Prospective Evaluation of the Risk of Serious Bacterial Infection in Children Who Present to the Emergency Department With Hyperpyrexia (Temperature of 106°F or Higher)

Design

The study is a cross-sectional observational study.

Setting

The Texas Children's Hospital ED is part of a tertiary care pediatric hospital in Houston, TX, with ∼80000 visits annually. At the time of this study, this ED was staffed by attending physicians 24 hours per day.

Selection of Participants

The standard ED protocol is to measure all children's temperatures at triage. From September 24, 1998, to September 24, 2000, children who had an oral, axillary, or ear temperature >104°F (40°C) had a rectal temperature obtained. All of the children with a rectal temperature ≥106°F (41.1°C) were enrolled in the study. Enrolled subjects had a complete history and physical examination performed by a pediatric ED fellow or attending. There were no exclusion criteria. Subjects received the standard of care for evaluation and management of hyperpyrexia in this institution. This study was approved by the Baylor College of Medicine Institutional Review Board.

Clinical and Laboratory Assessment

Each subject was assessed for the following viral symptoms by the pediatric ED fellow or attending: rhinorrhea, vomiting, diarrhea, sweating, and conjunctival injection. Per study protocol, initial laboratory evaluation for all of the children included a complete blood cell count with differential, blood culture, and viral cultures of the nasopharynx. The viral cultures were obtained via nasopharyngeal washes by trained respiratory therapists. Nasopharyngeal samples were tested by cell cultures for all cultivatable viruses, including respiratory syncytial virus (RSV), influenza A and B, parainfluenza viruses types 1 to 4, adenovirus, picornaviruses, rhinoviruses, enteroviruses, herpes simplex viruses types 1 and 2, varicella zoster virus, and cytomegalovirus. Urine for analysis and culture was obtained in all of the patients <2 years of age without a source for their fever and from any patient with a history of dysuria, urinary frequency, previous urinary tract infection (UTI), or renal abnormalities. Lumbar puncture was performed in children with clinical suspicion for meningitis. Chest radiograph (CXR) was obtained in children with respiratory complaints, clinical suspicion of pneumonia by examination, or in any child <3 years of age with a white blood cell (WBC) count of >20 × 10³ cells per mm³ and no other source of infection. Stool bacterial and viral cultures were sent for children with significant diarrhea. Stool viral cultures will detect adenovirus, enterovirus, and cytomegalovirus. The above studies were specified by study protocol and were considered standard of care. Other studies were performed at the discretion of the attending physician, including cultures of abscesses or wounds and rapid testing for Streptococcus pyogenes, RSV, or influenza A. Decisions concerning treatment and disposition were made by the attending physician.

Definitions

Any chronic condition resulting in impaired function of any organ system was classified as an underlying condition, with the exception of reactive airways disease. The presence of foreign bodies, such as central intravascular catheters, ventriculoperitoneal shunts, and renal stents, was also classified as an underlying condition, as was a previous history of UTI, because the history of UTI could be a marker for renal structural abnormality.

The following organisms in blood cultures were considered to be contaminants, unless regarded as significant by the treating physician: coagulase-negative staphylococci, α-hemolytic streptococci, or diphtheroids. UTIs were defined as the growth of a single pathogen of ≥10⁴ colony-forming units per mL or ≥10⁵ colony-forming units per mL on a clean catch specimen. Pneumonia was diagnosed if the attending radiologist read a focal parenchymal density on CXR (including the phrase bronchopneumonia) on routine dictation. The radiologists were blinded to the physician's interpretation and treatment plans. SBI was defined as the growth of a clinically significant bacterial pathogen from blood, urine, stool, cerebrospinal fluid (CSF), or any normally sterile body site. A viral illness was defined as the recovery of virus from nasopharyngeal or stool cultures or by a positive rapid test for viral antigens.

Statistical Analysis

Statistical analyses were performed using SPSS for Windows (SPSS Inc, Chicago, IL). Overall frequencies of subject ages, gender, ethnicity, and viral symptoms were calculated with 95% confidence intervals (CIs). Age was dichotomized into 3 to 35 months and ≥36 months. Overall frequencies of final diagnoses were also calculated with 95% CIs. The types of bacterial and viral pathogens were quantified. Subject treatment and disposition were also described.

