Timing and intensity of early fevers and the development of allergies and asthma

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1 Timing and intensity of early fevers and the development of allergies and asthma L. Keoki Williams, MD, MPH, a,b,c Edward L. Peterson, PhD, b Manel Pladevall, MD, MS, c Kaan Tunceli, PhD, c Dennis R. Ownby, MD, d and Christine C. Johnson, PhD, MPH b,c Detroit, Mich, and Augusta, Ga Background: Early childhood fevers appear to protect against later allergies and asthma. What is not known is the time in which fevers exert this effect and whether the degree of temperature increase is important. Objective: We sought to examine the relationship between the time and degree of early fevers and later allergies and asthma. Methods: Eight hundred thirty-five children from southeast Michigan were enrolled at birth. Clinic records from their first 2 years were abstracted for episodes of fever. At age 6 to 7 years, children underwent allergy testing. We examined fevers occurring within 6-month intervals in the first 2 years of life and outcomes at age 6 to 7 years. The primary outcome measures were allergic sensitization, asthma, asthma with allergic sensitization, and asthma without allergic sensitization. Results: In the unadjusted analysis each episode of fever between 7 and 12 months of age was associated with a lower odds of allergic sensitization (odds ratio [OR], 0.71; 95% CI, ) and asthma with allergic sensitization (OR, 0.43; 95% CI, ) at age 6 to 7 years. Likewise, every 1 C increase in the maximum temperature between 7 and 12 months was associated with a lower odds of allergic sensitization (OR, 0.77; 95% CI, ) and asthma with allergic sensitization (OR, 0.62; 95% CI, ). After adjusting for potential confounders, each episode of fever between 7 and 12 months was associated with a lower likelihood of asthma with allergic sensitization (adjusted OR, 0.33; 95% CI, ) at age 6 to 7 years. Conclusions: Both the timing and intensity of childhood fevers appear to be important factors in the development of allergies and asthma. (J Allergy Clin Immunol 2005;116: ) Key words: Hygiene hypothesis, fever, asthma, atopy, allergic sensitization Abbreviations used aor: Adjusted odds ratio LRI: Lower respiratory tract infection OR: Odds ratio The hygiene hypothesis posits that early infectious exposures protect against the development of atopy and other allergic conditions, such as asthma. This hypothesis finds support in a number of epidemiologic studies that demonstrate such a protective relationship. 1-4 However, because these studies differ dramatically in their assessment and measurement of infectious exposure, it is not possible to infer the critical early window period in which infections exert their effects. Recently, we reported data from a prospective birth cohort study showing that febrile episodes in the first year of life appeared protective against allergic sensitization and atopic asthma at age 6 to 7 years. 5 Others have likewise found a protective relationship between the number of febrile episodes in the first year of life and later atopy. 6,7 To determine whether the effect of early febrile infections differs by age of occurrence, we now examine the relationship between fevers at various times in the first 2 years of life and both allergy and asthma outcomes at age 6 to 7 years. We also look at the relationship between the degree of early fever, as measured on the basis of the maximum recorded temperature, and later allergy and asthma outcomes. From a the Department of Internal Medicine, b the Department of Biostatistics and Research Epidemiology, and c the Center for Health Services Research, Henry Ford Health System, Detroit, and d the Section of Allergy and Immunology, Department of Pediatrics, Medical College of Georgia, Augusta. Supported in part from grants from the Fund for Henry Ford Hospital, the National Institute of Allergy and Infectious Diseases (R01AI61774, R01AI50681, R21AI059415), and the National Heart, Lung, and Blood Institute (R01HL068971). Disclosure of potential conflict of interest: Dr Ownby received funding from the National Institute of Allergy and Infectious Diseases for this study. All other authors none disclosed. Received for publication December 31, 2004; revised March 16, 2005; accepted for publication April 18, Reprint requests: L. Keoki Williams, MD, MPH, Henry Ford Health System, 1 Ford Place, 3A CHSR, Detroit, MI kwillia5@hfhs.org /$30.00 Ó 2005 American Academy of Allergy, Asthma and Immunology doi: /j.jaci METHODS Setting and participants The Childhood Allergy Study has been well described elsewhere. 8 Briefly, all pregnant women due between April 15, 1987, and August 31, 1989, who belonged to a Detroit-area health maintenance organization and who resided in a contiguous geographic suburban region were eligible to enroll their children at birth. Informed consent was obtained, and the study was approved by the Institutional Human Rights Committee at Henry Ford Health System. Children born preterm (<36 weeks gestational age) or those without valid cord serum IgE measurements were excluded. After delivery, parents were contacted at least annually by telephone (years 1, 3, 5, and 6) or home visit (years 2 and 4) regarding their child s environmental exposures. At age 6 to 7 years, participating children had a clinical evaluation by a board-certified allergist, during which time both asthma and allergy status were assessed.

