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Date: June 11th, 2021

Guest Skeptic: Dr. Dennis Ren is a paediatric emergency medicine fellow at Children’s National Hospital in Washington, DC.

Reference: McLaren SH, et al. Invasive bacterial infections in afebrile infants diagnosed with acute otitis media. Pediatrics 2021

Case: You are working with a medical student at the emergency department when a 2-month-old boy is brought in by his parents for fussiness. They note that he has had upper respiratory symptoms for the past few days and fussier than usual. He has still continued to feed well and make wet diapers. He has not had any fever. Yesterday, they noticed that he seemed to be pulling at his right ear. On exam, he is afebrile, active, and alert. He cries and moves vigorously when you look into his ear. You see a bulging, red tympanic membrane. His left tympanic membrane is clear. The rest of his exam is unremarkable.

You turn to the medical student and ask her what she would like to do for this patient. She replies that she thinks the patient has an acute otitis media (AOM) but given his age, she is also thinking about the possibility of an invasive bacterial infection (IBI) and would like to obtain some blood for labs and even consider a lumbar puncture for cerebral spinal fluid.

How do you reply?

Background: Acute Otitis media is the second most diagnosed illness in children and the most common indication for antibiotic prescription [1-2]. We have covered the of AOM twice on the SGEM:

  • SGEM#132: One Balloon for Otitis Media with Effusion with Dr. Richard Lubell
  • SGEM#278: Seen Your Video for Acute Otitis Media Discharge Instructions SGEMHOP with lead author Dr. Naveen Poonai?

In 2013, the American Academy of Pediatrics (AAP) updated recommendations for the diagnosis and management of acute otitis media (AOM) for children older than 6 months. Unfortunately, there is limited guidance for patients younger than 6 months. The diagnosis of AOM becomes more complicated by the concern for concurrent invasive bacterial infections (IBI) in infants less than 3 months of age.

Previous studies have demonstrated low prevalence of concurrent IBI in infants with AOM, but sample size has been small and included a mix of afebrile and febrile infants [3-4]. Additionally, the microbiology of pathogens causing AOM has shifted after the implementation of the pneumococcal conjugate vaccine with a higher proportion of patients having culture negative AOM [5].

This uncertainty has led to wide practice variation and controversy surrounding diagnostic testing (blood and cerebrospinal fluid testing), antibiotic administration (IV vs oral), and disposition (discharge vs admission) in infants with AOM.

Clinical Question: What is the prevalence of invasive bacterial infections and adverse events in afebrile infants ≤ 90 days of age with acute otitis media?

Reference: McLaren SH, et al. Invasive bacterial infections in afebrile infants diagnosed with acute otitis media. Pediatrics 2021

  • Population: Afebrile infants ≤ 90 days of age with clinically diagnosed acute otitis media across 33 pediatric emergency departments (29 USA, 2 Canadian and 2 Spanish EDs) from 2007 to 2017
    • Excluded: Temperature ≥38°C and <36°C in the ED or within 48 hours, antibiotic use (other than topical) within 48 hours of presentation, concurrent mastoiditis, evidence of focal bacterial infection, transferred to ED with previous diagnostic testing/antibiotics
  • Intervention: Evaluation of invasive bacterial infections in blood or cerebrospinal fluid (CSF)
  • Comparison: None
  • Outcomes:
    • Primary Outcome: Prevalence of IBI (bacterial meningitis and bacteremia)
    • Secondary Outcomes: Variability in diagnostic testing for IBIincluding blood or cerebrospinal fluid (CSF), parenteral antibiotic administration, and hospitalization.
    • Safety Outcome: AOM-associated adverse events

Authors’ Conclusions: “Afebrile infants with clinician-diagnosed acute otitis media have a low prevalence of invasive bacterial infections and adverse events; therefore outpatient management without diagnostic testing may be reasonable.”

