By Neamat Ibrahim Almasri, MBBS; Maha Khalil Abass, MBChB; and Philip R. Fischer, MD

Drs. Almasri and Abass are pediatric residents at Sheikh Shakhbout Medical City in Abu Dhabi, United Arab Emirates. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates.

SYNOPSIS: New guidelines provide specific guidance for the use of diagnostic testing, antimicrobial treatment, and ongoing care based on age for children between 8 and 60 days of age.

SOURCE: Pantell RH, Roberts KB, Adams WG, et al. Evaluation and management of well-appearing febrile infants 8 to 60 days old. Pediatrics 2021;148:e2021052228.

Whether practicing pediatrics for 40 years or currently in training, the management of infants with fever who look well is challenging. Various practice parameters have been proposed, and care is far from standardized. In fact, the length of stay for hospitalized febrile infants varies from 30 to 100 hours at various children’s hospitals.1 Relevant to febrile infants, there have been changes in epidemiology (group B streptococcal infection is less common because of maternal screening and treatment), diagnosis (more rapid blood culture results, antigen detection, increasing use of inflammatory marker tests), and understanding of the risks of hospitalization (economic, social, infectious). Thus, the American Academy of Pediatrics convened an expert group that solicited broad input from a variety of professionals and from families while reviewing current knowledge and providing updated guidelines for the testing and treatment of febrile infants who look well.

Of note, these new guidelines apply to previously healthy term infants with rectal temperatures of greater than or equal to 38.0°C who appear to be well (other than the fever) with no indication from the history and physical exam of a site or source of infection (and no specific concern for herpesvirus infection). Because of varying risks by age, these guidelines do not deal with children during the first week of life. And, evaluation and management were customized for three different age subsets within the 8- to 60-day age range.

The expert committee suggests that these guidelines not be used for children with bronchiolitis. Children with bronchiolitis generally are very unlikely to have meningitis or bacteremia concurrently. These guidelines can be used in children younger than 1 month of age with otitis media and positive viral antigen tests, since neither otitis nor positive virus tests at this age seems to alter the risk of having meningitis or bacteremia.

With that background and context, we review some of the key action statements produced by this expert group. Of course, more clarification and detail are available in the original 38-page article.

Evaluation and Management of Well-Appearing Febrile Infants, Aged 8 to 21 Days

During the second through fourth weeks of life, clinical and initial laboratory evaluation is unable to definitively rule out invasive bacterial infection. Thus, in a well-appearing 8- to 21-day-old infant, it is strongly recommended that clinicians obtain the following:

  • urine specimen by catheterization or suprapubic aspiration of the bladder for urinalysis and, if the urinalysis result is positive, for culture; 
  • blood culture;
  • cerebrospinal fluid for analysis (white blood cells, protein, glucose, Gram stain) and culture for bacteria. 

At this age, inflammatory marker results should not have significant impact on the decisions of hospitalization and initiation of treatment. Infants in this age group should be hospitalized and monitored actively by experienced nursing staff while awaiting bacterial culture results, regardless of inflammatory marker levels.

To reduce morbidity and mortality from an anticipated bacterial infection in this age group, infants should be treated empirically with parenteral antimicrobials. The eventual duration of treatment depends on culture results, the nature of the infection, the responsible organism, and the infant’s response to the treatment. When initial cerebrospinal fluid results suggest the presence of meningitis, ampicillin and ceftazidime should be given. When initial urinalysis results suggest the presence of a urinary tract infection and when initial spinal fluid and urine results do not suggest a focus of infection, therapy with ampicillin and either ceftazidime or gentamicin is advised. When culture results are negative for 24-36 hours (or are positive only for contaminants) and infants are asymptomatic or improving with no other indication for hospitalization, parenteral antimicrobials should be discontinued, and hospitalized patients can be discharged home.

Evaluation and Management of Well-Appearing Febrile Infants, Aged 22 to 28 Days

During the final week of the first month of life, less aggressive testing may be considered. In well-appearing but febrile 22- to 28-day-old-infants, it is strongly recommended that clinicians obtain a blood culture and a urine specimen via catheterization or suprapubic aspiration for urinalysis. If the urinalysis is abnormal, culture should be performed. Alternatively, obtain a urine specimen by bag, spontaneous void, or stimulated void for urinalysis and, if the urinalysis result is positive, obtain a catheterization or suprapubic aspiration specimen for culture.

The recommendation of obtaining cerebrospinal fluid for analysis and culture from infants in this age group depends on the presence or absence of abnormal inflammatory markers. Inflammatory markers are considered abnormal at the following levels: procalcitonin > 0.5 ng/mL, C-reactive protein (CRP) > 20 mg/L, and absolute neutrophil count > 4,000 per mm3 (or > 5,200 per mm3, expert opinions vary). If any abnormal inflammatory marker result is obtained, physicians are recommended to obtain cerebrospinal fluid for analysis and culture. Thus, testing of inflammatory markers is recommended in this age group, unlike in younger infants.

