Rate of Concurrent Otitis Media in Upper Respiratory Tract Infections with Specific Viruses

ORIGINAL ARTICLE Rate of Concurrent Otitis Media in Upper Respiratory Tract Infections With Specific Viruses

Cuneyt M. Alper, MD; Birgit Winther, MD, PhD; Ellen M. Mandel, MD; J. Owen Hendley, MD; William J. Doyle, PhD

Objective: To estimate the coincidence of new otitis me- Results: A total of 176 children (81%) had isolated PCR dia (OM) for first nasopharyngeal detections of the more detection of at least 1 virus. The OM coincidence rates common viruses by polymerase chain reaction (PCR). were 62 of 144 (44%) for rhinovirus, 15 of 27 (56%) for New OM episodes are usually coincident with a viral up- respiratory syncytial virus, 8 of 11 (73%) and 1 of 5 (20%) per respiratory tract infection (vURTI), but there are con- for influenza A and B, respectively, 6 of 12 (50%) for ad- flicting data regarding the association between specific enovirus, 7 of 18 (39%) for coronavirus, and 4 of 11 (36%) viruses and OM. for parainfluenza virus detections (P=.37). For rhinovirus, new OM occurred in 50% of children with and 32% Design: Longitudinal (October-March), prospective fol- without a concurrent CLI (P=.15), and OM risk was pre- low-up of children for coldlike illness (CLI) by diary, middle dicted by OM and breastfeeding histories and by daily ear status by pneumatic otoscopy, and vURTI by PCR. environment outside the home.

Setting: Academic medical centers. Conclusions: New OM was associated with nasopharyngeal detection of all assayed viruses irrespective of Participants: A total of 102 families with at least 2 chil- the presence or absence of a concurrent CLI. Differ- dren aged between 1 and 5 years (213 children; mean [SD] ences among viruses were noted, but statistical signifi- age, 3.7 [1.5] years; 110 male; and 176 white) were recruited cance was not achieved, possibly because of the low from the local communities at 2 study sites by advertisement. power associated with the small number of nonrhinovirus detections. Main Outcome Measures: New OM and CLI episodes and nasopharyngeal virus detections. Arch Otolaryngol Head Neck Surg. 2009;135(1):17-21

T IS WELL ACCEPTED THAT MOST versely, that 20% to 40% of CLIs are as- new episodes of otitis media sociated with OM.8-11 Other studies (OM) are temporally coincident reported the recovery of virus, virus pro- with viral upper respiratory tract tein, and viral genomic sequences from the infections (vURTIs),1 and experi- middle ear in subjects with new-onset mental evidence supports causality for this symptomatic OM (acute OM [AOM]) or I 2-4 relationship. vURTIs may or may not persistent OM and related these findings present with a sign-symptom constella- to viral infection of the middle ear mu- tion recognized as a coldlike illness (CLI), cosa as the cause of those episodes.12-16 and the results of some studies show that However, this interpretation can be ques- Author Affiliations: a CLI is not a prerequisite for the devel- tioned based on the results of other stud- Department of Otolaryngology, opment of OM.5,6 Because vURTIs with- ies that reported recovery from the middle Children’s Hospital of out CLI expression do not present clini- ear of genomic sequences for viruses that Pittsburgh and the University of cally, most estimates of the frequency of do not infect the upper respiratory tract Pittsburgh School of Medicine, all OM episodes attributable to vURTIs are but rather establish a persistent infection Pittsburgh, Pennsylvania calculated as the number of OM episodes in other cell types (eg, human immuno- (Drs Alper, Mandel, and Doyle); and Departments of divided by the number of CLI episodes and deficiency virus, Epstein-Barr virus, cyto- Otolaryngology (Dr Winther) therefore are biased. megalovirus, varicella-zoster virus, and 17,18 and Pediatrics (Dr Hendley), Past studies report that more than 50% herpes virus). University of Virginia Health of all new OM episodes in children are tem- Perhaps as a consequence of the wide va- System, Charlottesville. porally associated with a CLI,6,7 and con- riety of study formats used to estimate

