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The relationship between early fever and allergic sensitization at age 6 to 7 years

  • L.Keoki Williams
    Correspondence
    Reprint requests: L. Keoki Williams, MD, MPH, Center for Health Services Research, 1 Ford Place, 3A, Detroit, MI 48202
    Affiliations
    Division of General Medicine, Department of Internal Medicine, Detroit, Mich, USA

    Center for Health Services Research, Detroit, Mich, USA

    Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Mich, USA
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  • Edward L. Peterson
    Affiliations
    Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Mich, USA

    National Institute of Environmental Health Sciences Center in Molecular and Cellular Toxicology with Human Applications, Wayne State University, Detroit, Mich, USA
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  • Dennis R. Ownby
    Affiliations
    Section of Allergy and Immunology, Department of Pediatrics, Medical College of Georgia, Augusta, Ga, USA
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  • Christine C. Johnson
    Affiliations
    Center for Health Services Research, Detroit, Mich, USA

    Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Mich, USA

    National Institute of Environmental Health Sciences Center in Molecular and Cellular Toxicology with Human Applications, Wayne State University, Detroit, Mich, USA
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      Abstract

      Background

      The hygiene hypothesis suggests that early infections might protect against later allergic sensitization.

      Objective

      The purpose of this study was to determine whether fevers before age 1 year were associated with allergic sensitization at age 6 to 7 years.

      Methods

      Eight hundred thirty-five children from suburban Detroit, Michigan, were enrolled at birth. Clinic records from their first year were abstracted for episodes of fever, antibiotic use, and respiratory infections. Fever was defined as a rectal temperature of 38.3°C (101°F) or greater or its equivalent measured at another site. At age 6 to 7 years, 441 children underwent allergy testing. The primary outcome measures were atopy (≥1 positive skin prick test result), seroatopy (≥1 positive allergen-specific IgE level), and allergic sensitization (either seroatopy or atopy).

      Results

      By age 1 year, 207 (46.9%) of the 441 participants had a documented fever. Among children with 0, 1, or 2 or more fevers in the first year, 33.3%, 31.3%, and 26.0% demonstrated atopy at age 6 to 7 years, respectively (P = .504); 43.4%, 39.7%, and 25.0% had seroatopy, respectively (P = .032); and 50.0%, 46.7%, and 31.3% had allergic sensitization, respectively (P = .028). After adjusting for potential confounders, each febrile episode in the first year was associated with reduced odds for allergic sensitization (adjusted odds ratio, 0.69; 95% CI, 0.47-1.00). Febrile upper respiratory tract infections, in particular, were associated with lower odds of allergic sensitization (adjusted odds ratio, 0.55; 95% CI, 0.31-0.97) per episode.

      Conclusion

      This study provides direct support for the hygiene hypothesis because children with fevers before age 1 year were less likely to demonstrate allergic sensitivity at age 6 to 7 years.

      Keywords

      Abbreviations:

