Friday, April 27, 2012

BMJ: The Protective Effect of Childhood Infections.



BMJ. 2001 February 17; 322(7283): 376–377.
PMCID: PMC1119618
The protective effect of childhood infections
The next challenge is to mimic safely this protection against allergy and asthma
Sebastian L Johnston, professor of respiratory medicine
Peter J M Openshaw, professor of experimental medicine
Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 IPG
Although infectious diseases are by no means defeated, the past 100 years have seen a dramatic decline in some previously common childhood infections. Many serious viral and bacterial infections can now be prevented or treated by vaccination or antibiotics. In contrast, the prevalence of asthma and atopic disease has increased, particularly during the past 30 years. This increase is certainly not accounted for by a change in genetic risk factors: genetically similar populations in East and West Germany had very different rates of asthma before unification (although former east Germany is now catching up with the west1). In a landmark study of hayfever, hygiene, and household size in 1989 Strachan proposed that improved hygiene was the factor that explained this rise.2
The immunological arguments that underlie this “hygiene” hypothesis can be summarised as follows. Many common viral infections induce a strong protective host response dominated by the production of interferon γ (IFNγ). This type 1 response is more effective at eliminating viruses than the alternative type 2 response (characterised by the production of interleukin 4 and interleukin 5), which promotes IgE production, eosinophilia, atopy, and asthma. Children are born with strong type 2 responses but mature their type 1 responses in the first year or so of life under environmental influence, mainly that of common childhood infections. Children born to atopic parents are slower to do this than those born to non-atopic parents.3
Thus, having many older siblings; attending day care at an early age4; growing up on a farm and in frequent contact with cattle, poultry, and cats; and having childhood measles5 and orofaecal infections such as hepatitis A6 are all helpful (directly or by association) in promoting normal immunological maturation and in preventing atopic disease. By contrast, living in a small family group in hygienic conditions and taking antibiotics in early life7 may promote the development of asthma and atopy.
In this issue of the BMJ, Illi et al show that episodes of uncomplicated common colds (runny nose) during infancy may also protect against episodes of wheezing in later childhood (p 390).8 Other childhood infections such as herpetic stomatitis, exanthema subitum, and chickenpox also seemed protective. By contrast, episodes of wheezy lower respiratory tract infection were strongly associated with subsequent episodes of wheezing by the age of 7 (odds ratio >6). In other words, children with frequent simple infantile colds are less likely to develop wheezing by the age of 7, while children with wheezy lower respiratory illnesses in the first year are more likely to wheeze later on.
The authors acknowledge the difficulty of showing cause and effect in observational studies of this type. Importantly, no attempt was made to confirm the clinical diagnosis of viral colds by laboratory studies, and the authors were unable to determine whether rhinovirus, coronavirus, or respiratory syncytial virus had different effects. However, the important conclusion is that the risk of a diagnosis of asthma by the age of 7 is reduced by about 50% percent in children with two or more reported episodes of common cold (without associated wheeze) by the age of 1 year.
The challenge before us is to find ways of reproducing the protective effects of early childhood infections, while at the same time reducing the burden of serious (and less serious but still troublesome) infectious diseases. With increasing numbers of effective vaccines, antiviral treatments, and antibiotics and with increasing affluence, how can we prevent the continued rise in asthma and atopic disease? Perhaps different common cold viruses have different effects. Since there is evidence that respiratory syncytial virus bronchiolitis is a risk factor for later asthma,9 preventing it by vaccination or passive immunotherapy10 might reduce the frequency of childhood wheezing in later life, while Illi et al's study suggests that preventing colds might have the opposite effect. Knowing exactly which “dirt” provides the best education for the immune system and how to mimic its effects in a cleaner environment seems to be the key to reversing the rise in atopic diseases.
Notes
Papers p 390
References
1. von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U. Increasing prevalence of hay fever and atopy among children in Leipzig, East Germany. Lancet. 1998;351:862–866. [PubMed]
2. Strachan DP. Hay fever, hygiene and household size. BMJ. 1989;299:1259–1260. [PMC free article][PubMed]
3. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999;353:196–200. [PubMed]
4. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, Wright AL. Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med. 2000;343:538–543. [PubMed]
5. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Hayes CB, Shiell AW, et al. Measles and atopy in Guinea-Bissau. Lancet. 1996;347:1792–1796. [PubMed]
6. Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L, Raicetta M, et al. Exposure to foodbourne and orofecal microbes versus airbourne viruses in relation to atopy and allergic asthma: epidemiological study. BMJ. 2000;320:412–417. [PMC free article] [PubMed]
7. Hopkin JM. Early life receipt of antibiotics and atopic disorder. Clin Exp Allergy. 1999;29:733–734.[PubMed]
8. Illi S, von Mutius E, Lau S, Bergmann R, Niggeman B, Sommerfeld C, et al. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ.2001;322:390–395. [PMC free article] [PubMed]
9. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B. Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med.2000;161:1501–1507. [PubMed]
10. Wenzel SE, Gibbs R, Lehr M, Park N, Simoes EAF. Asthma related clinical and physiologic outcomes in high risk children 5-9 years after prophylaxis with RSV Ig IV. Am J Respir Crit Care Med.2000;161:A898.

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