Symposium on Infectious Diseases — February 2017
Tex Med. 2017;113(20:54-59.
By Sheenal Patel, MD, and Rebecca Gruchalla, MD
The hygiene hypothesis began as an attempt to explain the relatively rapid rise in atopic diseases. Strachan's early hypothesis regarding the role of family size and exposure to early childhood infections in the development of atopic diseases has clearly evolved to integrate the possible effects of hygiene, eradication of parasitic infections, immunizations, improvements in home heating and ventilation, dust mite exposure, breastfeeding duration, diet, parental smoking, pollution, and exposure to pets and farm animals. However, as most of our understanding at the current time still comes from observational and epidemiologic studies, further investigations are needed to help uncover which of these genetic and environmental factors are indeed the causes behind the increases in allergic rhinitis and asthma.
Since the industrial revolution with the rising prevalence of atopic diseases, including allergic rhinitis and asthma, many have sought to explain this trend and the differential increases seen in various parts of the world. Although there has been no conclusive evidence identifying any specific causes, numerous epidemiologic studies have attempted to offer explanations.
In 1989, Strachan proposed an explanation that has since been famously referred to as the "hygiene hypothesis." He stated, in summary: "These observations ... could be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally … Over the past century, declining family size, improved household amenities, and higher standards of personal cleanliness have reduced opportunities for cross-infection in young families. This may have resulted in more widespread clinical expression of atopic disease."1 We will review the evolving body of evidence attempting to explain the rise in allergic diseases and theories behind the hygiene hypothesis.
The earliest descriptions of seasonal allergies can be traced back to the 1500s.2 In 1819, John Bostock, MD, wrote of his own illness and described seasonal symptoms of watery eyes, sneezing, and rhinorrhea. Over the next nine years, he discovered similar symptoms affecting a group of 27 patients.3,4 In 1873, Charles Blackley was the first to say that pollen grains were the cause of the above symptoms. He also observed agricultural laborers were more likely to be exposed to pollen but seemed to have fewer cases, and hay fever (allergic rhinitis) also appeared to be more common in the educated compared with the illiterate. Interestingly, he predicted that "as civilization and education advance, the disorder will become more common than it is at the present time."5
In the 20th century, the prevalence of allergic rhinitis rose dramatically. In England and Wales, the prevalence of allergic rhinitis was 5 percent in the 1950s but had risen to 20 percent in the 1980s.6 Asthma also became more prevalent, with the earliest reports documenting this increase beginning in the 1960s.7,8 However, it is important to note that this rise in allergic rhinitis appeared to affect certain parts of the world more than others, including rising prevalence in affluent populations, industrialized countries, and in urban areas compared with rural areas.9,10
Based on observations of differential rates in the rise of atopic disease around the world, investigators have sought to seek explanations by examining genetic and environmental factors that have included effects of hygiene, family size, early life infections, eradication of parasitic infections, immunizations, improvements in home heating and ventilation, dust mite exposure, breastfeeding duration, diet, parental smoking, pollution, and exposure to pets and farm animals.11
Immunologic Aspects of the Hygiene Hypothesis
One possible theory about the immunologic basis of the hygiene hypothesis is that both genetic factors and environmental factors may influence immune system development in a way that increases the risk of atopic disease. Different exposures may lead to the production or absence of cytokines that may influence the development of T-helper cells into a phenotype consistent with tolerance versus a phenotype consistent with atopic disease, including allergic rhinitis and asthma. (See Figure 1.) T-helper lymphocytes develop from a precursor, Th0 cells, and further differentiate into two subtypes, Th1 and Th2 lymphocytes. Th1 responses are thought to be protective against a wide variety of microbes. Th2 responses are important in activation, differentiation, and survival of eosinophils. Also, they are important in promoting antibody production by B cells (including IgE) and in growth of mast cells and basophils, which are cells involved in the allergic response.12
The hygiene hypothesis suggests that, in the absence of childhood infections or other environmental factors that would lead to decreased production of cytokines that favor Th1 development, a predominance of Th2 cells may develop, leading to atopic disease.
