Diagnosis and Management of Pneumonia in Infants Less Than 90 Days of Age Free

This retrospective cohort study used data obtained from the Pediatric Health Information System (PHIS), an administrative database that contains inpatient, emergency department (ED), ambulatory surgery, and observation encounter-level data from 50 not-for-profit, tertiary care pediatric hospitals in the United States. These hospitals are affiliated with the Children’s Hospital Association (Lenexa, KS). Data quality and reliability are assured through a joint effort between the Children’s Hospital Association and participating hospitals. Portions of the data submission and data quality processes for the PHIS database are managed by Truven Health Analytics (Ann Arbor, MI). Participating hospitals provide discharge and encounter data, including demographics, diagnoses, and procedures for external benchmarking. Nearly all of these hospitals also submit resource use data (eg, pharmaceuticals, imaging, and laboratory) into PHIS. Data are deidentified at the time of data submission and are subjected to several reliability and validity checks before being included in the database. Among hospitals participating in PHIS, those with data quality issues and those without complete ED data for the study period were excluded. For this study, data from 38 hospitals were included.

We reviewed initial encounter-level data from children 0 to 5 years of age who presented to the ED and were discharged or hospitalized between January 1, 2016, and December 31, 2021 with a primary or nonprimary diagnosis of CAP. Children <90 days of age were our primary study cohort, and children 90 days to 5 years of age served as the comparator group. We defined CAP using a validated set of diagnoses codes from the International Classification of Diseases, ninth Revision (ICD-9) and matching ICD-10 codes. This set of CAP diagnosis codes was previously validated in a multicenter study of pediatric CAP and have since been used in several investigations.^4–7 

Patients with complex chronic conditions were excluded given their diversity in presentation, comorbidities not representative of the general population, and the exclusion of these patients from prior studies on pediatric CAP.^4,5,7–9  We excluded patients with aspiration pneumonia or complicated pneumonia using established diagnosis codes because of differences in presentation and evaluation compared with CAP.^9,10  Given the fact that children with recurrent pneumonia may undergo more extensive diagnostic testing and receive broad spectrum antibiotic therapy, we restricted inclusion to the first episode of pneumonia during the study period. Patients were also excluded if they were transferred from another institution, given the inability to ascertain what diagnostic testing and treatment occurred before transfer.

Demographic characteristics included age (0 to 89 days of age and 90 days to 5 years of age), sex, race and ethnicity, and insurance type (private versus public). Infants <90 days of age were further categorized (0–28 days, 29–56 days, 57–89 days) based upon the differences in the management of young infants with fever. We used billing codes to assess for the performance of diagnostic testing, including complete blood count (CBC), blood gas analysis, C-reactive protein (CRP), procalcitonin, erythrocyte sedimentation rate (ESR), metabolic panel or chemistry, blood culture, viral studies, as well as performance of a chest radiograph (CXR). Only diagnostic testing that was performed during the initial or next hospital day was included. We also assessed rates and types of antibiotic administration in hospitalized patients (categorized into the following classes: aminopenicillin, ampicillin or sulbactam, cephalosporins, macrolides, vancomycin, and other (piperacillin or tazobactam, amoxicillin or clavulanate, clindamycin, meropenems, fluoroquinolones). Only medications administered during the initial or next hospital day were included.

We also evaluated hospitalization rate, hospital length of stay (LOS) (1–2, 3–7, or >7 days), admission to an ICU, and utilization of respiratory support. Respiratory support included supplemental oxygen administration via nasal cannula, facemask or high flow nasal cannula, noninvasive positive pressure ventilation including bilevel positive airway pressure and continuous positive airway pressure and invasive support via intubation and mechanical ventilation.¹¹ 

Hospital and patient-level characteristics were stratified by age (<90 days and ≥90 days of age). Characteristics were summarized by using frequencies and percentages or median and interquartile range (IQR) for categorical and continuous variables, respectively. Rates of diagnostic testing, hospitalization characteristics, and treatment were compared between infants <90 days and children ≥90 days of age using the χ-square test for categorical variables and the Wilcoxon rank sum test for continuous variables, given the non-normal distribution of the data. Given the fact that coexisting diagnoses may impact diagnostic testing and management, we additionally repeated analyses restricting the cohort to patients with a primary diagnosis of CAP. We also used a logistic regression model at the encounter level with the testing variable as the dependent variable and encounter year as in the independent variable to evaluate trends in the rates of diagnostic testing among infants <90 days.

We assessed whether variation existed in the utilization of diagnostic testing at the hospital level. Hospitals were characterized by geographic region, payer mix, annual number of CAP, and total ED visits by quartile. To assess whether hospital level-variation in diagnostic testing was impacted by hospital characteristics, we used a logistic regression model with the diagnostic testing as the dependent variable and the hospital-level categorical variable as the independent variable. We also examined seasonal variability in the rate of diagnosis of CAP and evaluated the proportion of ED visits that occurred during influenza season (early December through late March) and peak respiratory syncytial virus (RSV) seasons (late December through mid-February).^12,13  Additionally, we assessed the trends in pneumonia diagnoses among both age groups, focusing on changes that occurred around the coronavirus disease 2019 (COVID-19) pandemic (March 2020).