2 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Williams et al 103 Exposure data For each child in the study, all available medical records from the first 2 years of life were abstracted for information regarding respiratory infections (ie, involving the ears, upper respiratory tract, and lower respiratory tract), febrile episodes, and conditions requiring treatment with antibiotics. The trained abstractors who abstracted the medical records used a standardized data collection protocol and were unaware of the study hypothesis. Clinical encounters within 3 days of each other were considered part of the same event to avoid overcounting illnesses. A child was considered to have a fever when the rectal temperature (or its equivalent) measured at the visit equaled or exceeded 38.3 C. 9 When body temperature was measured at another site, the rectal temperature equivalent was estimated by using the following formulas: Rectal temperature ¼ Ear temperature 10 ; Rectal temperature ¼ Oral temperature 1 0:73 C; and Rectal temperature ¼ Axillary temperature 1 1:24 C. 9 Outcome data At age 6 to 7 years, children underwent a clinical evaluation by a board-certified allergist (DRO) who was unaware of the early fever status of each child. A child was considered to be asthmatic if the parent reported that the diagnosis had ever been made by a physician or if the child had symptoms consistent with asthma in the past 12 months, as assessed by the allergist. There were 4 previously undiagnosed children who were classified as having asthma at the 6- to 7-year evaluation. Skin prick testing was performed on the volar aspect of the child s arm by using commercial antigen extracts of dog, cat, short ragweed (Ambrosia artemissiifolia), bluegrass (Poa pratensis), and 2 dust mite species (Dermatophagoides farinae and Dermatophagoides pteronyssinus), along with saline and histamine controls (all extracts and controls were obtained from Bayer Inc, which is currently Hollister-Stier Laboratories, Spokane, Wash). Measurements of the resulting wheal and flare were taken 15 minutes after the skin test was performed. A skin prick test response was considered positive when the product of perpendicular wheal diameters was 4 mm greater than that elicited by the negative control and the associated flare was at least 10 mm. A commercial assay (AlaSTAT; Diagnostic Product Corp, Los Angeles, Calif) was used to measure serum allergen-specific IgE levels against dog, cat, short ragweed, bluegrass, Alternaria species, and both dust mite species from blood samples taken from each child. Allergen-specific IgE levels of 0.35 IU/mL (1 IU/mL corresponds to 2.4 ng/ml) or more were considered positive per the manufacturer s recommendation. Statistical analysis Our primary outcomes in this study were allergic sensitization, asthma with allergic sensitization, and asthma without allergic sensitization. Allergic sensitization was defined as having either a positive skin prick test reaction or a positive allergen-specific IgE test result to any one of the allergens tested. Asthma required a physician diagnosis. So as to avoid attribution, we do not use the terms atopic asthma and nonatopic asthma; rather, we use the terms asthma with allergic sensitization (ie, a physician s diagnosis of asthma and either a positive skin prick test reaction or a positive allergen-specific IgE test result) and asthma without allergic sensitization (ie, a physician s diagnosis of asthma and neither a positive skin prick test reaction nor a positive allergen-specific IgE test result). The x 2 test was used to compare demographic differences between children with varying lengths of clinical follow-up for the first 2 years of life. A generalized estimating equation approach was used to test for a difference in the proportion of subjects having 1 or more episodes of fever in each of the 4 time periods (ie, 0-6, 7-12, 13-18, and months). We used linear logistic regression to assess the relationship between the number of fevers in a particular time period and our primary outcomes. Univariate models were fit with the number of fevers for a given time period. Multivariate models included the following additional covariates: sex, birth order, parental education, home pet exposure, parental history of asthma or allergies, concentration of IgE in cord blood, parental smoking status, history