Over the past 14 years, our group sought to identify an immunologic explanation for otitis proneness (OP) among young children.1 To avoid the pitfall of including children misdiagnosed as OP based on clinical grounds alone, we sought the gold standard of diagnosis by performing tympanocentesis on each case as it occurred in a prospectively enrolled cohort from a single practice in Rochester, NY. Using this approach we found that ≈10% of children experience frequent microbiologically confirmed acute otitis media (AOM) infections.1 We have focused on the child with recurrent AOM because AOM is the most common bacterial infectious disease to cause parents to seek medical care for their child and receive antibiotics.2 The identified anomalies in different immune compartments among young children prone to AOM3 would be expected to manifest in other ways. Indeed, we previously reported that many of the OP children studied had subprotective antibody levels to routine pediatric vaccines when measured after primary immunizations.4 We also reported that OP children not only exhibited 8.86-fold more AOM episodes per child but also had a 1.42 higher relative risk of viral upper respiratory infection (URI) occurring between age 6 and 36 months old compared with nonprone children.5
In light of the immune dysfunction displayed by OP children and their propensity for increased occurrence of viral URI, in the first 3 years of life, we sought to understand if OP children were more susceptible to other respiratory infections and to ascertain how long their infection susceptibility persisted. Specifically we asked if OP children are more prone to relatively prevalent respiratory infections such as pneumonia, sinusitis and influenza compared with non-OP (NOP) children, if they have a propensity to experience other bacterial and viral infections that persist to age 4 to 5 years and if OP and nonprone children with a high respiratory infection illness visit frequency from 6–18 months of age continue to experience higher rates of infection from 18–60 months of age compared with their peers.
MATERIALS AND METHODS
The study setting was a private pediatric practice of suburban Rochester, NY comprised of a typical mixed demographic of largely middle class, health care–insured families. Children were prospectively enrolled at their 6 months of age well child visit and followed to 60 months of age. The inclusion criteria were healthy, full-term birth children where parental consent for tympanocentesis for all AOM episodes was accepted; about 50% of parents approached for study enrollment agreed. Exclusion criteria were facial anatomical defects and immunocompromise potentially impacting AOM susceptibility and AOM before enrollment. Children experiencing 3 AOM episodes within a 6-month time span or 4 episodes within a 12-month time span, all confirmed by tympanocentesis within the time frame of child age 6 to 24 months old, were termed stringently defined OP (sOP).1,3–5 Children experiencing less than or equal to 2 AOMs within a year within the time frame of child age 6 to 24 months old were termed NOP.1,3–5 The study design included capturing every physician-diagnosed, medically attended infectious disease illness. Of the 857 children in the study from June 2006 to August 2017, 285 (33%) were included in this report because they were followed up to 5 years of age, whereas most children completed their participation at 36 months of age. Demographic and infection risk factor data collected included gender, race, siblings in the home, daycare attendance, breastfeeding, tobacco smoke exposure and atopy. The diagnosis of atopy was based on identification of food allergies, antibiotic allergy, atopic dermatitis and/or asthma by a board-certified allergist/immunologist. The Rochester General Hospital Institutional Review Board approved the study, and written informed consent was obtained from parents before enrollment in the study.
Definition of AOM
AOM was diagnosed by pneumatic otoscopy by validated otoscopists as previously described according to the American Academy of Pediatrics guidelines.6 All episodes of clinically diagnosed AOM were confirmed by culture of middle ear fluid collected by tympanocentesis up to 36 months of age. We have previously reported that tympanocentesis cultures collected from our study cohort yield Streptococcus pneumoniae, Haemophilus influenzae or Moraxella catarrhalis by culture or polymerase chain reaction in ≈90% of middle ear fluid samples.7,8 The children in this report were included in that prior publication.
Other Respiratory Infection Visit Definitions
Viral URIs were diagnosed clinically as previously described.9 We have previously reported that viral URI clinical diagnosis in our study cohort is confirmed by polymerase chain reaction in 66% of nasopharyngeal (NP) samples.5,10 The children in this report were included in that prior publication. Community acquired pneumonia was diagnosed based on the presence of fever >39 °C, increased respiratory rate for age, chest retractions and rales. Lobar pneumonia was clinically distinguished by clinical toxicity and chest examination by auscultation revealing lobar consolidation in the left or right lower lobes with possible involvement of the right middle lobe when right lower lobe involvement was evident. Clinically, 5 of 7 sOP and 1 of 8 NOP children with pneumonia, had lobar pneumonia.