Family Size and Early Childhood Infections
Strachan's observations published in 1989 with respect to family size became the initial basis for his explanation of the rise in atopic diseases, later known as "the hygiene hypothesis." He studied a British birth cohort and found an inverse correlation between rates of allergic rhinitis and the number of children within the household.13 Strachan et al. in 1997 also showed factors related to smaller families (reduced number of older siblings) and higher socioeconomic status in childhood were associated with higher rates of atopic sensitization to a variety of aeroallergens in adulthood. This suggested the earlier observations of higher prevalence of allergic rhinitis in smaller, more affluent families were not just an artifact of symptom recognition, parental recall, or diagnostic labelling but indicated the underlying epidemiology of atopy.14 Other studies of West German schoolchildren and Finnish adolescents also showed inverse associations between numbers of siblings and atopic sensitization and incidence of allergic rhinitis, respectively.15,16
The predominant theory to explain these findings was that the presence of older siblings was a marker of exposure to more early childhood infections that thereby influenced immune system development. If this were the case, attendance at day care should have a similar effect. Ball et al. evaluated a birth cohort as part of the Tucson Children's Respiratory Study and showed an association between the presence of one or more older siblings at home or day care during the first six months of life with lower relative risks of atopic disease and asthma. They proposed a possible mechanism of a shifting of the Th2 phenotype to Th1 phenotype in the presence of early infections.17
More recently, Lynch et al. examined a birth cohort at high risk for developing asthma in multiple U.S. cities and determined the extent of early allergen and microbial exposure. They showed that exposure to certain allergens from cockroaches, mice, and cats and specific bacteria in house dust in the first year of life was inversely associated with recurrent wheezing at age 3 years.18 However, other studies have shown conflicting results with respect to the influence of early bacterial exposure (in the form of colonization). Bisgaard et al. evaluated children of asthmatic mothers in Denmark who were part of a prospective birth cohort. They found neonates colonized with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, or with a combination of these organisms at 1 month of age were associated with persistent wheeze, acute severe exacerbations of wheeze, and hospitalization for wheeze. Blood eosinophil counts, total IgE at 4 years of age, and the prevalence of asthma and the reversibility of airway resistance after beta2-agonist administration at 5 years of age were significantly increased in the children colonized neonatally with these organisms as compared with the children without such colonization.19
Additional studies also have suggested there are genetic factors such as maternal history of asthma that influence the relationship between day care attendance and risk of wheezing. Celedon et al. showed that in children without maternal history of asthma, day care attendance within the first year of life was associated with a decreased risk of asthma and recurrent wheezing at age 6 years and was associated with a decreased risk of any wheezing after the age of 4 years. However, in children with a maternal history of asthma who attended day care in the first year of life, the opposite was actually seen; there was an increased risk of wheezing in the first six years of life.20
Further studies continue to examine the effects of various infections on atopic disease development, but overall the role of infection and development of atopic disease remains somewhat controversial.
A history of tuberculosis infection has been associated with decreased rates of asthma and atopic disease. Von Mutius et al. evaluated data from the International Study of Asthma and Allergies in Childhood (that examined prevalence of symptoms of asthma, rhinitis, and eczema in children aged 13–14 years) in combination with tuberculosis notifications rates from the World Health Organization. They showed tuberculosis notification rates were significantly inversely associated with the lifetime prevalence of wheeze, asthma, and symptoms of allergic rhinoconjunctivitis.21 Matricardi et al. also showed in multiple studies hepatitis A seropositivity was inversely associated with atopic disease.22-24
On the other hand, studies with respect to history of measles infection have been conflicting. In a study of young adults from a semirural district of Guinea-Bissau in Africa, Shaheen et al. showed 12.8 percent who had had measles infection were atopic compared with 25.6 percent of those who had been vaccinated and not had measles (adjusted odds ratio=0.36).25 Measles infection also was associated with a large reduction in the risk of skin-prick test positivity to house dust mites. However, Paunio et al. showed the opposite in a cross-sectional study of Finnish residents aged 14 months to 19 years. They showed that history of measles infection was positively associated with eczema, allergic rhinitis, and asthma.26