of being breast-fed, history of day-care exposure, and antibiotic use (ie, 4 separate categories for the use of penicillins, macrolides, sulfa drugs, or cephalosporins) within the time period of interest. Linear logistic regression was also used to examine the univariate relationship between the maximum temperature in a given time period and our primary outcomes. To evaluate for potential nonlinear relationships between the logit function for outcomes and the continuous variable for temperature, we used the SAS routine PROC LOESS to plot a local, nonparametric, smoothed function of the logit versus temperature. All statistical analyses were performed with SAS v9.1 (SAS Institute Inc, Cary, NC). 11 An a level of.05 was considered statistically significant. RESULTS Of 1194 eligible pregnant women, 953 consented to enroll their child, and 835 children with cord blood IgE measurement were enrolled. Of the 835 enrolled children, some clinic information on early fevers was available for 784 children. Complete clinical information was available for 754 children for the time period of 0 to 6 months, 713 children for 0 to 12 months, 700 children for 0 to 18 months, and 656 children for 0 to 24 months. Of children with complete clinical information for 0 to 6 months, 0 to 12 months, 0 to 18 months, and 0 to 24 months, 447 (59.3%), 441 (60.4%), 431 (61.6%), and 416 (63.4%) participated in the clinical evaluation at age 6 to 7 years, respectively. As we have previously shown, baseline characteristics, such as the number of early fevers, were not significantly different between children who were examined at age 6 to 7 years and those who were not. 5 Table I shows the demographic characteristics of children with both clinical information for the first 2 years and follow-up assessment at age 6 to 7 years. Although the number of children with complete clinical information was smaller at each subsequent 6-month time window, the remaining group did not appear biased with regard to any of the demographic factors examined or the prevalence of later clinical outcomes. Differences in the number of fevers at each 6-month time window could not be explained by loss to follow-up. Fevers were least common in the first 6 months of life: 13.9% of children had a fever between months 0 and 6, 41.3% between months 7 and 12, 36.4% between months 13 and 18, and 26.7% between months 12 and 24 (P =.001). During the first 2 years of life, we identified a total of 647 separate febrile episodes: 540 (83.5%) were associated with the clinical diagnosis of an infection of the ears, upper respiratory tract, or lower respiratory tract; 21 (3.2%) were associated with an infection elsewhere; and 86 (13.3%) did not have a localizing site of infection. In the unadjusted analysis each episode of fever between 7 and 12 months of age was significantly associated with a lower odds of allergic sensitization (odds ratio [OR], 0.71; 95% CI, ) and the combination

3 104 Williams et al J ALLERGY CLIN IMMUNOL JULY 2005 TABLE I. Characteristics of children followed for the development of asthma and atopy, with data stratified by whether clinical information was available during the first 2 years of life Clinical information available for the time period of: 0-6 mo of age (n = 447) 7-12 mo of age (n = 441) mo of age (n = 431) mo of age (n = 416) Female sex (%) 221/447 (49.4) 219/441 (49.7) 216/431 (50.1) 209/416 (50.2) No. of older siblings (%) 0 174/390 (44.6) 171/386 (44.3) 170/378 (45.0) 164/367 (44.7) 1 143/390 (36.7) 143/386 (37.1) 139/378 (36.8) 134/367 (36.5) 2 73/390 (18.7) 72/386 (18.7) 69/378 (18.3) 69/367 (18.8) Parental education high school (%) 350/447 (78.3) 345/441 (78.2) 339/431 (78.7) 327/416 (78.6) Parental history of allergy (%) 208/412 (50.5) 203/406 (50.0) 200/396 (50.5) 193/384 (50.3) Parental history of asthma (%) 62/428 (14.5) 62/422 (14.7) 62/412 (15.1) 60/398 (15.1) Parental history of smoking (%) 131/445 (29.4) 131/439 (29.8) 129/429 (30.1) 125/414 (30.2) Child exposed to day care (%) 180/404 (44.6) 177/400 (44.3) 172/392 (43.9) 165/377 (43.8) No. of pets in the home (%) 0 207/437 (47.4) 205/432 (47.6) 202/423 (47.8) 194/408 (47.6) 1 162/437 (37.1) 159/432 (36.8) 154/423 (36.4) 147/408 (36.0) 2 68/437 (15.6) 68/432 (15.7) 67/423 (15.8) 67/408 (16.4) Cord blood IgE levels (IU/mL), mean 6 SD No. with 1 temperature measurement 292/447 (65.3) 366/441 (83.0) 305/431 (70.8) 295/416 (70.9) in time period Range of temperatures recorded in time period ( C) No. with 1 fever in time period* 62/447 (13.9) 182/441 (41.3) 157/431 (36.4) 111/416 (26.7) Outcomes at age 6 to 7 years Allergic sensitization 185/404 (45.8) 181/398 (45.5) 176/387 (45.5) 167/373 (44.8) Asthma 50/447 (11.2) 48/441 (10.9) 46/431 (10.7) 43/416 (10.3) Asthma with allergic sensitization 32/429 (7.5) 30/423 (7.1) 29/414 (7.0) 26/399 (6.5) Asthma without allergic sensitization 15/412 (3.6) 15/408 (3.7) 14/399 (3.5) 14/387 (3.6) *P =.001. of asthma and allergic sensitization (OR, 0.43; 95% CI, ) at age 6 to 7 years (Fig 1, A and C). Among children with 0, 1, or 2 or more fevers between the ages of 7 and 12 months, 49.8%, 43.3%, and 29.8% demonstrated allergic sensitization at age 6 to 7 years, respectively (P =.037, x 2 test; P =.012, test for trend), and 9.1%, 5.7%, and 0.0% had the combination of asthma and allergic sensitization, respectively (P =.059, x 2 test; P =.009, test for trend; data not shown). In contrast, each episode of fever between 0 and 6 months was associated with a greater odds of asthma without allergic sensitization (OR, 2.55; 95% CI, ; Fig 1, D), and each episode of fever between age 13 and 18 months was associated with a greater odds of allergic sensitization (OR, 1.39; 95% CI, ; Fig 1, A). After adjusting for multiple potential confounders, such as sex, birth order, parental education, pet exposure, parental history of asthma and allergies, level of cord blood IgE, parental smoking, history of being breast-fed, day-care exposure, and early antibiotic use, and stratifying by the age of fever occurrence, each episode of fever between the ages of 7 and 12 months was still associated with a lower odds of asthma with allergic sensitization (adjusted OR [aor], 0.33; 95% CI, ; Table II). In the adjusted analysis fevers between the ages of 13 and 18 months were also associated with lower odds of asthma (aor, 0.38; 95% CI, ) but higher odds of allergic sensitization (aor, 1.51; 95% CI, ) at age 6 to 7 years. In addition to the number of early childhood fevers, we examined whether the degree of fever early in life was related to allergy and asthma outcomes at age 6 to 7 years. These data were again stratified by the time of occurrence: 0 to 6, 7 to 12, 13 to 18, and 19 to 24 months of age. As can be seen in Fig 2, higher temperatures between the ages of 7 and 12 months appeared to protect against allergic sensitization and the combination of asthma and allergic sensitization at age 6 to 7 years. Every 1 C increase in the maximum temperature recorded (range, 35.5 C-40.9 C) between the ages of 7 and 12 months was associated with a lower odds of allergic sensitization (OR, 0.77; 95% CI, ) and the combination of asthma and allergic sensitization (OR, 0.62; 95% CI, ; Fig 2, A and C). Higher temperatures between the ages of 13 and 18 months also appeared protective against the development of asthma without allergic sensitization by age 6 to 7 years because every 1 C increase in the maximum temperature was associated with a lower likelihood of this outcome (OR, 0.48; 95% CI, ; Fig 2, D). We next used a localized regression technique to assess for nonlinear relationships between temperature and

4 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Williams et al 105 FIG 1. Unadjusted relationship between episodes of fever in the first 2 years of life and the occurrence of allergic sensitization (A), asthma (B), asthma with allergic sensitization (C), and asthma without allergic sensitization (D) at age 6 to 7 years stratified by the age at which fevers occurred. TABLE II. Odds of outcomes at age 6 to 7 years per episode of fever in each time frame* Outcome 0-6 mo, aor 7-12 mo, aor Time of fever mo, aor mo, aor Allergic Sensitization 0.89 ( ) 0.70 ( ) 1.51 ( ) 0.87 ( ) Asthma 0.68 ( ) 0.74 ( ) 0.38 ( ) 1.04 ( ) Asthma with 0.40 ( ) 0.33 ( ) 0.66 ( ) 1.04 ( ) allergic sensitization Asthma without allergic sensitization 1.87 ( ) 1.18 ( ) 0.21 ( ) 1.73 ( ) *Adjusted for sex, birth order, parental education, pet exposure, parental history of asthma and allergies, level of cord blood IgE, parental smoking status, history of being breast-fed, day-care exposure, and 4 classes (ie, penicillins, macrolides, sulfa drugs, and cephalosporins) of antibiotic use (count for each). P<.05. allergy and asthma