      aOR (Adjusted odds ratio), FEF25%-75% (Forced expiratory flow at 25%-75% of forced vital capacity), LRI (Lower respiratory tract infection), URI (Upper respiratory tract infection)
      The prevalence of asthma and other allergic disorders appears to be increasing worldwide.
      • Beasley R
      • Crane J
      • Lai CK
      • Pearce N
      Prevalence and etiology of asthma.
      For example, the prevalence rate of self-reported asthma in the United States increased 75.2% between 1980 and 1994.
      • Mannino DM
      • Homa DM
      • Pertowski CA
      • Ashizawa A
      • Nixon LL
      • Johnson CA
      • et al.
      Surveillance for asthma—United States, 1960-1995.
      The rapidity of the increase suggests that the underlying cause is a changing exposure rather than changing genetics. In 1989, Strachan
      • Strachan DP
      Hay fever, hygiene, and household size.
      demonstrated that children from large families were at lower risk for hay fever and eczema. He speculated that these findings could be explained if infections in early childhood, in this case passed on from “unhygienic” siblings, prevented the subsequent development of allergic disease. This theory, known as the hygiene hypothesis, has been proffered as an explanation for the increasing prevalence of allergic disorders in that diminished exposure to early childhood infections has resulted in a population predisposed to allergies. Studies examining the association between allergic sensitization and specific illnesses, such as respiratory infections, measles, and hepatitis A, have produced conflicting results, with some studies showing a protective relationship
      • Martinez FD
      • Stern DA
      • Wright AL
      • Taussig LM
      • Halonen M
      Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels.
      • Shaheen SO
      • Aaby P
      • Hall AJ
      • Barker DJ
      • Heyes CB
      • Shiell AW
      • et al.
      Measles and atopy in Guinea-Bissau.
      • Matricardi PM
      • Rosmini F
      • Ferrigno L
      • Nisini R
      • Rapicetta M
      • Chionne P
      • et al.
      Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus.
      and others not.
      • Cogswell JJ
      • Halliday DF
      • Alexander JR
      Respiratory infections in the first year of life in children at risk of developing atopy.
      • Forastiere F
      • Agabiti N
      • Corbo GM
      • Dell'Orco V
      • Porta D
      • Pistelli R
      • et al.
      Socioeconomic status, number of siblings, and respiratory infections in early life as determinants of atopy in children.
      • Svanes C
      • Jarvis D
      • Chinn S
      • Burney P
      Childhood environment and adult atopy: results from the European Community Respiratory Health Survey.
      • Bodner C
      • Anderson WJ
      • Reid TS
      • Godden DJ
      Childhood exposure to infection and risk of adult onset wheeze and atopy.
      Two recent cross-sectional studies found that having frequent febrile illnesses before age 1 year was associated with a lower odds of allergic sensitization later in life, suggesting that the effect of early infections might depend on both their frequency and their capacity to elicit a systemic response.
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.
      • Calvani Jr, M
      • Alessandri C
      • Bonci E
      Fever episodes in early life and the development of atopy in children with asthma.
      These studies relied on parental recall over many years rather than documented temperatures to ascertain fever. Studying a well-defined birth cohort of children followed for the development of allergies, we explored whether fevers in the first year of life were associated with a reduced risk for allergic sensitization.

      Methods

       Setting and participants

      The data are derived from the Childhood Allergy Study, which has been previously described.
      • Ownby DR
      • Johnson CC
      • Peterson EL
      Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.
      All pregnant women belonging to a Detroit area health maintenance organization and residing in a contiguous geographic suburban region were eligible to enroll their children at birth between April 15, 1987, and August 31, 1989. Informed consent was obtained, and the study was approved by the institutional human rights committee at Henry Ford Health System. During the prenatal interview, participating mothers were asked to provide information about prior pregnancies, parental education, allergic history, and smoking habits. Children born preterm (<36 weeks' gestational age) or those without valid cord serum IgE measurements were dropped from the study. After delivery, parents were contacted at least annually by telephone (years 1, 3, 4, and 6) or home visit (years 2 and 4). They were surveyed regarding the child's exposure to household pets, cigarette smoke, siblings, daycare, and breast-feeding.

       Exposure data

      For each child in the study, all available paper and electronic medical records of clinical encounters (ie, clinic visits, emergency department visits, and hospitalizations) were abstracted for the first year of life. Information was collected about respiratory illnesses (ie, those involving the ears, nose, throat, eyes, and lungs), febrile episodes, and conditions requiring antibiotics. Clinical encounters within 3 days of each other were considered part of the same event. 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.
      • Brown RD
      • Kearns G
      • Eichler VF
      • Wilson JT
      A probability nomogram to predict rectal temperature in children.
      When body temperature was measured at another site, the rectal temperature equivalent was estimated by using the following formulas: Math Eq; and rectal temperature = axillary temperature + 1.24°C.
      • Brown RD
      • Kearns G
      • Eichler VF
      • Wilson JT
      A probability nomogram to predict rectal temperature in children.
      Infections were categorized according to the site of involvement: ears (otitis media and eustachian catarrh); upper respiratory tract infection (URI; adenoiditis, herpangina, laryngitis, nasopharyngitis, rhinitis, sinusitis, and tonsillitis); and lower respiratory tract infection (LRI; bronchitis, bronchiolitis, croup, pneumonia, pneumonitis, influenza, and respiratory syncytial virus). We excluded from the analysis children without a complete clinical record for their first year; this included those with missing records, missing temperature measurements, or less than a year of follow-up within the health system.

