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Background In many academic centers it is standard practice to hospitalize all febrile infants younger than two months of age, whereas in community settings such infants are often cared for as outpatients.
Methods We conducted a controlled study of 747 consecutive infants 29 through 56 days of age who had temperatures of at least 38.2 °C. After a complete history taking, physical examination, and sepsis workup, the 460 infants with laboratory or clinical findings suggestive of serious bacterial illness were hospitalized and treated with antibiotics. The screening criteria for serious bacterial illness included a white-cell count of at least 15,000 per cubic millimeter, a spun urine specimen that had 10 or more white cells per high-power field or that was positive on bright-field microscopy, cerebrospinal fluid with a white-cell count of 8 or more per cubic millimeter or a positive Gram's stain, or a chest film showing an infiltrate. The 287 infants who had unremarkable examinations and normal laboratory results were assigned to either inpatient observation without antibiotics (n = 148) or outpatient care without antibiotics but with reexaminations after 24 and 48 hours (n = 139).
Results Serious bacterial illness was diagnosed in 65 infants (8.7 percent). Of these 65 infants, 64 were identified by our screening criteria for inpatient care and antibiotic treatment (sensitivity = 98 percent; 95 percent confidence interval, 92 to 100). Of the 287 infants assigned to observation and no antibiotics, 286 (99.7 percent) did not have serious bacterial illness. Only two infants assigned to outpatient observation were subsequently admitted to the hospital; neither was found to have a serious illness. Outpatient care without antibiotics of the febrile infants at low risk for serious illness resulted in a savings of about $3,100 per patient.
Conclusions With the use of strict screening criteria, a substantial number of febrile one-to-two-month-old infants can be cared for safely as outpatients and without antibiotics.
Methods
From July 1987 through June 1992, we enrolled all children 29 through 56 days of age who were presumed to be immunocompetent and who presented to the emergency department of the Children's Hospital of Philadelphia with rectal temperatures of 38.2 °C or higher as measured by an electronic digital thermometer. All children underwent a standard evaluation. A complete history was obtained from the infants' parents, and a physical examination was performed by the attending physician in the emergency department. The attending physician then assigned the infant an Infant Observation Score reflecting the clinical findings14. The standard laboratory evaluation included a complete blood count with differential, a microscopical urinalysis, a two-view chest film, a lumbar puncture with standard analysis, and bacterial cultures of blood, urine, and spinal fluid. From children with a history of diarrhea, stool specimens were obtained and sent for white-cell analysis and bacterial culture.
We considered the results of these tests to be normal if they met the following criteria: peripheral-blood white-cell count, fewer than 15,000 cells per cubic millimeter; urinalysis, fewer than 10 white cells per high-power field and few bacteria, or none, detected by bright-field microscopy (with spun specimens used in both tests); cerebrospinal fluid, fewer than 8 white cells per cubic millimeter in a non-bloody specimen and a negative Gram's stain; and chest film, no evidence of a discrete infiltrate as determined by the attending physician (and subsequently confirmed by an attending radiologist).
After a review of the initial Infant Observation Score and laboratory results, we classified the children as either screening-positive or screening-negative and assigned them to one of three management groups. Children with any laboratory value outside the defined normal ranges, with evidence of any bacterial infection on physical examination, or with an Infant Observation Score greater than 10 were considered screening-positive and assigned to the inpatient-antibiotic group. Children whose spinal fluid samples were grossly bloody were considered to have uninterpretable specimens and were also included in this group.
Children whose laboratory values all fell within the defined normal ranges, who had an Infant Observation Score less than or equal to 10, and who had no recognized bacterial infection on physical examination were considered screening-negative. If these children were enrolled on even-numbered days, they were assigned to the outpatient-observation group. Patients assigned to this group had to live within 30 minutes of the hospital, have a working telephone in the home, and have parents willing to return to the hospital for the reevaluation on each of the following two days. Children enrolled on odd-numbered days who were screening-negative were assigned to the inpatient-observation group.
After the group assignments were made, patients in the inpatient-antibiotic group were cared for according to the existing standard of care at the Children's Hospital of Philadelphia for febrile infants presumed to have serious bacterial illness, with administration of parenteral antibiotics chosen by the children's physicians. Our protocol required no deviation from standard care for these patients. The children in this group were usually discharged after 72 hours if bacterial cultures were negative.
