Fever without apparent source on clinical examination

Current Opinion in Pediatrics

Volumn 17, Issue 1, 2005, Pages 93-110

  McCarthy, Paul ^a,b  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b YALE UNIVERSITY   (United States)

Author keywords

Acute illness; Bacteremia; Clinical judgment; Diagnosis; Fever

Indexed keywords

CEFTRIAXONE; CEPHALOSPORIN; CORTICOSTEROID; DEXAMETHASONE; PENICILLIN G; PNEUMOCOCCUS VACCINE; RIFAMPICIN; VANCOMYCIN;

BACTEREMIA; BACTERIAL INFECTION; BACTERIAL MENINGITIS; CLINICAL EXAMINATION; CLINICAL FEATURE; CLINICAL TRIAL; DIAGNOSTIC APPROACH ROUTE; FEVER; HUMAN; LABORATORY DIAGNOSIS; LABORATORY TEST; PRIORITY JOURNAL; RESPIRATORY SYNCYTIAL PNEUMOVIRUS; REVIEW; SEROTYPE; STREPTOCOCCUS INFECTION; URINARY TRACT INFECTION; VACCINATION;

BACTEREMIA; CHILD, PRESCHOOL; FEVER OF UNKNOWN ORIGIN; HUMANS; INFANT; MENINGITIS; PNEUMOCOCCAL INFECTIONS; PNEUMOCOCCAL VACCINES; RESPIRATORY SYNCYTIAL VIRUS INFECTIONS; URINARY TRACT INFECTIONS;

EID: 12744262845     PISSN: 10408703     EISSN: None     Source Type: Journal    
DOI: 10.1097/00008480-200502000-00019     Document Type: Review

References (30)