       Outcome data

      At age 6 to 7 years, the children were invited to have a clinical evaluation by an allergist (DRO), including a medical history and physical examination, skin prick and serologic tests for sensitivity to common aeroallergens, pulmonary function tests, and airway challenges with methacholine. 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: Pharmaceutical Division, Bayer Inc, Spokane, Wash). Measurements of the resulting wheal and flare were taken 15 minutes after the skin test was performed. A skin prick test result 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 allergen-specific IgE 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 or more were considered positive (1 IU/mL corresponds to 2.4 ng/mL) per the manufacturer's recommendation.
      A child was considered to be asthmatic if the parent reported that the diagnosis had ever been made by a physician. At the time of the clinical evaluation, parents were also asked whether their children had a history of wheezing: “Has your child ever had wheezing or whistling in the chest?”
      Pulmonary function testing and airway challenge with methacholine were performed as previously described.
      • Ownby DR
      • Peterson EL
      • Johnson CC
      Factors related to methacholine airway responsiveness in children.
      Briefly, after baseline spirometry and no response to a control saline challenge, 5 doses of methacholine (0.025-25 mg/mL) were administered through a dosimeter (Pulmonary Data Services, Louisville, Colo). Methacholine airway responsiveness was defined as a decrease in the FEV1 value of 20% or more from the postsaline challenge value at a concentration of administered methacholine of 10 mg/mL or less.

       Statistical analysis

      The primary outcomes of this study were atopy, seroatopy, and allergic sensitization at age 6 to 7 years. Atopy was defined as having a positive skin prick test reaction to any one of the allergens tested, seroatopy was defined as having a positive result on allergen-specific IgE testing to any one allergen, and 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. Secondary outcomes at age 6 to 7 years included both atopic and nonatopic asthma, atopic and nonatopic wheeze, results of individual antigen-specific IgE and skin prick tests, total serum IgE levels, pulmonary function test results (ie, the percentage of predicted value for FEV1, forced vital capacity, and forced expiratory flow at 25%-75% of forced vital capacity [FEF25%-75%]), and methacholine airway responsiveness. Atopic asthma required both a physician diagnosis of asthma and at least one positive skin prick test reaction, whereas persons with nonatopic asthma had a diagnosis of asthma but a negative skin prick test reaction. Similarly, we considered children to have atopic wheezing if, regardless of asthma status, they had both a history of wheezing and at least one positive skin prick test reaction. Children with nonatopic wheezing were those with a history of wheezing but a negative skin prick test reaction.
      The χ2 test was used to compare the variables for differences between subjects included in the analysis and those excluded. The variable number of separate episodes of fever in the first year of life was evaluated for its relationship to outcome measures by using χ2 tests to evaluate a general relationship, a Cochran-Armitage test for trend to evaluate the data for monotonic linear relationships, linear logistic regression to evaluate the odds ratio, and multiple variable logistic regression to estimate an adjusted odds ratio (aOR). The covariates included in this latter model included the child's sex, the mother's and father's history of allergy and asthma, parental education, cord blood IgE levels, exposure to daycare in the first year, history of being breast-fed, pet exposure in the first year, number of siblings, parental smoking, and oral antibiotic use by class (ie, penicillin, macrolides, sulfa drugs, and cephalosporins). A Spearman correlation approach was used to compare the number of febrile episodes with the continuous variables for spirometry (FEV1, forced vital capacity, and FEF25%-75%) and total serum IgE levels. Linear logistic regression was used to evaluate the effect of site of infection stratified by the presence or absence of fever. The comparison group for this analysis was children who in their first year had neither an infection at the location of interest nor a fever.