All analyses were performed by using the software package Stata SE, version 16.0 (Stata Corp, College Station, TX). All statistical tests were 2-tailed, and α was set at 0.05. The study was approved by the Institutional Review Board at the study institution.

After excluding ED encounters in which a patient was transferred from a different institution (n = 11 011), had a prior pneumonia within the past 3 months (n = 114), or had a complex chronic condition (n = 2490), there were 109 796 children included over the 6-year study period: 3128 infants less than 90 days of age (2.8%), and 106 668 children ≥90 days of age (Fig 3). Among infants <90 days, approximately 9% were under 29 days old, 44% were 29–56 days old, and 47% were 57–89 days old. Pneumonia was the primary diagnosis for 75% of older kids, but for infants <90 days, pneumonia accounted for only 37% of primary diagnoses. For infants <90 days with a nonprimary diagnosis of pneumonia, the most common primary diagnoses were acute bronchiolitis (26.0%) and acute respiratory failure (23.0%).

Compared with children ≥ 90 days of age, infants <90 days of age were more likely to be female, of white race, of non-Hispanic ethnicity, and to carry public insurance (P < .001 for all, Supplemental Table 3). Seasonal variation was observed among ED encounters for CAP in both age cohorts, with 65.2% of visits in infants <90 days and 61.9% of visits in children ≥90 days of age occurring during influenza and RSV seasons (Fig 1). ED encounters for CAP decreased for both age groups after the onset of the COVID-19 pandemic (Fig 1).

A higher proportion of infants <90 days of age with CAP underwent laboratory testing compared with older children (88.6% vs 48.8%, P < .001). The median number of laboratory tests performed in infants <90 days compared with children between 90 days and 5 years was 4 (IQR: 2–5) vs 0 (IQR: 0–3), respectively (Table 1). Among infants <90 days of age, there was an inverse relationship between the age and median number of laboratory tests performed (Supplemental Table 6). Respiratory viral testing rate was also more commonly performed among infants <90 days of age compared with older children (69.9% vs 34.7%, P < .001). Moreover, the rates of procalcitonin (odds ratio [OR] 1.75; confidence interval [CI] 1.52–2.01), viral testing (OR 1.19; CI 1.12–1.27), CRP (OR 1.14; 1.02–1.29) and total overall testing (OR 1.14; CI 1.06–1.23) increased among infants <90 days over the study period. There were no statistically significant changes in the rates of CXR, CBC, or blood culture among infants <90 days over the study period (Supplemental Fig 4).

Compared with older children, infants <90 days of age were more likely to be hospitalized (84.8% vs 35.3%, respectively; P < .001), and among hospitalized infants, median LOS was longer than for older children (5 vs 2 days; P < .001). Additionally, infants were more likely to receive care in an ICU setting (54.8% vs 18.9%; P < .001). Compared with older children, infants <90 days of age were more likely to require noninvasive respiratory support (53.2% vs 43.0%), as well as invasive ventilatory support (26.2% vs 5.9%) (Table 2). Among young infants, those <28 days of age had the greatest rates of hospitalization, ICU admission, and invasive respiratory support (Supplemental Table 7). Importantly however, among infants <90 days of age who required admission to the hospital, the proportion of patients with a primary diagnosis of CAP was 37%, primary diagnosis of bronchiolitis was 25.96%, and primary diagnosis of acute respiratory failure was 21.52%. Repeat analyses restricted to patients with a primary diagnosis of CAP did not materially differ from the main analyses (Supplemental Tables 4 and 5).

Antibiotics were administered less often for younger infants compared with older children (74.1% versus 84.4%; P < .001). Cephalosporins were most frequently used for younger infants <90 days of age, whereas aminopenicillins were most frequently prescribed for older children (Table 2).

Across hospitals, more variation in diagnostic testing was observed for infants <90 days of age compared with older children. Among younger infants, the highest variation in utilization occurred for procalcitonin (IQR: 5.6–30.1) and viral testing (IQR: 58.2–78.1), whereas the least variation occurred for CXR usage (IQR: 76.0–83.1) (Fig 2). Analysis at the hospital level showed that the odds of receiving viral testing in the ED at hospitals in the South or West were 1.54 and 2.35 times more likely respectively compared with those in the East. Otherwise, there was no statistically significant hospital level variation in diagnostic evaluation based on hospital payer-mix or annual CAP ED visits.

In this large retrospective multicenter cohort study of children with CAP, we observed major differences in diagnostic testing rates, antibiotic administration, and outcomes between infants <90 days of age and children 90 days to 5 years of age. Pneumonia encounters among young infants were more severe, as evidenced by higher rates of respiratory support and ICU level of care and longer length of hospitalization.