Chest radiographs were not obtained, in keeping with the guideline of the Infectious Diseases Society of America.11 Acute bacterial rhinosinusitis was diagnosed consistent with the American Academy of Pediatrics guidelines.12 Influenza infection was diagnosed clinically and etiology by detection of the virus in NP swab. Other respiratory infections were clinically diagnosed: bronchiolitis, conjunctivitis, pharyngitis and tracheobronchitis. The diagnosis of pharyngitis was made if the pharynx was erythematous, with or without cervical adenopathy and not in the context of a clinical viral URI. If exudates were present, then a rapid streptococcal test was performed. No rapid tests were positive.
For concomitant illness, only the more clinically significant illness was counted, for example, if pneumonia and AOM occurred concomitantly, only pneumonia was counted. Comparisons of lobar pneumonia (despite pneumococcal conjugate vaccination), sinusitis and influenza (despite vaccination) frequency in the sOP versus NOP children were made using models with the log-transformed number of illness visits. The possibility of confounding by differences in risk factors for infection occurrence was assessed as dichotomous variables for covariates gender, race, smokers in the home, siblings <5 years old, atopy in the child, out-of-home daycare attendance and partial or exclusive breastfeeding to 6 months old. Each risk factor was added to the model, taken to be additive with respect to each year of age of the child. In each case, the significance of the contribution of covariable to the model was assessed by controlling for the remaining risk predictors using the Wald test. Comparisons of other respiratory illness visits were accomplished using the same modeling approach. Because illness status is unknown for some children and not all children are brought to medical attention when ill, we calculated the frequency of infections present when sOP and NOP children were brought for regularly scheduled well visits to identify whether medical care–seeking behavior could explain the observed results.
Two hundred eighty-five children were included in the study population. Designation as sOP and NOP occurred during child age 6 to 24 months with subsequent prospective follow-up to age 5 years. Thirty-nine children (13.7%) were classified as sOP, and 246 children (86.3%) were classified as NOP. AOM was less frequent after child age 24 months, as previously reported,7 and no child in the study cohort came to meet the definition of sOP after that age. Demographic and epidemiologic risk factors often associated with frequency of respiratory infections are shown in Table 1. Daycare attendance and male gender were enriched in sOP children compared with NOP children. The sOP cohort started day care early and stayed in day care, whereas the NOP cohort was a mixture of children who had early and late onset of day care attendance.
TABLE 1. -
||All Children (n = 39 sOP, 246 NOP)
|Smoking at home
Lobar Pneumonia, Sinusitis and Influenza
Taking into account the relative covariables that might influence the observations (see Methods), the frequency of physician-diagnosed, medically attended lobar pneumonia, sinusitis and influenza across the study time frame of child age 6 months to 5 years was significantly higher among sOP children. Specifically, the sOP child experienced lobar pneumonia 6-fold more frequently (P < 0.001, despite being up to date with pneumococcal conjugate vaccination), sinusitis 2.1-fold more frequently (P = 0.026) and influenza illness 2.9-fold more frequently (P = 0.002 despite having received seasonal influenza vaccine) than the NOP child (Fig. 1). Modeling of pneumonia, sinusitis and influenza illness over time is shown in the Figure, Supplemental Digital Content 1, https://links.lww.com/INF/E438. The model estimates the time trend and frequency of each infection type for sOP versus NOP child cohorts, demonstrating the highest frequency of the infections at the youngest age and significant differences between cohorts for pneumonia (P < 0.0001), sinusitis (P = 0.0033) and influenza (P < 0.0001), taking into account demographic and risk factors, as well as consideration of possible missed diagnoses and misdiagnoses.