      Results

      Of 1194 eligible pregnant women, 953 consented to enroll their children, and 835 children with cord blood IgE measurement were enrolled. Clinical records were missing for 27 children, 24 had missing temperature readings, and 71 did not have a complete year of follow-up (presumably because of change of insurance, clinician, or residence). Of the 713 remaining children, 441 (62%) participated in the clinical evaluation at age 6 to 7 years, 171 children were unavailable, and 101 did not undergo the examination. The baseline characteristics of children examined at age 6 to 7 years were not significantly different from those not followed up for all evaluated variables (Table I).
      TABLE IBaseline characteristics of children who completed the clinical evaluation at 6 to 7 years of age compared with those who did not
      VariableParticipants (n = 441)Nonparticipants (n = 272)P value
      Female sex221/441 (50.1%)142/272 (52.2%).59
      No. of older siblings.78
      0171/383 (44.7%)112/247 (45.3%)
      1141/383 (36.8%)85/247 (38.4%)
      ≥271/383 (18.5%)50/247 (20.2%)
      No. of dogs or cats exposed to in first year.11
      0204/433 (47.1%)113/232 (48.7%)
      1162/433 (37.4%)71/232 (30.6%)
      ≥267/433 (15.5%)48/232 (20.7%)
      Enrolled in daycare in first year176/401 (43.9%)96/230 (41.7%).62
      Breast-fed258/402 (64.2%)154/231 (66.7%).55
      One or both parents with education beyond high school347/441 (78.7%)209/272 (76.8%).58
      One or both parents smoke132/439 (30.1%)83/271 (30.6%).93
      Maternal allergy127/441 (28.8%)74/272 (27.2%).67
      Maternal asthma37/440 (8.4%)19/272 (7.0%).57
      Paternal allergy107/388 (27.6%)68/251 (27.1%).93
      Paternal asthma24/422 (5.7%)23/259 (8.9%).12
      Diagnosis in first year
      Fever207/441 (46.9%)129/272 (47.4%).94
      Ear infection305/441 (69.2%)191/272 (70.2%).80
      With fever117/392 (29.9%)70/237 (29.5%).99
      Without fever264/421 (62.7%)170/260 (65.4%).51
      URI358/441 (81.2%)225/272 (82.7%).62
      With fever115/371 (31.0%)70/226 (31.0%).99
      Without fever307/421 (72.9%)193/260 (74.2%).72
      LRI128/441 (29.0%)72/272 (26.5%).49
      With fever28/414 (6.8%)12/256 (4.7%).32
      Without fever93/421 (22.1%)58/260 (22.3%).99
      Fever was common in the first year of life, affecting 207 (46.9%) of the 441 participants (Table I). By age 1 year, there were 321 episodes of fever among these 441 children (average of 0.73 episodes per child; SD, 1.00; range, 0-6). Of these febrile episodes, 269 (83.3%) were associated with an infection of the ears, upper respiratory tract, or lower respiratory tract; 9 (2.8%) were associated with an infection at another site; and 43 (13.4%) did not have an associated site.
      At 6 to 7 years of age, 31.5% children had atopy, 39.2% had seroatopy, and 45.8% had allergic sensitization (ie, either atopy or seroatopy; Table II). Seroatopy, allergic sensitization, atopic asthma, and atopic wheeze were significantly less common among children who had fevers in their first year. Atopy showed a similar pattern but did not reach statistical significance.
      TABLE IIOutcomes at age 6 to 7 years stratified by the number of febrile episodes in the first year
      No. with outcome
      Febrile episodes in first year
      OutcomeTotal
      Denominators represent the number of children for whom data are available.
      01≥2Overall P valueTrend P value
      Atopy136/432 (31.5%)76/228 (33.3%)41/131 (31.3%)19/73 (26.0%).504.260
      Seroatopy150/383 (39.2%)88/203 (43.4%)46/116 (39.7%)16/64 (25.0%).032.015
