of atopy and functional gastrointestinal disorders among 23,471 patients in primary care. Aliment Pharmacol Ther 2014;40:382-91.  Back to cited text no. 8
[PUBMED]    
9.
Tobin MC, Moparty B, Farhadi A, DeMeo MT, Bansal PJ, Keshavarzian A, et al. Atopic irritable bowel syndrome: A novel subgroup of irritable bowel syndrome with allergic manifestations. Ann Allergy Asthma Immunol 2008;100:49-53.  Back to cited text no. 9
    
10.
Drossman DA, Thompson WG, Talley NJ, Funch-Jensen P, Janssens J, Whitehead WE. Identification of subgroups of functional bowel disorders. Gastroenterol Int 1990;3:159-72.  Back to cited text no. 10
    
11.
Thompson WG, Creed F, Drossman DA, Heaton KW, Mazzacca G. Functional bowel disorders and chronic functional abdominal pain. Gastroenterol Int 1992;5:75-91.  Back to cited text no. 11
    
12.
Marsland BJ, Salami O. Microbiome influences on allergy in mice and humans. Curr Opin Immunol 2015;36:94-100.  Back to cited text no. 12
[PUBMED]    
13.
Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM, Finlay BB, et al. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 2013;4:158-64.  Back to cited text no. 13
    
14.
Gollwitzer ES, Saglani S, Trompette A, Yadava K, Sherburn R, McCoy KD, et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med 2014;20:642-7.  Back to cited text no. 14
[PUBMED]    
15.
Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC, et al. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy 2014;44:842-50.  Back to cited text no. 15
    
16.
Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. Decreased gut microbiota diversity, delayed bacteroidetes colonisation and reduced th1 responses in infants delivered by caesarean section. Gut 2014;63:559-66.  Back to cited text no. 16
[PUBMED]    
17.
Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between caesarean section and childhood asthma. Clin Exp Allergy 2008;38:629-33.  Back to cited text no. 17
[PUBMED]    
18.
Bruzzese E, Callegari ML, Raia V, Viscovo S, Scotto R, Ferrari S, et al. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with lactobacillus GG: A randomised clinical trial. PLoS One 2014;9:e87796.  Back to cited text no. 18
[PUBMED]    
19.
Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014;20:159-66.  Back to cited text no. 19
[PUBMED]    
20.
Ekbom A, Brandt L, Granath F, Löfdahl CG, Egesten A. Increased risk of both ulcerative colitis and crohn's disease in a population suffering from COPD. Lung 2008;186:167-72.  Back to cited text no. 20
    
21.
Young RP, Hopkins RJ, Marsland B. The gut-liver-lung axis. Modulation of the innate immune response and its possible role in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2016;54:161-9.  Back to cited text no. 21
[PUBMED]    
22.
Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol 2012;5:7-18.  Back to cited text no. 22
[PUBMED]    
23.
Rutten EP, Lenaerts K, Buurman WA, Wouters EF. Disturbed intestinal integrity in patients with COPD: Effects of activities of daily living. Chest 2014;145:245-52.  Back to cited text no. 23
    
24.
Birrenbach T, Böcker U. Inflammatory bowel disease and smoking: A review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis 2004;10:848-59.  Back to cited text no. 24
    
25.
Somerville KW, Logan RF, Edmond M, Langman MJ. Smoking and crohn's disease. Br Med J (Clin Res Ed) 1984;289:954-6.  Back to cited text no. 25
[PUBMED]    
26.
Danese S, Fiocchi C. Etiopathogenesis of inflammatory bowel diseases. World J Gastroenterol 2006;12:4807-12.  Back to cited text no. 26
[PUBMED]    
27.
Cosnes J, Nion-Larmurier I, Afchain P, Beaugerie L, Gendre JP. Gender differences in the response of colitis to smoking. Clin Gastroenterol Hepatol 2004;2:41-8.  Back to cited text no. 27
[PUBMED]    
28.
Cosnes J. Tobacco and IBD: Relevance in the understanding of disease mechanisms and clinical practice. Best Pract Res Clin Gastroenterol 2004;18:481-96.  Back to cited text no. 28
[PUBMED]    
29.
Shapiro SD. Proteinases in chronic obstructive pulmonary disease. Biochem Soc Trans 2002;30:98-102.  Back to cited text no. 29
[PUBMED]    
30.
Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med 2007;13:567-9.  Back to cited text no. 30
[PUBMED]    
31.
Lundström O, Manjer J, Ohlsson B. Smoking is associated with several functional gastrointestinal symptoms. Scand J Gastroenterol 2016;51:914-22.  Back to cited text no. 31
    
32.
Strober W, Kitani A, Fuss I, Asano N, Watanabe T. The molecular basis of NOD2 susceptibility mutations in crohn's disease. Mucosal Immunol 2008;1 Suppl 1:S5-9.  Back to cited text no. 32
[PUBMED]    
33.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. Aframeshift mutation in NOD2 associated with susceptibility to crohn's disease. Nature 2001;411:603-6.  Back to cited text no. 33
[PUBMED]    
34.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to crohn's disease. Nature 2001;411:599-603.  Back to cited text no. 34
    
35.
Kinose D, Ogawa E, Hirota T, Ito I, Kudo M, Haruna A, et al. ANOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population. Respirology 2012;17:164-71.  Back to cited text no. 35
[PUBMED]    
36.
Van Durme YM, Eijgelsheim M, Joos GF, Hofman A, Uitterlinden AG, Brusselle GG, et al. Hedgehog-interacting protein is a COPD susceptibility gene: The Rotterdam study. Eur Respir J 2010;36:89-95.  Back to cited text no. 36
[PUBMED]    
37.
Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. Agenome-wide association study of pulmonary function measures in the Framingham heart study. PLoS Genet 2009;5:e1000429.  Back to cited text no. 37
[PUBMED]    
38.
Madison BB, Braunstein K, Kuizon E, Portman K, Qiao XT, Gumucio DL, et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development 2005;132:279-89.  Back to cited text no. 38
    
39.
Shu W, Lu MM, Zhang Y, Tucker PW, Zhou D, Morrisey EE, et al. Foxp2 and foxp1 cooperatively regulate lung and esophagus development. Development 2007;134:1991-2000.  Back to cited text no. 39
    
40.
Ramalho-Santos M, Melton DA, McMahon AP. Hedgehog signals regulate multiple aspects of gastrointestinal development. Development 2000;127:2763-72.  Back to cited text no. 40
[PUBMED]    
41.
Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol 1987;7:265-76.  Back to cited text no. 41
[PUBMED]    
42.
Mestecky J, McGhee JR, Michalek SM, Arnold RR, Crago SS, Babb JL, et al. Concept of the local and common mucosal immune response. Adv Exp Med Biol 1978;107:185-92.  Back to cited text no. 42
    



 
 
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