outcomes. The relationship between the maximum temperature recorded at 7 to 12 months and these later outcomes are shown in Fig 3. As can be seen, increasing temperatures of less than 37.3 C did not appear to be associated with a dramatic decrease in the prevalence of allergic sensitization (Fig 3, A), asthma (Fig 3, B), or asthma with allergic sensitization (Fig 3, C) at age 6 to 7 years. However, past a threshold temperature that ranged between 37.3 C and 38 C, the prevalence of these outcomes did appear to decrease rapidly with increasing temperatures. The plot for allergic sensitization (Fig 3, A) also suggested that the protective association between increasing temperatures and this outcome might begin to plateau past 39 C. DISCUSSION Our findings here provide new evidence in support of the hygiene hypothesis that early infections might protect against the development of allergic sensitization or asthma. When Strachan 12 first described the protective association between increasing birth order and both hay fever and eczema, he reasoned that these findings could be

5 106 Williams et al J ALLERGY CLIN IMMUNOL JULY 2005 FIG 2. Unadjusted relationship between the maximum temperature recorded during 6-month intervals for the first 2 years of life and the occurrence of allergic sensitization (A), asthma (B), asthma with allergic sensitization (C), and asthma without allergic sensitization (D) at age 6 to 7 years. explained if allergic diseases were in some way prevented by infections contracted through exposure to older siblings. Some have argued, however, that the relationship between birth order and the development of allergies might have its origins in utero. Proponents of this theory suggest that increasing parity results in maternal immune tolerance, which in turn influences cord blood IgE levels and atopy in the child. 13,14 Although the effect of birth order on atopy might relate to a changing in utero environment, in this study we demonstrate that the protective relationship between early febrile infections and later asthma and allergic sensitization is independent of cord blood IgE levels and birth order, and it is temporally distinct from the perinatal period. Although a number of studies suggest that early childhood infections might protect against subsequent atopy or asthma, 1-7 the window in which infections can exert this effect on the developing immune system is unknown. We observed that in the first 2 years of life, febrile infections between 7 and 12 months of age were most strongly associated with a reduction in the likelihood of both allergic sensitization and asthma with allergic sensitization at age 6 to 7 years. Interestingly, our findings comport with those of Krämer et al, 15 who examined the relationship between the age of entry into day care, a proxy for infectious exposure, and asthma and allergic outcomes at age 5 to 14 years. Among children from small families (ie, 3 household members), day-care entry between 6 and 11 months of age was associated with a lower likelihood of skin prick test reactivity at age 5 to 14 years when compared with day-care entry at age 12 to 23 months (OR, 1.99; 95% CI, ) and 24 months or greater (OR, 2.03; 95% CI, ). They also demonstrated a statistically significant trend for asthma, hay fever, and positive RAST results, with children entering day care at age 6 to 11 months having the lowest rates. In addition to the frequency of febrile episodes, we now show that the degree of temperature increase also appears to be negatively associated with later allergy and asthma outcomes. These relationships again appeared to be time dependent because higher temperatures between 7 and 12 months of age appeared protective for both allergic sensitization and asthma with allergic sensitization at age 6 to 7 years, and higher temperatures between 13 and 18 months of age appeared to protect against asthma without allergic sensitization. Further examination also suggested that the relationship was nonlinear. For example, temperatures in the low to normal range at 7 to 12 months of age did not appear protective for later outcomes. In contrast, temperatures of greater than 38 C were consistently and inversely associated with the prevalence of allergic sensitization, asthma, and asthma with allergic sensitization at age 6 to 7 years. Although this further supports our contention that a protective association exists for fevers, it