      Allergic sensitization180/393 (45.8%)103/206 (50.0%)56/120 (46.7%)21/67 (31.3%).028.014
      Methacholine airway responsiveness99/424 (23.4%)56/220 (25.5%)28/131 (21.4%)15/73 (20.6%).563.310
      Asthma48/435 (11.0%)27/229 (11.8%)12/133 (9.0%)9/73 (12.3%).668.873
      Atopic asthma23/410 (5.6%)17/219 (7.8%)5/126 (4.0%)1/65 (1.5%).101.033
      Nonatopic asthma24/411 (5.8%)10/212 (4.7%)6/127 (4.7%)8/72 (11.1%).110.087
      Wheeze160/435 (36.8%)92/229 (40.2%)44/133 (33.1%)24/73 (32.9%).302.160
      Atopic wheeze49/324 (15.1%)36/173 (20.8%)8/97 (8.3%)5/54 (9.3%).009.007
      Nonatopic wheeze109/384 (28.4%)56/193 (29.0%)34/123 (27.6%)19/68 (27.9%).962.821
      Denominators represent the number of children for whom data are available.
      After adjusting for potential confounders, each febrile episode in the first year was associated with reduced odds for allergic sensitization (aOR, 0.69; 95% CI, 0.47-1.00) at age 6 to 7 years (Table III). Individually, the adjusted odds of atopy and seroatopy were lower per episode of fever but were of borderline statistical significance at 0.77 (95% CI, 0.55-1.09) and 0.69 (95% CI, 0.47-1.02), respectively. Fevers in the first year were also significantly associated with a lower odds for atopic asthma (aOR, 0.21; 95% CI, 0.05-0.86) and atopic wheeze (aOR, 0.47; 95% CI, 0.24-0.91) but not for nonatopic asthma (aOR, 0.72; 95% CI, 0.39-1.34) or nonatopic wheeze (aOR, 0.78; 95% CI, 0.53-1.13). Fevers in the first year were not significantly correlated with FEV1, FEF25%-75%, or total serum IgE levels at age 6 to 7 years (data not shown).
      TABLE IIIUnadjusted and adjusted relationship between having had fever in the first year of life and markers of allergy or airway hyperresponsiveness at age 6 to 7 years
      Per febrile episode
      Outcome variableOR (95% CI)P valueaOR (95% CI)
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the first year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      P value
      Atopy0.88 (0.71-1.09).2500.77 (0.55-1.09).143
      Seroatopy0.72 (0.57-0.92).0080.69 (0.47-1.02).063
      Allergic sensitization0.76 (0.61-0.94).0120.69 (0.47-1.00).048
      Methacholine airway responsiveness0.85 (0.67-1.09).2000.91 (0.64-1.31).624
      Asthma0.92 (0.67-1.27).6110.63 (0.38-1.05).078
      Atopic asthma
      Control group is children without asthma or atopy.
      0.48 (0.23-0.98).0440.21 (0.05-0.86).031
      Nonatopic asthma
      Control group is children without asthma or atopy.
      1.24 (0.87-1.76).2320.72 (0.39-1.34).303
      Wheeze0.90 (0.73-1.10).2860.69 (0.49-0.97).032
      Atopic wheeze
      Control group is children without wheeze or atopy.
      0.62 (0.41-0.95).0270.47 (0.24-0.91).024
      Nonatopic wheeze
      Control group is children without wheeze or atopy.
      1.00 (0.80-1.24).9730.78 (0.53-1.13).184
      Specific IgE
      Cat0.79 (0.54-1.16).2370.56 (0.24-1.34).194
      Dog0.48 (0.24-0.94).0320.70 (0.23-2.20).547
      Ragweed0.72 (0.50-1.02).0660.72 (0.38-1.36).316
      Bluegrass0.56 (0.36-0.85).0060.43 (0.21-0.91).027
      Alternaria species0.54 (0.36-0.83).0040.29 (0.13-0.64).002
      Der f0.86 (0.63-1.17).3270.75 (0.45-1.24).258
      Der p0.76 (0.53-1.10).1400.72 (0.42-1.24).234
      Positive skin prick test result
      Cat0.96 (0.72-1.28).7800.81 (0.51-1.31).399
      Dog0.65 (0.38-1.14).1310.65 (0.31-1.38).263
      Ragweed0.79 (0.58-1.08).1340.54 (0.28-1.02).059
      Bluegrass0.65 (0.43-0.98).0380.35 (0.13-0.89).028
      Der f0.81 (0.61-1.08).1570.83 (0.55-1.26).373
      Der p0.88 (0.68-1.15).3480.88 (0.59-1.31).536