1. McCarthy P, Walls T, Cicchetti D, et al. Prediction of resource use during acute pediatric illnesses. Arch Pediatr Adolesc Med 2003; 157:990-996. The authors observed a cohort of 316 children until 30 months of age. They found that during the 1983 ill-child visits the best predictor of resource use among multiple predictors measured was the quality of the mother - child interaction, the less optimal the interaction the greater the resource use. The authors recommend that teaching about clinical judgment should incorporate assessment of the mother - child interaction.
2. Flores G, Abreu M, Chaisson CE, Sun D: Keeping children out of hospitals: parents' and physicians' perspectives on how pediatric hospitalizations for ambulatory care-sensitive conditions can be avoided. Pediatrics 2003; 112:1021-1030. The authors studied 554 children consecutively hospitalized for potential avoidable hospital conditions and documented that the perceptions of parents and physicians differed as to how the hospitalization could have been avoided and the proportion that are avoidable. Based on study results the authors recommend teaching about these conditions to patients they identify as being at risk for this type of hospitalization.
3. Benin AL, Vitkauskas G, Thonquist E, et al. Improving diagnostic testing and reducing overuse of antibiotics for children with pharyngitis: a useful role for the electronic medical record. Pediatr Infect Dis J 2003; 22:1043-1047. The authors studied data from the electronic medical record and administrative databases and focused on the diagnosis and treatment of pharyngitis. They documented that the electronic medical record allowed better analysis of the factors related to noncompliance with published guidelines for diagnosis and management of pharyngitis. Based their findings, the authors planned to initiate interventions to improve compliance with guidelines.
4. Ruggeberg JU, Ketteler K, MacKenzie CR, et al. Blood culture sampling rates at a German pediatric university hospital and incidence of invasive pneumococcal disease. Infection 2004; 32:78-81. The authors reported on blood cultures of children at their pediatric center in Germany in a 3-year period and documented that the rate of performing blood cultures in certain conditions, such as fever of unknown origin and pneumonia, was low. The authors stated that there may be under-ascertainment of a common etiology of these conditions, pneumococcal bacteremia, and call for increased surveillance and standardized methods of ascertainment to provide better estimates of the occurrence of invasive pneumococcal disease.
5. Ulloa-Gutierrez R, Avila-Aguero ML, Herrera ML, et al. Invasive pneumococcal disease in Costa Rican children: a seven year survey. Pediatr Infect Dis J 2003; 22:1069-1074. The authors reported on 135 episodes of pneumococcal isolates from normally sterile body sites at their children's hospital in Costa Rica. The results documented a significant morbidity and mortality. For example, 41% of children had meningitis and, in the total group of children, the case fatality rate was 14%. Sequelae at discharge were seen in 73% of children with meningitis. Nearly one half of children with bacteremia had an underlying illness. The study documented significant morbidity and mortality from pneumococcal disease; the authors believe their data will help in the evaluation of implementation of the pneumococcal vaccine in their country.
6. Campbell JD, Kotloff KL, Sow SO, et al. Invasive pneumococcal infections among hospitalized children in Bamako, Mali. Pediatr Infect Dis J 2004; 23:642-649. The report, from the largest pediatric inpatient facility in Bamako, Mali, reported on invasive pneumococcal disease at their institution over a 1-year period after prospective surveillance with blood cultures was initiated. Of the 106 children with invasive pneumococcal disease, 47 had meningitis. The overall case fatality rate was 24% and may have been due to the late presentation of gravely ill children according to the authors. Ninety-one percent of serotypes that caused invasive pneumococcal disease are contained in the 11-valent pneumococcal conjugate vaccine. The authors believe their data will be helpful to public health officials making decisions implementing pneumococcal conjugate vaccine in Mali.
7. Black S, Shinefield H, Baxter R, et al. Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J 2004; 23:485-489. This is an excellent report and documented the effect of initiation of heptavalent pneumococcal conjugate vaccine on children who were provided primary care in Northern California Kaiser Permanente. The study documented a significant decline in invasive pneumococcal disease, a decrease in antimicrobial resistance, a herd effect in children and adults and no replacement of vaccine serotypes of S. pneumoniae by non-vaccine serotypes as the cause of invasive disease.
8. Kaplan SL, Mason EO Jr, Wald ER, et al. Decrease of invasive pneumococcal infections in children among 8 children's hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004; 113:443-449. This study reported on invasive pneumococcal disease in a 9-year period at 8 children's hospitals and compared the occurrence of this entity in the 7 years before and 2 years after the introduction of the 7-valent pneumococcal conjugate vaccine. There was a 63% and 77% decline in pneumococcal disease in children < 24 months of age in the 2 years, respectively, post-vaccine introduction. Unlike the study of Black et al., there was an increase in the occurrence of non-vaccine serogroups (especially serogroups 15 and 33) as the cause of invasive disease in the 2 years post-vaccine introduction, 28% in 2001 and 66% in 2002 in children < 24 months of age. Penicillin nonsusceptibility of pneumococcal isolates decreased post-vaccine introduction. The authors make useful recommendations about surveillance for invasive pneumococcal disease.
9. Stoll ML, Rubin LG: Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine. Arch Pediatr Adolesc Med 2004; 158:671-675. At their institution, and based on their study result that only 3 of 329 blood cultures on highly febrile young children were positive for S. pneumoniae and that an elevated total white blood count and absolute Neutrophil count were not highly predictive of pneumococcal bacteremia because of the low occurrence of disease, the authors questioned the value of obtaining blood cultures and complete blood counts on previously well, highly febrile young children, especially those who have received the 7-valent pneumococcal vaccine.