Parasitic infections also have been associated with decreased rates of asthma. Infections with parasites, particularly intestinal helminths, result in a similar immunologic response as is seen in atopic diseases involving IgE production, Th2 cells, and eosinophilia. In fact, it is believed that humans evolved an immediate hypersensitivity in response to the parasitic environment to which they were exposed. In the absence of parasites, an IgE response to common aeroallergens develops by default.27
Epidemiologic studies have generally shown an inverse relationship between parasitic infections and asthma prevalence. For example, in rural areas of Africa where parasitic infections are common, asthma is exceedingly rare. However, no causal relationships can be implied as many other differences are also at play, including diet, animal exposure, other infections, antibiotic use, etc.27 Specific studies of parasitic infections, such as one examining urinary schistosomiasis in Gabonese schoolchildren, showed lower prevalence of a positive skin reaction to house dust mites compared with those free of this infection. In a subset of children who underwent further study, infected children were shown to have significantly higher Schistosoma-antigen-specific concentrations of interleukin-10, and higher specific concentrations of this anti-inflammatory cytokine were negatively associated with skin test reactivity to dust mites. The authors therefore suggested Schistosoma-induced IL-10 appears central to suppressing atopy in African children.28
Recent attention has focused on a potential role of gut microflora and links to atopic disease, as well. Some have hypothesized that specific microbes in the commensal gut microflora may play a more important role than sporadic infections in preventing atopic disease or in altering immune system development. Studies comparing children from Sweden and Estonia have shown differences in intestinal microflora with a high prevalence of allergies in Sweden and a low prevalence in Estonia. Counts of aerobic bacteria were 10- to 1,000-fold higher in stool samples in Estonian than in Swedish newborn babies during the first week of life.29 Lactobacilli were more commonly found in Estonian children at 1 month30 and 1 year.31
Kalliomaki et al. provided further support by performing a double-blind, randomized, placebo-controlled trial that involved giving Lactobacillus GG (a probiotic culture of healthy gut microflora) prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for six months to their infants at high risk for atopy.32 The frequency of atopic eczema at age 4 years in the probiotic group was half that of the placebo group; however, no difference in allergic sensitization was shown. This study suggests gut microflora might be a potential source of natural immunomodulators and probiotics may play a role in the prevention of atopic disease.
Studies examining associations between vaccines and atopic diseases also have been conflicting. A study of Japanese schoolchildren given the BCG (tuberculosis) vaccine after birth and at ages 6 years and 12 years showed a strong inverse association between delayed hypersensitivity to Mycobacterium tuberculosis and atopy.33 Positive tuberculin responses predicted a lower incidence of asthma, lower serum IgE levels, and cytokine profiles biased toward a Th1 type. A study on measles vaccination did not show any significant effect on atopy development.34
A retrospective telephone survey performed after the completion of a randomized trial examining the efficacy of various acellular pertussis vaccines revealed no differences in reported wheeze, itching, or sneezing at age 2 years among the groups.35 While another study showed pertussis vaccination increased the risk of diagnosed asthma, the study also involved a retrospective phone interview only, and confirmatory prospective data have not been provided to support this finding.36 Overall, no convincing evidence exists that childhood vaccinations have any impact on atopic disease development.
Pet and Farm Exposure
With respect to pet exposure, many studies have shown inverse associations between early cat and dog exposure and atopic sensitization and/or asthma. These associations have held up in prospective studies, eliminating the possibility of recall bias. Moreover, they have held up when adjustments have been made for parental atopy, as it was thought those families with allergy would be less likely to have pets.37-43 Proposed mechanisms have included the possibility that pet exposure may lead to increased exposure to infectious agents such as Toxoplasma and Bartonella, which may skew to Th1 development, increased endotoxin exposure, and the induction of an altered Th2 response, i.e., the production of IgG antibodies without development of an allergic response or asthma.44-49
With fewer people now living on farms, it has been of interest to examine farm exposure and its association with decreased atopic disease prevalence in many North American countries, Europe, and Australia.50-52 A German study of 5- to 7-year-old children showed that within the same villages, those children raised on a farm versus those not raised on a farm had lower rates of allergic rhinitis.50 Even in larger scale studies that adjusted for potential confounding variables including pet exposure, parental history of allergy, number of siblings, and severe respiratory infections in childhood, living on a farm in childhood was associated with a reduced risk of atopic sensitization as an adult.53 No protective effect was seen on asthma or wheezing.