The decision of hospitalization or home management can be challenging. It is strongly recommended to hospitalize and initiate parenteral antimicrobials for infants in this age group with either a positive urinalysis or a cerebrospinal fluid analysis that is suggestive of bacterial meningitis, regardless of inflammatory marker levels. Clinicians may consider parenteral antibiotics in hospitalized infants if the cerebrospinal fluid analysis is normal, urinalysis is negative, and an abnormal inflammatory marker result is obtained. An abnormal inflammatory marker result indicates a risk of bacteremia > 5%, a threshold sufficiently high to recommend empiric antimicrobial treatment in the hospital even if cerebrospinal fluid and urinalysis results are normal.

If all inflammatory marker levels are normal and the urinalysis and cerebrospinal fluid analysis do not suggest infection, the risk of bacteremia is between 1% and 2% (i.e., to prevent one necessary treatment being missed, the number needed to treat is 50 to 100). There are insufficient data to estimate precisely the risk of bacterial meningitis with a normal cerebrospinal fluid analysis, but the risk appears to be quite low. Physicians may administer parenteral antimicrobials in hospitalized infants when they have negative initial cerebrospinal fluid and urine results with no elevation of inflammatory marker levels. Clinicians may consider use of parenteral antimicrobials in infants who will be managed at home with negative urinalysis, negative cerebrospinal fluid analysis, and normal inflammatory marker levels.

Infants can be managed at home when the following criteria are met: 1) the urinalysis is normal; 2) no tested inflammatory maker level is abnormal; 3) cerebrospinal fluid analysis is normal or enterovirus-positive; 4) verbal and written instructions have been given for monitoring during the period of time at home; 5) follow-up plans have been created and are in place for reevaluation in 24 hours; and 6) plans have been created and are in place in case the patient’s clinical status changes, including a method of communication between the family and providers and access to emergency medical care.

Whether a decision was made for hospitalization or home management, it is recommended to stop parenteral antimicrobials when all cultures are negative after 24 to 36 hours and if the infant still looks clinically well. On the other hand, when blood, cerebrospinal fluid, or urine bacterial cultures are positive, infants should be treated with antimicrobials for the duration that is indicated by the nature of infection, causative agent, and clinical response of the infant. When cerebrospinal fluid is suggestive of bacterial meningitis, parenteral ampicillin and ceftazidime, in combination, are the first-choice antibiotics. Parenteral ceftriaxone has been shown to be effective against urinary tract infection and bacteremia with no other focus identified.

Evaluation and Management of Well-Appearing Infants, Aged 29 to 60 Days

At this age, a urinalysis should be done. If the urinalysis is abnormal, urine obtained via catherization or suprapubic aspiration should be cultured. Blood culture should be done, and inflammatory markers should be tested. Cerebrospinal fluid analysis and culture are not necessarily needed if the urinalysis and inflammatory marker testing are normal. Absolute neutrophil counts are helpful but are not as accurate as the newer inflammatory markers CRP and procalcitonin.

Parenteral antimicrobial therapy with ceftriaxone or ceftazidime and vancomycin (for the possibility of resistant S. pneumococcus) should be administered if the cerebrospinal fluid analysis suggests the presence of meningitis and may be administered if an inflammatory marker result is elevated in the absence of abnormal urine and cerebrospinal fluid results. Oral antimicrobial therapy (cephalexin or cefixime) should be provided if the urinalysis suggests infection and cerebrospinal fluid and inflammatory marker results are normal. Pending culture results, antimicrobial therapy is not necessarily required if the urinalysis is not suggestive of infection, the cerebrospinal fluid results are normal (or enterovirus-positive), and all inflammatory markers tested yield normal results. As for children in the previously described age group, observation at home is possible with follow-up plans established if the urinalysis, cerebrospinal fluid results, and inflammatory marker tests all are normal. Antimicrobial therapy should be stopped, and the child should be discharged from the hospital (if hospitalized) if cultures are negative at 24 to 36 hours and the child is doing well with no other indication for hospitalization and antibiotic treatment. Urinary tract infection (with other test results normal and the child improving) can be treated with oral antimicrobial therapy.

Conclusion

These expert recommendations are reasonable and are based on solid evidence. And, they are novel. Knowing and experiencing extreme variations in the care of febrile well-appearing infants in and between different pediatric centers, we believe that application of these recommendations will reduce invasive testing, target the use of CRP and calcitonin testing and interpretation, reduce initiation of antibiotic therapy, minimize the duration of presumptive antibiotic treatments, and result in better outcomes for children.

REFERENCE

  1. Stephens JR, Hall M, Cotter JM, et al. Trends and variation in length of stay among hospitalized febrile infants 60 days old. Hosp Pediatr 2021;11:915-926.