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 OM-vURTI coincidence in children, the literature is in- servation time, both ears were examined by a validated otoscopist consistent with respect to the relative importance of the and classified as to the presence or absence of OM based on different vURTI viruses.7,8,12,16,19-22 However, because most ratings of the tympanic membrane with respect to visibility, con- interventions that are potentially useful in preventing new dition, position, appearance, color, vascularity, light reflex, and OM during a vURTI are virus specific, unbiased esti- mobility. A positive diagnosis for OM was made when middle ear effusion (with or without air-fluid level) was observed ir- mates of virus-specific OM risk are needed.1,8 This study respective of the presence or absence of concurrent signs of addresses that need using a longitudinal format with high- middle ear infection. Acute OM was diagnosed by the pres- density assessments for detection of OM, CLI, and naso- ence of OM with concurrent signs of middle ear infection in- pharyngeal virus in a large group of unselected children. cluding parental report of ear pulling, otalgia, irritability, and The null hypothesis tested is that the new OM coinci- fussiness and otoscopic signs of erythema and/or white opaci- dence rate of a vURTI is not virus specific. Acceptance or fication (other than from scarring) of the tympanic mem- rejection of this hypothesis is important for developing ra- brane, bulging or fullness of the tympanic membrane, or otor- tional strategies to prevent that complication. rhea from a perforation of a previously intact tympanic membrane. Otitis media with effusion (OME) was assigned to OM episodes without concurrent signs of infection. Episodes METHODS of AOM but not OME were treated empirically with antibiot- ics. Because otoscopy was not necessarily performed at a time The data for this report were abstracted from those available for when the child first presented with otologic symptoms (the chil- the first 4 years of an ongoing, 5-year study designed to charac- dren were seen and treated by their primary care physician for terize the causal relationships among vURTIs, CLIs, and OM in most illnesses), subclassification of OM for this report was bi- young children. The protocol was approved by the institutional ased to OME assignment. review boards at the University of Pittsburgh and the University Otoscopic data were coded for the left and right ears as OME of Virginia. Families at 2 study sites (Pittsburgh, Pennsylvania, present or absent (0=absent; 1=present), and AOM present or and Charlottesville, Virginia) with 2 children aged between 1 and absent (0=absent; 2=present). Between otoscopic assess- 5 years were recruited for participation by advertisement. Ex- ments, daily OM assignment for each ear was made based on clusion criteria included the presence in either child of a seri- that at the preceding visit, to yield a string of observations for ous medical condition, a medical condition that predisposes to each day of the study period. A new OME episode was defined persistent OM, a nonintact or structurally abnormal tympanic as a sequence of 1s preceded and followed by a sequence of 0s, membrane, a preexisting sensorineural hearing loss, or an in- and an episode of AOM was defined as a newly introduced string ability to cooperate sufficiently with the examination and test of 2s, irrespective of preceding and subsequent observations. procedures. After affirmation of willingness to participate and In the analysis, the child was considered to be the unit of mea- acquisition of written informed consent, families were entered sure, and either new unilateral or bilateral OM episodes were into the study in October with an anticipated follow-up through assigned as a new OM episode. April of that year and were reimbursed for participation. The study The technique for collecting nasal secretions from the chil- subjects included the 2 index children