Frequency of All Respiratory Infection Illness Visits
The total frequency of all physician-diagnosed, medically attended respiratory infection illness visits, after excluding AOM visits, in sOP and NOP children is shown in Fig. 2. In addition to viral URI, the respiratory infections that were included in this analysis were bronchiolitis, conjunctivitis, pharyngitis and tracheobronchitis. The frequency of all respiratory infections combined, excluding AOM, was significantly different between groups. Overall, sOP children had significantly more frequent respiratory illnesses at age 6–18 months (sOP median 6 vs. NOP median 2, or 3-fold). Similar comparisons at child age 18–30 months (sOP median 7 vs. NOP median 2, or 3.5-fold) and 30–42 months (sOP median 3 vs. NOP median 1, or 3-fold) identified the persistence of more frequent respiratory infection illness at those ages but not at 42–54 or 54–60 months of age (Fig. 2). Covariate-adjusted fold difference between sOP and NOP children at age 6–18 months, 18–30 months and 30–42 months was significant (Fig. 2). With some variation year to year, ≈80% of the respiratory illnesses in Fig. 2 were viral URIs. Seventy-eight percent were associated with fever, 15% with rash and all with symptoms severe enough that parents sought medical care. The frequency of physician-diagnosed, medically attended viral URI illness visits is shown in the Figure, Supplemental Digital Content 2, https://links.lww.com/INF/E438.
Infection Illness Visits by 18 Months of Age Associate With Future Illness Visits
We sought to determine if frequent infection illnesses in early life (age, 6–18 months) predicted whether the same child would have frequent infection illnesses later in life. To address this, illness visits from 6 to 18 months of age in individual children were compared with the total number of respiratory infection illness visits that occurred in the same children from 18 months to 5 years of age, excluding AOM. We found that frequent bacterial and viral infection illness during 6–18 months of age correlated with subsequent frequent infection illnesses up to age 4 to 5 for sOP children (Fig. 3A). We unexpectedly found that a subset of about 20% of NOP children experienced frequent viral but not bacterial respiratory infection illness during age 6–18 months that correlated with subsequent frequent viral respiratory infection illnesses up to age 4–5 years (Fig. 3B).
Analysis of Care-Seeking Behavior
The child who is ill more often tends to be brought for medical care more often. To address care-seeking behavior as a potential confounding factor in our cohort, we analyzed the frequency of infections that were occurring at regularly scheduled well child visits at 6, 9, 12, 15, 18, 24 and 36 months of age, reasoning that regularly scheduled well visits were not illness care–seeking visits. We found that sOP children significantly more often came to well child visits with respiratory infections compared with NOP children (P < 0.01; see Figure, Supplemental Digital Content 3, https://links.lww.com/INF/E438), suggesting care-seeking behavior alone did not account for the observed differences in infections between sOP and NOP children.
Here, for the first time, we show that children with recurrent AOM are not only prone to AOM but also more prone to pneumonia, sinusitis, influenza and other respiratory infections. These data, therefore, illustrate that infection susceptibility in sOP children extends beyond AOM to other bacterial and viral respiratory tract infections. Second, we show that the propensity for more frequent physician-diagnosed, medically attended respiratory tract infections among sOP compared with NOP children resolves by 4 to 5 years of age. Third, we show that both sOP and NOP children who experience frequent respiratory infections during age 6–18 months have a likelihood to continue that pattern to age 4–5 years. Fourth, unexpectedly, we identified a subset of NOP children who experience frequent viral respiratory infections but not bacterial AOM during age 6–18 months who have a likelihood to continue that pattern to age 4–5 years .
The results of this clinical infection study provide important support for an immunologic basis for OP. It would be expected that the deficiencies in innate and adaptive immune responses to respiratory bacterial and viral pathogens we have described among sOP children1 would not only lead to recurrent AOM1 and inadequate antibody responses to routine pediatric vaccinations4 but also to a general pattern of respiratory infection proneness compared with children who are not OP. Increased risk of exposure to infectious organisms could also contribute to differences; however, demographic and risk factors that contribute to infection exposure such as daycare attendance and siblings were insufficient to explain the observed differences.