Odds ratios (ORs) and 95% CIs were used to explore the association among age, duration of fever, underlying medical condition, WBC count, absolute neutrophil count (ANC), and viral symptoms with bacterial or viral illness. WBC count was categorized as <15 × 10³ and ≥15 × 10³ cells per mm³. ANC was categorized as <10 × 10³ and ≥10 × 10³ cells per mm³. Receiver operating characteristic curves were created to determine how well WBC count, ANC, and absolute band count would predict the presence of bacterial or viral illness.

Study Population

During the 2-year study period, there were 130828 visits to the ED, and 103 children had hyperpyrexia, defined as a rectal temperature ≥106°F (41.1°C; 1 per 1270 patient visits). All 103 of the children with hyperpyrexia were enrolled in the study. Subjects' ages ranged from 3 months to 16.9 years with a median of 17 months (interquartile range [IQR]: 11–25 months). The distributions of subject age, gender, and ethnicity are presented in Table 1. No child under the age of 3 months seen in the ED during the 2-year period of the study had a temperature ≥41.1°C (106°F). The median rectal temperature recorded in the ED was 106.2°F (IQR: 106.1–106.5), with a maximum of 108.9°F. For the 103 subjects, the median WBC count was 15.0 × 10³ cells per mm³ (IQR: 9.6–22.0). Table 2 presents the frequency of studies performed on study subjects, as well as the rates of positive study results.

Diagnoses

The final diagnoses are presented in Table 3, and culture results are presented in Table 4. Overall, of the 103 subjects, 20 had a culture-proven SBI (18.4%), including 1 subject who had both a bacterial and a viral infection. Eleven of the subjects had bacteremia, including 2 who were bacteremic secondary to UTI and 2 with bacteremia secondary to infection of an indwelling central venous catheter. One of the subjects with bacteremia secondary to an intravascular catheter infection had 4 different species of Gram-negative organisms recovered from blood cultures: Enterobacter cloacae, Escherichia coli, Citrobacter freundii, and Stenotrophomonas maltophilia. Eight subjects had a UTI, including a 3-month-old boy who grew E coli from urine and blood. This child also had meningitis by CSF parameters (WBC count of 269 cells per mm³; 95% neutrophils) and was treated as such, but his CSF was collected after >12 hours on antibiotics and showed no growth. One subject, a 4-year-old boy with muscular dystrophy, presented with both neuroleptic malignant syndrome and apparent septic shock. His temperature reached 108.9°F, and he expired during subsequent hospitalization despite aggressive management. A tracheal aspirate collected in the ED grew Pseudomonas. Because the same organism was recovered from autopsy blood cultures, the Pseudomonas was regarded as the cause of sepsis. The subject who had both positive bacterial and viral cultures was a 25-month-old female with sickle cell anemia who presented to the ED with a septic appearance. Her nasopharyngeal viral swab tested positive for RSV, and her blood also grew an α-hemolytic streptococcus, which was judged to be a true bacteremia by the infectious diseases service during the patient's subsequent hospitalization. Other etiologies for SBI included dysentery caused by Shigella flexneri and an epidural abscess, which grew Peptostreptococcus magnus.

In terms of establishing the diagnosis of SBI in the ED, 2 of the 20 subjects with culture-proven SBI had a CXR compatible with lobar pneumonia; both of these subjects also grew Streptococcus pneumoniae from the blood. The 2 other subjects with S pneumoniae bacteremia had negative CXR results. None of the 20 children with positive bacterial cultures were thought to have otitis media on physical examination.

The number of subjects with culture- or rapid test-proven viral illness was 22 (21.4%) of 103 including 7 with adenovirus, 1 with picornavirus, 2 with enterovirus, 6 with RSV, 5 with influenza A, 1 with cytomegalovirus, and 1 with parainfluenza 3. Of the 6 subjects with RSV, 1 grew adenovirus from a nasopharyngeal wash, and another subject with RSV also had α-hemolytic streptococcal bacteremia. The 2 subjects who grew adenovirus from stool viral cultures also grew adenovirus from nasopharyngeal cultures, whereas the 2 with enterovirus in the stool had negative nasopharyngeal viral cultures. Three of the 22 subjects with proven viral illness had a lobar infiltrate on CXR. These subjects' diagnoses were coinfection with adenovirus and RSV, adenovirus alone, and influenza A. Only 1 child in the viral illness group, also with influenza A, was diagnosed with otitis media by physical examination.