      OR, Odds ratio; Der f, antigen from the dust mite Dermatophagoides farinae; Der p, antigen from the dust mite Dermatophagoides pteronyssinus.
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the first year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      Control group is children without asthma or atopy.
      Control group is children without wheeze or atopy.
      Only febrile URIs were significantly associated with a lower odds of allergic sensitization (aOR, 0.55; 95% CI, 0.31-0.97) per episode (Table IV), but this also happened to be the most common site of febrile infections in the first year (Table I). Nonfebrile infections of the ears, upper respiratory tract, and lower respiratory tract were not significantly associated with atopy, seroatopy, or allergic sensitization (data not shown).
      TABLE IVRelationship between the site of febrile infection in the first year and seroatopy, atopy, and allergic sensitization at age 6 to 7 years
      Comparison group is children who in their first year had neither an infection at that location nor a fever; odds ratios represent the effect per episode.
      SeroatopyAtopyAllergic sensitization
      LocationOR (95% CI)aOR (95% CI)
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the 1st year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      OR (95% CI)aOR (95% CI)
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the 1st year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      OR (95% CI)aOR (95% CI)
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the 1st year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      Ears0.76 (0.54-1.06)0.97 (0.60-1.57)0.92 (0.67-1.26)0.93 (0.59-1.49)0.84 (0.62-1.13)0.99 (0.62-1.58)
      URI0.66 (0.45-0.97)
      P = .032.
      0.66 (0.37-1.17)0.91 (0.65-1.28)0.78 (0.45-1.35)0.69 (0.49-0.97)
      P = .031.
      0.55 (0.31-0.97)
      P = .038.
      LRI1.31 (0.62-2.76)1.25 (0.33-4.68)1.51 (0.73-3.09)1.79 (0.51-6.25)1.54 (0.74-3.19)1.86 (0.50-7.02)
      OR, Odds ratio.
      Comparison group is children who in their first year had neither an infection at that location nor a fever; odds ratios represent the effect per episode.
      Adjusted for sex, parental history of asthma and allergies, parental education, level of cord blood IgE, exposure to daycare in the 1st year, history of being breast-fed, pet exposure in the first year, birth order, parental smoking, and oral antibiotic use in the first year by class (ie, penicillins, macrolides, sulfa drugs, and cephalosporins).
      P = .032.
      § P = .031.
      P = .038.
      Because some fevers might have resolved by the time of the medical visit, we repeated the analysis, including cases of fever that were reported as part of a current illness but with the temperature taken at the visit not being measurably abnormal. This addition strengthened the protective association between fever and atopy (aOR, 0.76; 95% CI, 0.54-1.06), seroatopy (aOR, 0.68; 95% CI, 0.46-0.99), and allergic sensitization (aOR, 0.66; 95% CI, 0.46-0.95). Also, because some fevers might have been the result of immunization rather than infection, we repeated the analysis, excluding fevers occurring within a week of vaccination. This did not change the significance of any relationship. Using other established cutoffs for fever, such as a rectal temperature of 38.0°C (100.4°F) and an axillary temperature of 37.2°C (99.0°F),
      • El-Radhi SA
      • Carroll JE
      Fever and Hyperthermia.
      resulted in similar statistically significant associations. Too few oral or ear temperatures were taken to make these a potential source of error.