The study protocol was discussed with the parents of patients who were assigned to either the outpatient-observation group or the inpatient-observation group. Written informed consent was obtained from those willing to participate. In addition, the management plans were reviewed with the patients' private physicians when they were available. Patients in the outpatient-observation group were discharged to their homes without antibiotics. Patients in the inpatient-observation group were hospitalized but received no antibiotics. Patients who were assigned to either group were permitted to cross over to the alternate group at the request of the parents or the private physician.
Within 24 and 48 hours of the initial evaluation, all the patients were reexamined by attending physicians in the emergency department and the results of cultures were reviewed. Patients in the outpatient-observation group were subsequently hospitalized if this step was warranted by the severity of their illness or if any bacterial culture was positive. Cultures of blood and spinal fluid that were free of bacterial pathogens at 72 hours were considered negative. All urine specimens were obtained by bladder catheterization. Cultures of these specimens were considered negative or contaminated if fewer than 1000 colony-forming units of a single organism per milliliter were recovered. Urine cultures were also considered contaminated if 105 colony-forming units or more were isolated with three or more colony types present and none predominant.
Serious bacterial illness was defined as bacterial growth of a known pathogen in cultures of blood, spinal fluid, urine, or stool. Blood cultures were considered to be contaminated if the symptoms resolved without appropriate treatment (in the case of coagulase-negative staphylococcus) or if the bacteria isolated were not pathogens (for example, diphtheroids, nonpathogenic neisseria species, and alpha-hemolytic streptococcus). Infants were considered to have serious illness if they had serious bacterial illness, pneumonia, or aseptic meningitis. Infants with obvious cellulitis or abscess were considered to have serious bacterial illness. Pneumonia was defined as a new discrete infiltrate on the chest film that was confirmed by an attending radiologist. Aseptic meningitis was defined as pleocytosis ( 
8 white cells per cubic millimeter in a non-bloody specimen) and an absence of bacterial pathogens in cerebrospinal fluid samples obtained from children who had not previously received antibiotic treatment.
After the resolution of the patients' illnesses, all medical records were reviewed by the investigators, and information on the duration of hospitalization, the duration of intravenous therapy, the duration of antibiotic treatment, and any documented complications was noted. Total hospital charges for each patient's illness were obtained from the hospital billing department.
The data were analyzed by the chi-square technique for categorical variables, with Yates' correction for two-by-two tables. When the expected number of patients in any cell was less than five, Fisher's exact test was used.
The original study protocol was approved by the institutional review board of the Children's Hospital of Philadelphia. During the third year of the study, preliminary data analysis called for two modifications. Added to the entrance criteria for screening-negative patients assigned to the outpatient-observation group and the inpatient-observation group were the absence of any recognizable immunodeficiency syndrome and the presence of a normal band-to-neutrophil ratio (<0.2). The latter had previously been found to be helpful in identifying young infants at risk for sepsis15.
Results
During the 60-month study period, 747 infants were enrolled in the study. The majority (420 infants, or 56.2 percent) were boys. Most patients (460 infants, or 61.6 percent) were assigned to the inpatient-antibiotic group; 139 (18.6 percent) were assigned to the outpatient-observation group and 148 (19.8 percent) to the inpatient-observation group. No patient's parents denied consent for their infant's enrollment in either the outpatient-observation group or the inpatient-observation group. Six patients originally assigned to the outpatient-observation group were switched to the inpatient-observation group, and five patients assigned to the inpatient-observation group were switched to the outpatient-observation group at the request of their private physicians. Because of increasing severity of illness, one patient assigned to outpatient care was hospitalized at 24 hours, and one at 48 hours. Neither was found to have serious bacterial illness. Antibiotics were administered to two patients in the inpatient-observation group after 24 hours of hospitalization. One patient had bacteremia. The other appeared acutely ill; a second sepsis workup yielded an abnormally elevated spinal fluid white-cell count. Antibiotics were administered until the diagnosis of viral meningitis was confirmed; the repeat culture of spinal fluid was positive for enterovirus. Both patients recovered uneventfully.
The discharge diagnoses of all the infants are listed in Table 1. Serious bacterial illnesses are listed in Table 2. Table 3 shows a breakdown of major categories of illness according to treatment group. All but one child with a serious bacterial illness were identified by our initial screening criteria. Our modified screening criteria (which included the band-to-neutrophil ratio) identified all patients with serious bacterial illness. When considered alone, the Infant Observation Score was generally not predictive of serious bacterial illness; 43 (66.2 percent) of the 65 children with serious bacterial illness scored 10 or less, placing them in a low-risk category for serious illness on the basis of appearance alone.