Quality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method to answer their question? Yes
  3. Was the cohort recruited in an acceptable way? Unsure
  4. Was the exposure (diagnostic testing) accurately measured to minimize bias? Yes
  5. Was the outcome accurately measured to minimize bias? Unsure
  6. Have the authors identified all-important confounding factors? Unsure
  7. Was the follow up of subjects complete enough? Yes
  8. How precise are the results? Unsure
  9. Do you believe the results? Yes
  10. Can the results be applied to the local population? Unsure
  11. Do the results of this study fit with other available evidence? Yes

Results: They screened 5,270 infants from 33 sites to establish a cohort of 1,637 who met inclusion/exclusion criteria. The median age was 68 days and 89% met the simplified American Academy of Pediatrics diagnostic criteria for AOM.

Key Result: No infant with blood cultures had bacteremia and no infant was diagnosed with bacterial meningitis by CSF culture.

  • Primary Outcome: Prevalence of Invasive Bacterial Infections
    • 0/278 with blood cultures had bacteremia (95% CI 0%-1.4%)
    • 0/102 with CSF cultures had bacterial meningitis (95% CI 0% to 3.6%)

Two infants had adverse events in 30-day follow up and hospitalization history:

  1. Culture negative sepsis vs. severe dehydration from milk protein allergy
  2. Lymphadenitis (20 days after ED visit) after initial discharge on amoxicillin
  • Secondary Outcomes: Diagnostic Testing, Antibiotic Administration, and Hospitalization Rates.

  • One-fifth (21.7%, 355 of 1637) had ≥1 diagnostic test.
  • One-third (34%, 34 of 100) of infants ≤28 days had a lumbar puncture.
  • For infants with upper respiratory symptoms (n=1179), ~5% had a lumbar puncture, and 13.7% had blood cultures.
  • ~10% received IV or IM antibiotic
  • 90% received a prescription for oral antibiotic (most commonly amoxicillin followed by amoxicillin-clavulanate)
  • 5% were discharged from the emergency department
  • Almost half (47%) of infants 0-28 days were hospitalized
  • 72-hour return rate was 63 (4.3%) of which 15 infants were hospitalized.
  • Most common reason for hospitalization was bronchiolitis
  • Older infants were less likely to have blood cultures, lumbar puncture, and hospitalization compared to younger infants.
  • Ear discharge was significantly associated with diagnostic testing and hospitalization.

1. Diagnostic Uncertainty: The diagnosis of otitis media remains challenging. It is a clinical diagnosis and there is variability amongst clinicians. Here is the American Academy of Pediatrics (AAP) 2013 diagnostic criteria for AOM [6].

But even the AAP concedes that there is no gold standard for the diagnosis of AOM because it exists in a spectrum of findings as the disease process develops. This becomes challenging in a retrospective review as the diagnosis of AOM cannot be verified.

The authors chose to use a simplified diagnostic criteria defined by presence of tympanic membrane erythema, bulging tympanic membrane, or otorrhea. Unfortunately, the presence of tympanic membrane erythema alone is not specific for AOM as it can be because the infant is crying. This may falsely increase the number of infants with AOM included in the analysis and underestimate the prevalence of IBI. Although, zero infants in the study had confirmed bacteremia or bacterial meningitis on cultures.

2. Primary Outcomes: They had two primary outcomes, prevalence of IBI (bacteremia and bacterial meningitis) and AOM-associated adverse events. We know from the movie Highlander…There can be only one! Primary outcome. I am uncertain that the two reported adverse events are truly associated with AOM. One patient who was initially discharged on amoxicillin presented 20 days later  with cervical lymphadenitis and perforated AOM. The other patient did grow Staphylococcus aureus from middle ear effusion and was hospitalized for culture-negative sepsis but was also thought to have a severe milk protein allergy. The authors note that this patient presented with severe illness during the index ED visit so was likely not going to be discharged home regardless.

3. Partial Verification Bias: There were several potential biases in this study that could have impacted the results. One was already mentioned in nerdy point number one that there is not a gold standard. This is called the imperfect gold standard bias or the copper standard bias.

Another potential bias is partial verification bias. Not all infants in the study underwent the same testing for IBI. This can cause an underestimation of IBI. It is possible that some infants with bacteremia on whom blood cultures were not obtained were treated by oral antibiotics. The authors did try to perform follow up on patients within 30 days by reviewing medical records but acknowledge that this may not fully capture all patients with bacterial meningitis that was seen outside of the index ED or hospital system.