      Discussion

      Epidemiologic studies have consistently demonstrated that children with siblings, particularly an older sibling, are less likely to have atopy
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      Sibship size, birth order, and atopy in 11,371 Italian young men.
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      Childhood antecedents of allergic sensitization in young British adults.
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      In addition, early exposure to daycare appears to lower the risk of allergic sensitization,
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      • Martinez FD
      • Wright AL
      Siblings, day-care attendance, and the risk of asthma and wheezing during childhood.
      whereas belonging to a higher socioeconomic stratum
      • Strachan DP
      • Harkins LS
      • Johnston ID
      • Anderson HR
      Childhood antecedents of allergic sensitization in young British adults.
      and being breast-fed
      • Sears MR
      • Greene JM
      • Willan AR
      • Taylor DR
      • Flannery EM
      • Cowan JO
      • et al.
      Long-term relation between breastfeeding and development of atopy and asthma in children and young adults: a longitudinal study.
      are associated with an increased risk. Although these studies indirectly suggest that infections influence the development of allergies, by Strachan's own admission, “Studies which have more directly addressed infection as the explanatory factor have been disappointing and often difficult to interpret.”
      • Strachan DP
      Family size, infection and atopy: the first decade of the “hygiene hypothesis.”.
      This study shows that fever before age 1 year is inversely associated with the risk of allergic sensitization by age 6 to 7 years and that the effect is dose dependent. Therefore these findings support a hygiene hypothesis whereby exposure to infections early in life decreases the risk of becoming allergic. This study also extends the findings of 2 prior cross-sectional studies
      • von Mutius E
      • Illi S
      • Hirsch T
      • Leupold W
      • Keil U
      • Weiland SK
      Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children.
      • Calvani Jr, M
      • Alessandri C
      • Bonci E
      Fever episodes in early life and the development of atopy in children with asthma.
      to show that the protective effect of fever can be seen in a general population of children followed from birth.
      We also found that febrile URIs, in particular, were associated with significantly lower odds of allergic sensitization at age 6 to 7 years. This agrees with recent results from a German birth cohort study that found that children with 2 or more episodes of runny nose in their first year were less likely to demonstrate seroatopy at ages 1 and 3 years and were less likely to wheeze or be given a diagnosis of asthma at age 7 years when compared with children with fewer episodes.
      • 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.
      However, this latter study did not stratify for fever. We found no association between nonfebrile URIs and allergic sensitization.
      Early infections might influence TH cell differentiation and therefore shape the manner in which these cells respond to allergens.
      • Martinez FD
      Role of viral infections in the inception of asthma and allergies during childhood: could they be protective?.
      • Martinez FD
      • Holt PG
      Role of microbial burden in aetiology of allergy and asthma.
      TH cells that become TH1-type memory cells elaborate cytokines, such as IFN-γ, which promote the innate immune response to infections.
      • Romagnani S
      Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response?.
      TH2-type memory cells produce cytokines that stimulate the production of the allergic mediators, IgE and eosinophils.
      • Romagnani S
      Induction of TH1 and TH2 responses: a key role for the ‘natural’ immune response?.
      At birth, the response of TH cells to stimulation is skewed toward the production of TH2-type cytokines.
      • Prescott SL
      • Macaubas C
      • Holt BJ
      • Smallacombe TB
      • Loh R
      • Sly PD
      • et al.
      Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile.
      This pattern continues in atopic individuals, whereas nonatopic individuals show a marked increase in their capacity to produce IFN-γ in their first year.
      • Prescott SL
      • Macaubas C
      • Smallacombe T
      • Holt BJ
      • Sly PD
      • Holt PG