The increased likelihood for more frequent medically attended respiratory infection illness visits among sOP children diminished over time such that the differences between sOP versus NOP children were no longer significant by age 4 to 5 years of life. It is likely that infection susceptibility in sOP children is from a delay in immune development1,3,4 that normalizes to a more canonical phenotype by the fourth to fifth year of life, discussed below. This suggests there is a specific age span where children are highly susceptible to AOM and other respiratory conditions where preventative interventions should be focused. Further studies are required to better understand how various risk factors and immunity may identify the most susceptible children for which therapy would be beneficial.
We found that both sOP and NOP children who experience frequent respiratory infections during age 6–18 months have a likelihood to continue that pattern to age 4–5 years, Among sOP children, the infections were both bacterial (predominantly AOM) and viral URI. Among NOP children, the infections were predominantly viral URI. The identification of a subset of NOP children who are prone to viral but not bacterial respiratory infections was an unexpected and novel finding that our laboratory intends to further investigate in the future.
We have recently summarized the body of work from our group regarding immune deficiencies in sOP children.1 In brief, in prior work, we showed that when sOP children experience a viral URI, they fail to generate an adequate protective innate proinflammatory response in the nasopharynx5 and they respond to viral URI infections with decreased expression of toll-like receptors (that serve as pathogen recognition receptors) and generate lower levels of antiviral antibody.13 We have shown that the sOP child is more frequently colonized in the nasopharynx by potential respiratory bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenza and Moraxella catarrhalis14 and more frequently by 2 or more potential respiratory pathogens.15 When colonized, their innate immune response to the bacteria is altered,13,16–18 and they generate lower antibody levels to the bacteria compared with NOP children19–21 thereby leaving the child with greater susceptibility for additional colonization events that set the stage for bacterial infections. Adaptive immune deficits also occur. Similar to neonates,22–24 the sOP child has a general skewing toward increased T helper 1 and T regulatory cell responses.25 They also have deficient T helper 17 cell function, likely leading to inadequate neutrophil recruitment—a defect that we showed could be reversed by adding pro-T helper 17 cytokines to the peripheral blood mononuclear cells of sOP children.25 In addition, early-life NP colonization by pathobionts, Streptococcus pneumoniae and Haemophilus influenzae, may play a contributing role in OP and respiratory infection susceptibility later in childhood.10 An association of early-life NP colonization by pathobionts with increased febrile and lower respiratory infections, pneumonia and bronchiolitis, and general respiratory infections has been described.10,26–28
To our knowledge, the study design we employed and executed within a primary care practice setting is unprecedented. Therefore, placing our findings in context of prior work by others is challenging and potentially misleading. Indeed, prior studies in tertiary referral centers relying on the clinical diagnosis of AOM by primary care providers undoubtedly include contamination by cases of AOM that were incorrectly diagnosed, thereby disguising and/or diluting immunologic and other infection differences between OP and nonprone children.
Our study design has limitations. Increased risk of exposure to infectious organisms could contribute to differences. We addressed this limitation by statistical consideration of differences in risk factors for the sOP versus the NOP child, and the differences between groups remained significantly different. Differences in medical care–seeking behavior could contribute to identification of more frequent infection illnesses. We addressed this limitation by examining the frequency of infection illness when parents were bringing their child for regularly scheduled “well visits” and found this explanation to be an unlikely significant factor. We captured infectious disease illness visits other than respiratory illness visits, but the occurrence of skin/soft tissue infections, gastroenteritis and urinary tract infections was too low to allow group comparisons. More stringent criteria, including radiography, were not used to diagnose sinusitis and pneumonia. The study cohort included 39 sOP children. A larger study in another child population would be of value to confirm the results. A majority of children were Caucasian and lived in a specific geographic location (Rochester, NY); both of these hamper generalizability of the study at a global level.
In conclusion, the sOP child is generally infection prone to other bacterial and viral infections in addition to proneness to AOM. The mechanistic explanation is likely immune dysfunction in the innate and adaptive system. New strategies focused on immune dysfunction are needed to help children who are OP and respiratory infection prone.
We thank Dr. Janet Casey, the nurses, staff and patients of Legacy Pediatrics for their assistance in this study. Dr. Anthony Almudevar, Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, prepared the Figure, Supplemental Digital Content 1, https://links.lww.com/INF/E438. Dr. Janet Casey prepared the Figure, Supplemental Digital Content 2, https://links.lww.com/INF/E438.
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