and any older siblings dren and the methods and protocols for storage and transport younger than 10 years who provided assent. of the specimens to the virology laboratory were previously de- The data for this report consist of demographic information scribed.24 Samples were assayed in batches for PCR detection of for each child (age, sex, and race), information on selected OM adenovirus, coronavirus, influenza virus A and B, parainflu- risk factors (history of OM, frequent colds, breastfeeding, and enza virus, rhinovirus (picornavirus), and respiratory syncytial exposure to tobacco smoke and the child’s daily environment virus (RSV) using a protocol adapted from the commercially avail- for a subset of children [those enrolled at the Pittsburgh site in able Hexaplex procedure (Prodesse Inc, Waukesha, Wiscon- years 1-4 and at the Charlottesville site in years 2-4]),23 the lon- sin) as described in previous publications.6 Each viral species was gitudinal daily assignments of the presence or absence of a CLI assigned a numeric code, and the temporal distribution for these day as recorded by a parent and weekly assignments of the pres- codes was overlaid onto the sequence strings for CLI and new ence or absence of OM as assessed by bilateral pneumatic otos- OM episodes. Detections of the same virus within a 20-day pe- copy performed by validated study personnel. These data were riod and without an intermittent observation of a different vi- supplemented with virus detections by polymerase chain reac- rus or “no detectable virus” were linked as a single virus detection (PCR) assay of nasal secretions collected from the children tion. To avoid bias associated with multiple same-virus detections during a parent-identified CLI episode in the child or in an en- for a long-standing infection and bias associated with dispro- rolled sibling, at the onset of a new OM episode (either unilat- portionate representation of those children with a greater num- eral or bilateral, asymptomatic or symptomatic) in the child or ber of independent same-virus detections, the data analyses were in a sibling, and at random times during illness-free periods. Not based on the concurrence in each child of OM for the first de- all samples during these designated target periods could be col- tection of each assayed virus in isolation (ie, disregarding as- lected because some children refused at times to cooperate with says with multiple identified viruses). the requisite procedures, and this was especially true when free The data map (longitudinal sequence strings for CLI, OM, nasal secretions were absent. and virus detections) was read from entry to termination of each For each subject, parent-recorded CLI days were coded as child’s participation, and the first detection of each assayed vi- longitudinal strings of 0s (CLI absent) and 1s (CLI present). A rus in isolation was identified. Associated new CLI and new CLI episode was defined as 3 or more consecutive days with a OM episodes were assigned if the episode duration embedded parent-reported CLI separated from other episodes by at least the detection or occurred within 7 days after or 3 days before 4 days. We did not provide the parents with a definition of a the virus detection. For the first detection of each virus in each CLI day based on a specific symptom-sign set, and those as- child, the presence or absence of a new OM episode and of the signments were made as was typical for each parent’s usual CLI OM subtype was assigned based on those criteria. Data for OM diagnosis in their children. episodes of long durations and with multiple, nonidentical vi- Bilateral pneumatic otoscopy on enrolled children was sched- rus detections at different times were not included in the cal- uled at approximately weekly intervals at an in-home visit (Pitts- culation of OM coincidence. For each virus, the OM coinci- burgh) or at a study clinic visit (Charlottesville). At each ob- dence rate of a first virus detection was calculated as the sum