      Development of allergen-specific T-cell memory in atopic and normal children.
      A role for infections in influencing this early T-cell differentiation was suggested by Martinez et al,
      • Martinez FD
      • Stern DA
      • Wright AL
      • Taussig LM
      • Halonen M
      Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels.
      who found that peripheral blood mononuclear cells from children with nonwheezing LRIs before age 3 years produced higher levels of IFN-γ at age 9 months when compared with PBMCs from children without early LRIs.
      Infections are the most common cause of fever in young children.
      • El-Radhi SA
      • Carroll JE
      Fever and Hyperthermia.
      The precise mechanisms controlling fever are incompletely understood, but the initiating event is considered to be the stimulation of leukocytes by microbes and their products.
      • Netea MG
      • Kullberg BJ
      • Van der Meer JW
      Circulating cytokines as mediators of fever.
      This stimulation results in large increases in circulating cytokines, such as IL-1, IL-6, IL-10, TNF-α, and IFN-γ.
      • Wright SD
      • Ramos RA
      • Tobias PS
      • Ulevitch RJ
      • Mathison JC
      CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein.
      • Krabbe KS
      • Bruunsgaard H
      • Hansen CM
      • Moller K
      • Fonsmark L
      • Qvist J
      • et al.
      Ageing is associated with a prolonged fever response in human endotoxemia.
      • Shtrichman R
      • Samuel CE
      The role of gamma interferon in antimicrobial immunity.
      IL-1, IL-6, TNF-α, and IFNs are known pyrogens,
      • Netea MG
      • Kullberg BJ
      • Van der Meer JW
      Circulating cytokines as mediators of fever.
      whereas IL-10 might act as an antipyretic.
      • Pajkrt D
      • Camoglio L
      • Tiel-van Buul MC
      • de Bruin K
      • Cutler DL
      • Affrime MB
      • et al.
      Attenuation of proinflammatory response by recombinant human IL-10 in human endotoxemia: effect of timing of recombinant human IL-10 administration.
      Some of these cytokines are also thought to be important in modulating immune responses to allergens, either increasing or decreasing the probability of an allergen-specific IgE response.
      • Johnson CC
      • Ownby DR
      • Zoratti EM
      • Alford SH
      • Williams LK
      • Joseph CL
      Environmental epidemiology of pediatric asthma and allergy.
      The complexity of these cytokine changes makes it hazardous to speculate on a precise mechanism for the association between fever and allergic sensitization; however, the hypothesis proposed by Yazdanbakhsh et al might be helpful.
      • Yazdanbakhsh M
      • Kremsner PG
      • van Ree R
      Allergy, parasites, and the hygiene hypothesis.
      This hypothesis suggests that repeated stimulation of the immune system results in a regulatory network of dendritic cells and T cells that downregulate allergic responses through the production of TGF-β and IL-10. Therefore if fevers indicate periods of intense immune stimulation, each episode would be expected to reduce the likelihood of development of allergic sensitization.
      This study had certain limitations. First, only 441 (53%) of the original study participants were evaluated at age 6 to 7 years. However, baseline characteristics were not different between those children with and without follow-up. Second, our reliance on documented fevers might have resulted in an underestimation of febrile episodes in the first year. However, when we included cases of fever mentioned in history of present illness but not documented at the clinic visit, the associations remained. We also realize that standardizing temperatures taken at different body sites might have resulted in misclassifying some cases of fever. Yet we expect that if a true relationship exists between fever and allergy, this misclassification would have resulted in an underestimation of the association.
      In summary, this study directly supports an association between early febrile episodes and the later risk of allergic sensitization. More information is needed about the types of infections that protect against allergies and the pathways by which they mediate their effect. Hopefully, this will lead to strategies to prevent the development of allergies.

      Acknowledgements

      We acknowledge the work of all the staff who made this study possible and would like to extend especial thanks to Drs Manel Pladevall and Edward Zoratti for their thoughtful review of the manuscript.

      References

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