6 J ALLERGY CLIN IMMUNOL VOLUME 116, NUMBER 1 Williams et al 107 FIG 3. Smoothed plots of the relationship between the maximum recorded temperature at 7 to 12 months of age and the prevalence of allergic sensitization (A), asthma (B), and asthma with allergic sensitization (C) at age 6 to 7 years. also suggests that either the severity of the underlying infection or the intensity of the immune response to it, as indicated by the degree of temperature increase, are related to future allergy and asthma risk. It is now well recognized that fevers result from the release of inflammatory cytokines, also known as endogenous pyrogens, from cells involved in our innate response to infections. 16 Therefore fever might be a marker for the intensity of innate immune system stimulation. Although the precise immunologic mechanism has yet to be worked out, there is now greater appreciation for the innate immune system s influence on the development of

7 108 Williams et al J ALLERGY CLIN IMMUNOL JULY 2005 adaptive immune responses, such as those involved in allergies and asthma. 17 Some suggest that the protective mechanism involves the early skewing of helper T-cell development toward the T H 1 phenotype. 18 At birth, the newborn immune system has a limited ability to produce T H 1 cytokines, 19,20 which appears to be due in part to the immaturity of antigen-presenting cells. 21,22 Our data suggest that febrile infections might influence the future development of allergies and asthma as early as the latter part of the first year of life. This finding agrees with those of Martinez et al, 23 who showed that PBMC IFN-g production was significantly higher at age 9 months, but not at birth, in children with 1 or more nonwheezing lower respiratory tract infections (LRIs) when compared with children with no LRIs. Children with 1 or more nonwheezing LRIs also had lower total serum IgE levels and were less likely to be atopic at age 6 years when compared with children with no LRIs. This study must be interpreted in light of its limitations. First, a number of children who where enrolled in this study at birth did not undergo allergy testing at age 6 to 7 years. However, as reported elsewhere, we have not found differences in baseline characteristics between the children of this cohort who had follow-up at age 6 to 7 years and those who did not. 5,8 Similarly, in this study we did not find the demographic characteristics of participating children to differ on the basis of the availability of clinical information in the first 2 years of life. Therefore we have not found evidence that our findings here were systematically biased by follow-up. Second, we cannot exclude the possibility of reverse causation bias in that children predisposed to atopy or asthma might be less likely to manifest a febrile response to infections. However, were this the case, we would have expected fevers to be consistently and negatively associated with either allergic sensitization or asthma outcomes at all time points. Instead, only febrile episodes occurring within specific time windows, such as 7 to 12 months of age, appeared protective. This suggests that the protective relationships that we observed were the result of the febrile infection and not reverse causation bias. Because our temperature data were based on measurements taken at the clinic visit, it is possible that some episodes of fever were missed. However, we would expect this type of misclassification to result in an underestimation of the effect of fever. Lastly, because microbial cultures were not obtained at the time of these febrile events, we could not associate outcomes with specific causative agents. In summary, this article suggests that both the timing and the intensity of fevers early in life are important factors in the development of later allergies and asthma. However, further study is needed to identify the causative agents that mediate this effect and the underlying immunologic mechanism. REFERENCES 1. Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol 2002;110: Illi S, von Mutius E, Lau S, Bergmann R, Niggemann 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: Bodner C, Anderson WJ, Reid TS, Godden DJ. Childhood exposure to infection and risk of adult onset wheeze and atopy. 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