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table. Results Summarizing the New Otitis Media (OM) Coincidence Rates for the First PCR Detection of Each Assayed Virus

Total No. of Persons OM Coincidence Rate (Virus With Virus Detection Analyzable, No. OM؉ (AOM؉), No. (95% Confidence Interval Rhinovirus 151 140 62 (5) 0.44 (0.36-0.53) RSV 27 27 15 (5) 0.56 (0.35-0.75) Influenza A 11 11 8 (3) 0.73 (0.39-0.94) B 7 5 1 (0) 0.20 (0.01-0.72) Adenovirus 12 12 6 (1) 0.50 (0.21-0.79) Coronavirus 229E 2 2 1 (1) 0.50 (NA) OC43 17 16 6 (1) 0.38 (0.15-0.65) All 19 18 7 (2) 0.39 (0.17-0.64) Parainfluenza 1 2 2 0 (0) 0.00 (NA) 2 7 7 3 (2) 0.43 (0.10-0.82) 3 2 2 1 (1) 0.50 (NA) All 11 11 4 (3) 0.36 (0.11-0.69)

Abbreviations: AOM, acute otitis media; NA, not applicable; PCR, polymerase chain reaction; RSV, respiratory syncytial virus.

of all subjects of associated new OM detections for that virus theless, with the exception of parainfluenza type 1 for divided by the number of individuals with virus detection for which only 2 detections were observed, new OM epi- which the assignment could be made (eg, excluding episodes sodes were coincident with the detection of all assayed with multiple viruses, long-duration OM episodes, missing data virus species in the nose and/or nasopharynx. for the virus detection interval). Results are presented as OM The percentages of all associated OM episodes clas- coincidence rates for each virus and the associated 95% confidence intervals. Comparisons among viruses of OM rates were sified as AOM were 8%, 33%, 38%, 17%, 29%, and 75% performed using the ␹2 or Fisher exact test. for rhinovirus, RSV, influenza A virus, adenovirus, coro- For children with rhinovirus detections, the demographic navirus, and parainfluenza virus, respectively. Pairwise and included risk factors were entered into a logistic regres- comparisons of these percentages with rhinovirus were sion equation to predict CLI coincidence and, with CLI as an statistically significant for RSV (P=.02) and parainflu- additional variable, to predict OM coincidence. For each sub- enza virus (P=.005) but was not significant for the other ject, the presence or absence of OM for all first virus detec- viruses (Fisher exact test). tions was assigned. The predictor variables were entered into The large number of isolated rhinovirus detections al- a stepwise regression equation to determine their contribu- lowed for a comparison of OM coincidence between vi- tion to this response variable. rus detections with and without a concurrent CLI. Of the 134 detections with data for both OM and CLI, 32 (24%) RESULTS were not associated with either CLI or OM, 18 (13%) were associated with OM without CLI, 42 (31%) were asso- The data for 213 children (176 white and 110 male) were ciated with CLI without OM, and 42 (31%) were asso- available for analysis. These children ranged in age from ciated with both OM and CLI. Thus, for rhinovirus de- 1.0 to 8.6 years (mean [SD] age, 3.7 [1.5] years); 63, 54, tections, 42 of 84 (50%) with and 18 of 50 (32%) without 60, and 36 different children were studied in years 1 a concurrent CLI were associated with new OM (Fisher through 4, respectively. Of these, 176 (81%) had at least exact test, P=.15). For this subset, the OM risk of rhi- 1 detection of an assayed virus; 114, 51, 6, 1, and 4 chil- novirus detection was 45% and of rhinovirus CLI was 50%. dren had at least 1 detection of 1, 2, 3, 4, and 5, respec- When the demographic variables (age, sex, and race), tively, of the assayed viruses. For each virus, the Table OM history (yes or no), frequent cold history (yes or no), reports the number of persons with at least 1 detection, breast feeding history (yes or no), exposure to tobacco the number of first detections that were included in the smoke (yes or no), and daily environment (day care, calculation of OM coincidence rate, the number of as- school, or home with mother and/or father) were en- sociated new OM episodes, the number assigned to AOM, tered into a logistic regression equation to predict rhi- and the OM coincidence rate with 95% confidence in- novirus-associated CLIs (n=121), only race (whiteϾblack; tervals. At least 1 rhinovirus detection occurred in 70% odds ratio, 0.31; P=.03) was a significant predictor. When of enrolled subjects, and new OM was coincident in 44% these variables and CLI presence or absence were en- of the first detections. The other viruses were detected tered into the equation to predict rhinovirus-associated in less than 13% of the subjects, and the new OM coin- OM episodes, history of OM (presentϾabsent; odds ra- cidence rate varied from a low of 20% for influenza B vi- tio, 2.6; P=.03), daily environment (out of homeϾhome rus to a high of 73% for influenza A virus detections. The with mother and/or father; OR, 2.4; P=.03) and breast- difference in the OM coincidence rate among these vi- feeding history (presentϾabsent history; odds ratio, 3.7; ␹2 ruses was not statistically significant ( 6=6.5; P=.37). P=.02) were identified as predictors. When these vari- However, the low detection frequency for most viruses ables were entered into a stepwise regression equation greatly constrained the power of the statistical test. None- to predict the frequency of OM episodes associated with