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Discussion
The care of febrile infants remains a hotly debated issue. Infants with bacterial disease are often difficult to identify on the basis of clinical presentation alone8. To ensure the early identification of all infants with serious bacterial illness, many physicians routinely use evaluation for sepsis, hospitalization, and expectant treatment with antibiotics for all febrile infants1,2,3,4,7. This approach arguably subjects many infants to excessive testing12 and exposes them to unnecessary risks and morbidity11.
One alternative management protocol calls for the outpatient treatment with parenteral antibiotics of all febrile infants judged to be at low risk for serious bacterial illness10. This approach, however, results in unnecessary antibiotic treatment for many infants (95 percent in the population described10), and it may contribute to the development of antibiotic-resistant pathogens13. The outpatient management of fever in infants without antibiotics has also been reported,9 but methodologic flaws, including the lack of consistent diagnostic workup, the lack of consistent follow-up, and the small study population make the interpretation of the results difficult.
Our large study clearly indicates that a strictly defined low-risk group of febrile infants can be cared for at home safely and effectively without the administration of antibiotics. We propose that this form of management be used only after complete laboratory evaluation for sepsis and after clinical assessment of the infant by an experienced pediatrician. Our data indicate that neither component of the evaluation is expendable. Several children in our study group who had serious bacterial illness were identified only in the clinical assessment. Other children with serious bacterial illness appeared normal on clinical assessment but had abnormal laboratory results.
There are notable differences between our protocol and that of Baskin et al.10 in terms of the methods used in identifying infants at low risk for serious bacterial illness. We used a lower peripheral-leukocyte threshold, a criterion based on the band-to-neutrophil ratio, a strictly defined tool for clinical assessment (the Infant Observation Score), and microscopical urinalysis in all cases. Our modified screening procedure was 100 percent effective in identifying infants with serious bacterial illness.
Complications of care were substantially more frequent in the inpatient-antibiotic group than in the other groups. Although two patients in each of the observation groups became more seriously ill after enrollment and required additional intervention, we did not consider these illnesses to be complications of care. None of these four patients had serious bacterial disease. For the patient in whom viral meningitis developed, the initial enrollment in the inpatient-observation group was actually beneficial. Because the initial management did not include the empirical administration of antibiotics, the possibility of partially treated bacterial meningitis at the time of reevaluation was eliminated. Thus, this child was spared an additional eight days of hospitalization and antibiotic treatment.
The advantages of our management protocol include reduced morbidity, avoidance of unnecessary antibiotic use, and reduced patient charges. We estimated that a savings of $435,000 resulted from caring for 139 febrile infants without antibiotics as outpatients. Outpatient care of all our low-risk infants would have yielded a savings of more than $898,000. The vast majority of parents preferred to care for their infants at home and seemed relieved when this option was offered to them. However, we were unable to measure the effects of home care on intangible factors such as the parents' level of emotional stress and the disruption of daily routines.
We conclude that it is possible to identify a group of febrile infants more than 28 days of age who are at low risk for serious bacterial illness and who can be safely and effectively cared for at home without antibiotics. We caution those who choose to treat infants in this way that they must first evaluate the infants carefully and completely and that subsequent evaluation procedures must be strictly carried out. Meticulous adherence to this management strategy should prove both safe and cost effective.
We are indebted to the following physicians, without whose help this project could not have been completed: Steven M. Selbst, M.D., Stephen Ludwig, M.D., Kathy N. Shaw, M.D., Jane M. Lavelle, M.D., Jacalyn S. Maller, M.D., Fred M. Henretig, M.D., and the emergency-medicine fellows and residents of the Children's Hospital of Philadelphia; we are also indebted to Patricia Parkinson, Sheila Hingorani, and Sharon Saunders for their assistance in the preparation of the manuscript.
Source Information
From the Division of General Pediatrics, Section of Emergency Medicine (M.D.B., L.M.B., J.R.A.), and the Division of Allergy, Immunology, and Infectious Diseases (L.M.B.), Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia. Presented in part at a meeting of the Ambulatory Pediatric Association, New Orleans, May 6, 1993.
Address reprint requests to Dr. Baker at the Section of Emergency Medicine, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104.
References
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