Most recent investigations on pediatric CAP have largely focused on children beyond infancy.^4,5  Given the lack of evidence and guidelines applicable to this age group, the approach to management of infants <90 days with pneumonia is less certain. The higher frequency of laboratory testing in infants <90 days is likely reflective of not only the absence of CAP guidelines and difficulty differentiating CAP from other lower respiratory tract infections (LRTI) in young infants, but also the fact that many febrile infants undergo standard diagnostic testing to identify a potential source of infection. Increasing rates of procalcitonin, viral testing, and CRP over time likely reflects the diagnostic challenges in differentiating CAP from other LRTI in infants as well as the inclusion of procalcitonin in febrile infant guidelines. Older infants and children with pneumonia typically have signs or symptoms of lower-respiratory tract infection. Despite differences in rates of laboratory testing, the rate of CXR did not differ between children less than and greater than 90 days of age. One multicenter prospective study of febrile infants demonstrated 36% of febrile infants <60 days had CXR performed, 6.6% of which had possible or definite radiographic pneumonia.² 

Respiratory viral testing was more commonly performed among infants <90 days than for older children. This may relate to the high prevalence in respiratory viral infections in this age group, as well as to inherent differences in the way pneumonia is diagnosed based on age. We suspect that many cases of pneumonia in young infants are made based upon an evaluation of fever without source, whereas in older children, the diagnosis of pneumonia is probably pursued based on specific signs and symptoms and physical examination findings.^2,14  However, it is important to note that distinguishing bacterial CAP from viral LRTI can be difficult in absence of reliable clinical, radiographic or laboratory differentiating factors.¹⁵  This suggests the importance of considering viral etiologies in the evaluation of the infant CAP, particularly in young infants.

There was greater hospital-level variation in diagnostic evaluation among infants <90 days, with the widest variation observed for procalcitonin and viral testing, and least variation in the performance of CXR (Fig 2). A recent study observed that among children with LRTIs, the rates of diagnosing and treating bacterial CAP varied widely across hospitals. Hospitals with lower rates of bacterial CAP diagnoses obtained fewer CXRs and blood tests, with similar hospital LOS and revisits compared with hospitals with high rates of CAP diagnoses.¹⁵  Variation in bacterial CAP diagnosis rates without disparate outcomes highlights potential opportunities for diagnostic and antibiotic stewardship in pediatric CAP.

Compared with older children, antibiotics were administered less frequently among young infants. Additionally, cephalosporins were most commonly administered for young infants, whereas older children more frequently received aminopenicillins. Within our study, the increased use cephalosporins for young infants may be secondary to the empirical treatment of the febrile infant.¹⁶  The difficulty in differentiating bacterial from viral LRTI, for example, between CAP and bronchiolitis among younger infants, may explain the lower rate of antibiotic use in young infants when compared with older children. Possible variability in diagnosis coding may also be contributory.

Compared with older children, young infants were more likely to be hospitalized, have longer hospitalizations, receive respiratory support, and require ICU-level of care; all suggesting a higher illness severity among infants diagnosed with pneumonia. These findings are consistent with a prior study that demonstrated higher rates of hospitalization among neonates compared with older children.¹⁴  These differences suggest the need for management guidelines and algorithms specific to infants <90 days of age. The proportion of primary diagnoses of CAP (37%) compared with primary diagnoses of bronchiolitis (25.96%) and acute respiratory failure (21.52%) among infants <90 days of age who were admitted to the hospital further suggests that these infants are sicker but also that there is variability in diagnostic coding likely secondary to the difficulty differentiating CAP from bronchiolitis in the younger infant.

We recognize that differences exist between young infants and children in the diagnostic approach to fever. We suspect that many young infants may receive a diagnosis of pneumonia after CXR is performed as part of the diagnostic work-up for fever, and that older children often present with respiratory symptoms and localizing findings. Although these differences may partially explain increased rates of diagnostic testing among young infants, repeat analyses including only patients with primary diagnoses of CAP revealed consistent findings for diagnostic evaluation, management, and outcomes.

We observed similar temporal trends in pneumonia rates between younger infants and older children. Both groups had seasonal variation in pneumonia cases corresponding to influenza season, consistent with prior studies, and also had similar decrease in cases corresponding to the onset of the COVID pandemic.^17,18  It is unclear whether the decrease in pneumonia cases relate to a decrease in ED volume overall or to a decrease in respiratory illness corresponding to isolation and masking measures instituted as part of the pandemic, as observed in other studies.^18,19 

Our study has several limitations. Given the lack of consistent and universal definition or diagnostic criteria for pneumonia, there is inherently some uncertainty with studies on CAP. The use of administrative data creates limitations because of possible subjectivity and differences in coding and billing practices at both the provider and hospital levels. In effort to minimize any bias resulting from this subjectivity and variability, we used codes that have been previously described or validated in the literature to identify CAP.^4–7  Additionally, by utilizing data from PHIS, we included only freestanding children’s hospitals, thus these results may not be generalizable to other health care settings. We are unable to ascertain medications prescribed, as PHIS only contains medications billed during the ED encounter or hospitalization. Thus, we cannot fully assess which medications were prescribed to children discharged from the ED.

We observed differences in the rates of diagnostic testing, antibiotic administration, and outcomes of infants <90 days compared with older children. This may reflect inherent differences in the pathophysiology of pneumonia by age, the difficulty differentiating CAP from other LRTI in infants, the manner in which pneumonia is diagnosed, or possible overuse of testing in infants given the diagnostic evaluation of the febrile infant.