4. Selection Bias: As someone who works mainly in community hospitals, I’m concerned about selection bias. Are the infants who present to free-standing pediatric hospitals the same as those who present to community or rural EDs? Are those in large urban areas more likely or less likely to bring in a “fussy” infant? Are parents in the USA less likely to go to the ED because of co-pays, insurance status or other financial issues? It is unclear how any of these biases could alter the findings in this study.

5. Age: A last point to highlight is that there is a very low number of infants ≤28 days old (n=100, 6.1% of study population). This low number could be due to a variety of reasons. An ear exam on a small child is difficult but even more challenging in this neonatal population. I am rarely able to obtain a pristine view of the tympanic membrane in this age group making it difficult to make a diagnosis of AOM. Unless there is evidence of otorrhea, I do not usually perform an otoscopic exam. As such, I would still be cautious in this particular age group with AOM.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: In general, we agree that this retrospective study supports that the prevalence of invasive bacterial infections and AOM-associated adverse events in afebrile infants with acute otitis media is low and outpatient management without additional work up may be appropriate. However, there are limitations due to diagnostic variability/uncertainty. Clinicians should still be cautious, especially in infants ≤28 days as this age group was not well-represented in the study population.

SGEM Bottom Line: This study supports previous research that the prevalence of IBI in afebrile infants ≤90 days with AOM is low. In otherwise well-appearing infants, additional diagnostic workup may not be necessary, and outpatient management may be appropriate. Continue to be cautious with infants ≤28 days.

Case Resolution: You confirm the diagnosis of otitis media on otoscopy and reply to the medical student once you are outside the examination room. You tell her, “I agree with your diagnosis and appreciate your caution with this age group. However, there is data to support that the risk of invasive bacterial infections in afebrile infants of this age with AOM is low. I do not feel strongly about doing any additional testing at this time. We can discharge them from the emergency department with amoxicillin and ask them to follow up with their pediatrician.”

Dr. Dennis Ren

Clinical Application: For most infants ≤90 days of age who are afebrile, well-appearing, with a diagnosis of AOM, it is reasonable to defer additional diagnostic testing and manage them with outpatient antibiotics. However, continue to be cautious with infants ≤28 days of age.

What Do I Tell My Patient? Your child has an ear infection called acute otitis media. In this age group, I always think of the possibility that other infections may be present in the blood or spinal fluid. However, given that your child has not had any fevers and appears well, my suspicion for these scary things is low. I do not think he needs additional testing at this time. I would like to send you home with some oral antibiotics. Please follow up with your pediatrician in the next few days. If your child gets worse, stops eating/drinking/no wet diapers, developed a fever and rash,  or you are worried, bring them back we are happy to see him agai

Keener Kontest: Last weeks’ winner was…a few people (including previous winners Daniel McCollum and Guilherme Resener) and it is complicated. The first recorded use was in the early 1660’s from New Latin penumbra (coined by Johann Kepler in 1604), equivalent to Latin paen- prefix meaning “almost” + umbra “shade”; see pen-, umbra

Listen to the podcast this week to hear the trivia question. Email your answer to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Other FOAM Resources:

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine

References:

  1. Schappert SM, Reichsteiner EA. Ambulatory medical care utilization estimates for 2007. Vital Health Stat 13 2011; (169):1–38. 2.
  2. Grijalva CG, Nuorti JP, Griffin MR. Antibiotic prescription rates for acute respiratory tract infections in US ambulatory settings. JAMA 2009;302:758–66.
  3. Nozicka CA, Hanly JG, Beste DJ, Conley SF, Hennes HM. Otitis media in infants aged 0-8 weeks: frequency of associated serious bacterial disease. Pediatr Emerg Care. 1999;15(4):252-254.
  4. Turner D, Leibovitz E, Aran A, et al. Acute otitis media in infants younger than two months of age: microbiology, clinical presentation and therapeutic approach. Pediatr Infect Dis J. 2002;21(7):669-674.
  5. Ziv O, Kraus M, Holcberg R, et al. Acute otitis media in infants younger than two months of age: Epidemiologic and microbiologic characteristics in the era of pneumococcal conjugate vaccines. Int J Pediatr Otorhinolaryngol. 2019;119:123-130.
  6. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute otitis media. Pediatrics. 2013;131(3):e964-999.