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 any first virus detection for each subject (n=137), his- 8% for rhinovirus to a high of 75% for parainfluenza vi- tory of OM (presentϾabsent [P=.009]), daily environ- rus. Notably, OM was coincident with detection of all vi- ment (out of homeϾhome with mother and/or father ruses assayed, but the differences among viruses in that [P=.03]), and breastfeeding history (presentϾabsent his- rate did not achieve statistical significance. The latter may tory [PϽ.001]) were again identified as significant have resulted from low power, given the small sample sizes predictors. for nonrhinovirus detections and the uncontrolled differences in OM risk factors among the subpopulations with specific virus detections. COMMENT Past studies reported an excess OM risk for RSV infections vis-à-vis infection with other viruses,7,8,12,19-21 but The results for the present study demonstrate temporal our results show that if a difference exists, its magni- coincidences among CLI expression, new OM, and vi- tude is small. Some of those studies were biased by de- rus detection in the upper respiratory tract at rates con- sign factors that included dependence on otologic signs sistent with those previously reported.9,10,21 While the ob- and/or symptoms for OM identification (restricting the served relationships are associative, past studies of identified OM episodes to AOM, which our data show experimental vURTIs in adult human volunteers pro- to be virus specific), the source population (eg, children vide strong evidence for causality with vURTIs precipi- in a hospital, where viruses that cause more serious com- tating both CLI expression and otologic complica- plications such as RSV and influenza A would be over- tions.2-4 As expected, most of the children (71%) had at represented), and study season (eg, seasonal epidemics least 1 rhinovirus detection, but the detection rates for where viruses circulating at the time of sampling would the other assayed viruses were much lower, varying be- be overrepresented). Reports that estimated coinci- tween 5% and 13%. This distribution is consistent with dence rates from virus detections in the middle ear are the results of studies focusing on the viral cause of CLIs especially vulnerable to these biases because the denomi- with sampling over the typical CLI season.21 nator for rate calculations (number infected with the vi- For rhinovirus, not all detections were associated with rus in the population) is not known. a CLI, and a CLI was not a prerequisite for OM devel- In conclusion, our null hypothesis that there are no opment. While the OM coincidence rate was higher for differences in the new OM coincidence rates for differ- CLI rhinovirus detections, this was not significant. Oto- ent viruses could not be rejected. Overall, the OM coin- logic complications in the absence of CLIs were previ- cidence rate for virus detection was 0.43. For most vi- ously reported for experimental vURTIs in adults5 and ruses, the 95% confidence interval placed on the OM rates for natural vURTIs in children.25 These data suggest that was large, but for rhinovirus that interval was much the pathways activated during a vURTI leading to OM smaller (0.36-0.53). Rhinovirus is the most common vi- and to the symptoms and/or signs representing a CLI are rus infection in children and, unlike some of the other somewhat independent. viruses, children can be reinfected with a different strain An analysis of the possible predictors of CLI expres- of the virus in the same season. Combined with our data, sion and new OM during rhinovirus detection showed that these observations suggest that most new OM episodes children identified by their parents as being white pre- are coincident with a rhinovirus vURTI. Because of the dicted CLI expression, while a positive history of OM, a large number of rhinovirus stains, it is unlikely that a vac- positive history of breastfeeding, and a daily environ- cine will be developed any time soon, and the effective- ment outside of the home predicted OM risk. The effect ness of the limited number of antipicornavirus agents (eg, of OM history and daily environment on OM risk is