Of the remaining 62 subjects with hyperpyrexia, 60 were diagnosed with a febrile illness with negative cultures. One 7-year-old boy developed neuroleptic malignant syndrome in response to malfunction of his ventriculoperitoneal shunt. Another subject, a 16-year-old girl with renal stents and recurrent pyelonephritis, was ultimately diagnosed with new onset of systemic lupus erythematosus during hospitalization. Of the 60 with negative cultures and no other diagnosis to account for their fever, 13 had a CXR with a lobar infiltrate compatible with pneumonia, and 11 were diagnosed with otitis media by physical examination (including 2 with both pneumonia and otitis media). Interestingly, although daily temperatures in Houston exceed 90°F for several months of the year, none of the children with hyperpyrexia in the ED had heat-related illness, nor were any children with hyperpyrexia diagnosed with hyperthermia secondary to ingestion.

Outcomes

Of the 103 subjects, 28 (27.2%) were admitted to the hospital, and 75 (72.8%) were discharged from the hospital. One subject with muscular dystrophy died of neuroleptic malignant syndrome and sepsis, as described above. Of those discharged from the hospital, 35 (46.7%) were given intramuscular ceftriaxone, and 1 (1.3%) was given intravenous cefotaxime before discharge. Of the 39 subjects who did not receive intramuscular or intravenous antibiotics in the ED, 10 (25.6%) went home with a prescription for antibiotics. Of the 8 subjects with otitis media who were discharged from the hospital from the ED, all were prescribed antibiotics. Of the 29 who neither received antibiotics nor were prescribed antibiotics in the ED, 3 had an SBI. One of the subjects with an untreated SBI was a 16-month-old girl who presented with a febrile seizure after 3 days of fever. Her blood culture grew E coli. Another subject with untreated SBI was a 14-month-old girl with polycystic kidney disease who presented with fever and diarrhea. She subsequently grew E cloacae from blood cultures. Also, a 10-month-old girl grew E cloacae from urine culture. The WBC counts of these subjects, 11.9, 6.8, and 10.9 × 10³ cells per mm³, respectively, were not markedly elevated and, indeed, were lower than the median WBC count of subjects with hyperpyrexia (15 × 10³ cells per mm³). These relatively normal WBC counts may have misled the treating physician into suspecting a viral etiology. In all of the cases of hyperpyrexia, subjects were scheduled to receive follow-up with their primary care physician on the following day, as per ED practice.

Predictors of SBI

Table 5 presents the ORs for the associations between possible predictive variables and confirmed bacterial illnesses. There was a trend toward increased risk of bacterial illness in children ≥36 months old. As expected, the presence of an underlying medical condition was associated with an increased risk of bacterial illness. The incidence of SBI in children with underlying illness was 7 (36.8%) of 19, whereas the incidence of SBI in children without underlying illness was 13 (15.5%) of 84. The presence of rhinorrhea or any viral symptom was associated with a decreased risk of bacterial illness. However, the presence of diarrhea was associated with an increased risk of bacterial illness. There were no significant predictors of viral illness, although the presence of any viral symptom approached significance (OR: 2.08; 95% CI: 0.56–7.76). Neither WBC count nor ANC was predictive of bacterial or viral illness, either by ORs or by receiver operating characteristic curves. Likewise, the absolute band count was not predictive of either bacterial or viral illness. The median WBC count was slightly higher for viral illness (15.3 × 10³ cells per mm³; IQR: 10.1–19.1) than for bacterial illness (14.4 × 10³ cells per mm³; IQR: 10.5–24.2), although this difference was not statistically significant. Of the 5 subjects with a positive rapid viral test (3 RSV and 2 influenza), 1 had concurrent bacteremia, 2 had a CXR consistent with lobar pneumonia, 4 were ill enough to warrant hospitalization, and all but 1 were treated with antibiotics.