Another study found that clinical disease indeed may be modified by farm exposures and that timing is important. Reidler et al. found children younger than 1 year who were exposed to stables and those who consumed farm milk demonstrated less asthma, hay fever, and atopic sensitization than children ages 1 to 5 years who were similarly exposed.54 In contrast to some earlier studies that didn't show a protective effect of farm exposure on asthma, Ege et al. showed that children raised on farms had lower asthma and atopy prevalence and that they were exposed to a greater variety of environmental microorganisms than the children in the reference group.55
The reasons that farm exposures may protect against atopy remain unclear, but it is thought that exposure to livestock and to materials found in high amounts in stables (molds, ammonia, feces, animal proteins, constituents of feed, and endotoxin) may render individuals less susceptible to the development of Th2 responses. Moreover, the exposure to raw milk, which contains more gram-negative bacteria and lipopolysaccharide than pasteurized milk, may lead to alterations in the commensal gut flora that are not favorable to the development of Th2 responses.54,56 Endotoxin has been found in higher levels in house dust and mattresses of children raised in farm families,56 and some reports suggest higher levels of endotoxin exposure may downregulate Th2 immune responses.57
A big undue consequence of the push for industrialization has been air pollution, which has been implicated as a cause of increasing asthma rates, but the literature also is somewhat controversial. If pollution was a significant driver, one would expect to see higher asthma rates in large cities with air pollution compared with other less-polluted areas. However, as Platts-Mills points out, asthma also has increased in areas were pollution is not a problem, such as coastal towns in New Zealand, or in other areas where pollution has decreased, such as London.7
In Katowice, Poland, where pollution is a significant problem, likely from coal smoke, higher asthma rates were not demonstrated.7,58 However, studies have shown associations particularly with diesel exhaust particles and atopic sensitization. Diesel exhaust particles have been thought to act as adjuvants to the immune system,59 and some studies have shown specific synergistic effects between diesel exhaust particles and ragweed pollen with increases in IgE and mRNA for Th2 cytokines.60 These studies suggest an environmental factor such as diesel exhaust particles may cause genetically susceptible individuals to become sensitized to allergens that ordinarily would not affect them.61
Although many have sought to offer explanations for the relatively rapid rise in atopic diseases, it is clear that complex interactions between genetic factors and multiple environmental factors are likely contributing to this trend. Strachan's early hypothesis regarding the role of family size and exposure to early childhood infections in the development of atopic diseases has clearly evolved to integrate the possible effects of hygiene, eradication of parasitic infections, immunizations, improvements in home heating and ventilation, dust mite exposure, breastfeeding duration, diet, parental smoking, pollution, and exposure to pets and farm animals. However, as most of our current understanding still comes from observational and epidemiologic studies, further prospective investigations will be needed to help uncover which of these genetic and environmental factors are indeed the causes behind the increase in allergic disease. Once this information is known, preventive strategies hopefully can be developed.
Sheenal V. Patel, MD, is a second-year allergy and immunology fellow at The University of Texas Southwestern Medical Center at Dallas.
Rebecca S. Gruchalla, MD, is a professor of internal medicine and pediatrics and director of the Division of Allergy and Immunology at UT-Southwestern.
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- Bostock J. A case of a periodical affection of the eyes and chest. Medico-Chirurgical Trans. 1819;10:161–162.
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- Lynch SV, Wood RA, Boushey H. et.al. Effects of early-life exposure to allergens and bacteria on recurrent wheeze and atopy in urban children. J Allergy Clin Immunol. 2014;134(3):593–601.e12.
- Bisgaard H, Hermansen MN, Buchvald F, et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med. 2007;357(15):1487–1495.
- Celedon JC, Wright RJ, Litonjua AA, et al. Day care attendance in early life, maternal history of asthma, and asthma at the age of 6 years. Am J Respir Crit Care Med. 2003;167(9):1239–1243.
- von Mutius E, Pearce N, Beasley R, et al. International patterns of tuberculosis and the prevalence of symptoms of asthma, rhinitis, and eczema. Thorax. 2000;55(6):449–453.
- Matricardi PM, Rosmini F, Ferrigno L, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ. 1997;314(7086):999–1003.
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- Matricardi PM, Rosmini F, Panetta V, et al. Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol. 2002;110(3):381–387.
- Shaheen SO, Aaby P, Hall AJ, et al. Measles and atopy in Guinea-Bissau. Lancet. 1996;347(9018):1792–1796.
- Paunio M, Heinonen OP, Virtanen M, Leinikki P, Patja A, Peltola H. Measles history and atopic diseases: a population-based cross-sectional study. JAMA. 2000;283(3):343–346.
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