con- interferon, pleconaril) available has not been evaluated sistent with previous reports, but the effect of breastfeed- with respect to preventing OM. A generalized approach ing is directionally opposed to that of past studies.23 It to preventing OM episodes associated with a vURTI should be noted that previous studies of OM “risk fac- should target those events responsible for interpersonal tors” did not condition the enumerated OM events on vi- virus transmission with the goal of preventing vURTIs rus presence (or, more weakly, on CLIs) as was done here in the at-risk population. for rhinovirus (and all viruses). These comparative results suggest that breastfeeding may be protective against Submitted for Publication: February 1, 2008; final re- vURTI but not against OM once virus infection is estab- vision received April 10, 2008; accepted May 7, 2008. lished; that negative OM history is protective against OM Correspondence: Cuneyt M. Alper, MD, Children’s Hos- during established virus infections; and that daily envi- pital of Pittsburgh, 3705 Fifth Ave at DeSoto Street, Pitts- ronment at home with the mother and/or father protects burgh, PA 15213 ([email protected]). against vURTIs and OM during established vURTIs. Author Contributions: Dr Doyle had full access to all the In the present study, nasopharyngeal secretion samples data in the study and takes responsibility for the integ- were collected for virus assay in all enrolled siblings on rity of the data and the accuracy of the data analysis. Study the detection of OM (irrespective of concurrent otologic concept and design: Alper, Winther, and Doyle. Acquisi- symptoms and/or signs) in any sibling, on the detection tion of data: Winther, Mandel, and Hendley. Analysis and of a CLI in any sibling, and at random times throughout interpretation of data: Alper, Winther, Mandel, and Doyle. the typical CLI season. The rate of concurrent new OM Drafting of the manuscript: Alper, Mandel, and Doyle. Criti- varied from a low of 20% for influenza B to a high of 73% cal revision of the manuscript for important intellectual con- for influenza A, and the rate of OM episodes assigned to tent: Alper, Winther, Mandel, Hendley, and Doyle. Sta- AOM was different among viruses, varying from a low of tistical analysis: Doyle. Obtained funding: Doyle.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Administrative, technical, and material support: Alper and 10. Antonio SM, Don D, Doyle WJ, Alper CM. Daily home tympanometry to study Mandel. Study supervision: Alper, Winther, Hendley, and the pathogenesis of otitis media. Pediatr Infect Dis J. 2002;21(9):882-885. 11. Winther B, Doyle WJ, Alper CM. A high prevalence of new onset otitis media dur- Doyle. ing parent diagnosed common colds. Int J Pediatr Otorhinolaryngol. 2006; Financial Disclosure: None reported. 70(10):1725-1730. Funding/Support: This research was supported in part 12. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in by grant DC005832 from the National Institutes of Health. the middle ear during acute otitis media. N Engl J Med. 1999;340(4):260-264. Previous Presentation: This study was presented at the 13. Shaw CB, Obermyer N, Wetmore SJ, Spirou GA, Farr RW. Incidence of adenovirus and respiratory syncytial virus in chronic otitis media with effusion using the 2008 American Society of Pediatric Otolaryngology Sci- polymerase chain reaction. Otolaryngol Head Neck Surg. 1995;113(3):234-241. entific Program; May 4, 2008; Orlando, Florida. 14. Williams JV, Tollefson SJ, Nair S, Chonmaitree T. Association of human meta- Additional Contributions: Kathleen Ashe assisted with pneumovirus with acute otitis media. Int J Pediatr Otorhinolaryngol. 2006; the virologic assays; Harriette Wheatley and Ellen Rey- 70(7):1189-1193. nolds assisted with sample procurement; and James T. 15. Pitkäranta A, Jero J, Arruda E, Virolainen A, Hayden FG. Polymerase chain reaction- Seroky, Allison P. Cullen-Doyle, and Brendan C. Doyle based detection of rhinovirus, respiratory syncytial virus, and coronavirus in otitis media with effusion. J Pediatr. 1998;133(3):390-394. assisted with data entry. 16. Nokso-Koivisto J, Raty R, Blomqvist S, et al. 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