10. Bonsu BK, Harper MB: Differentiating acute bacterial meningitis from acute viral meningitis among children with cerebrospinal fluid pleocytosis: a multi variable regression model. Pediatr Infect Dis J 2004; 23:511-517. This study developed a diagnostic model to differentiate bacterial from enteroviral meningitis that was based on the analysis of 60 children with bacterial and 82 children with enteroviral meningitis. They incorporated three predictors in their model: age (higher in patients with viral meningitis); total neutrophil count in the cerebrospinal fluid (higher in bacterial meningitis); and total protein content in the CSF (higher in bacterial meningitis).
11. Gorelick MH, Shaw KN: Clinical decision rule to identify young febrile children at risk for UTI. Arch Pediatr Adolesc Med 2000; 154:386-390.
12. Gorelick MH, Hoberman A, Kearney D, et al. Validation of a decision rule identifying febrile young girls at high risk for urinary tract infection. Pediatr Emerg Care 2003; 19:162-164. The study tested a prediction model for urinary tract infection in girls up to 2 years of age published by investigators at another site. In this validation study of the prediction model, 98 patients with urinary tract infection and 114 comparison patients with negative urine cultures were evaluated. Three of the five risk factors published in the original model were found to be the best predictors: white race, absence of another source of fever, and fever for at least two days. A fourth predictor in the original model, fever ≥ 39°C, had borderline association. The fifth predictor in the original model, age < 12 months, was not found to add to prediction of UTI. The authors then reported on the effect of using two or three risk factors on the sensitivity and false positive rates for predicting UTI.
13. Ibia EO, Imoisili M, Pikis A: Group A β-Hemolytic streptococcal osteomyelitis in children. Pediatrics 2003; 112:e22-e26 (accessed July, 2004). This is an excellent report of osteomyelitis in 29 children caused by Group A beta hemolytic streptococcus (GABHS) over a 16 1/2 year period at one institution. The report compared this entity with osteomyelitis caused by S. pneumoniae and S. aureus at their institution over the same period and documented important similarities and differences. A risk factor for GABHS osteomyelitis was identified: varicella infection was seen in 17% of patients with this entity but not in patients with osteomyelitis caused by S. pneumoniae or S. aureus.
14. 3 per cu mm). No significant difference in the clinical severity score (based on fever, irritability and tympanic membrane bulging and redness) was seen in patients with differing bacterial etiologies.
15. Mandl K, Stack A, Fleisher G: Incidence of bacteremia in infants and children with fever and petechiae. J Pediatr 1997; 131:398-404.
16. Willwerth BM, Harper MB, Mandl KD: Prolonged partial thromboplastin times in children with fever and petechiae without bacteremia or sepsis. Pediatr Emerg Care 2003; 19:244-247. The authors performed a secondary analysis of a cohort of 258 children with fever and petechiae who had Prothrombin Time (PT) and Partial Thromboplastin Times (PTT) done; in this report they constructed a control group of age-matched patients without fever with blood drawn for PT and PTT. The PTT was prolonged in 23% of study patients but only 6% of controls. The authors speculate that the prolonged PTT in study patients may be due to undiagnosed Von Willebrand's Disease or the presence of Lupus anticoagulant.
17. Freedman SB, Roosevelt GE: Utility of anaerobic blood cultures in a pediatric emergency department. Pediatr Emerg Care 2004; 20:433-436. In a retrospective analysis, the authors studied the utility of obtaining anaerobic blood cultures in an emergency department over a three year period. Thirty-one of 278 blood cultures that grew a pathogen were positive only in the anaerobic medium and 26 of these patients had an underlying medical condition, such as a central venous line, being immunocompromised, or having congenital heart disease. The authors question the value of obtaining anaerobic blood cultures in febrile children who do not have underlying medical conditions.
18. Feigin RD: Use of corticosteroids in bacterial meningitis. Pediatr Infect Dis J 2004; 23:355-357. This is a concise and useful review of the rationale and effectiveness of dexamethasone therapy in children with bacterial meningitis. The author provided support from the literature that dexamethasone is useful in preventing hearing loss in children with meningitis caused by H. influenzae b; there is a possible benefit of dexamethasone if used early in children 6 weeks of age and older with meningitis caused by S. pneumoniae.
19. Purcell K, Fergie J: Concurrent serious bacterial infections in 912 infants and children hospitalized for treatment of respiratory syncytial virus lower respiratory tract infection. Pediatr Infect Dis J 2004; 23:267-269. This is one of four reports in the study period (see references [20, 21, 22] below) that focused on the occurrence of serious bacterial infections in infants with Respiratory Syncytial Virus (RSV) infection. This study was retrospective and reported on 912 patients seen at one institution over a 2-year period; 338 were 90 days of age or less. None of the 198 blood cultures and 83 CSF cultures done on children < 90 days of age was positive. However, of the 142 urine cultures done on infants < 90 days of age, 13.3% were positive in those < 30 days and 14.9% were positive in those 30 to 90 days of age. The rate of positive urine cultures was higher than in other reports [references 20, 21, 22] and may have been due to not quantitating urine bacterial colony counts < 50,000 per cu mm or greater than 50,000 organisms per cu mm.
20. Levine DA, Platt SL, Dayan PS, et al. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 2004; 113:1728-1734. This is the only multi-institution prospective study in the review period of the relation of RSV positivity to serious bacterial infections in febrile infants (in this study, ≤ 60 days of age) and was done over a 3-year period at 8 centers participating in the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. In the study, 1248 patients were enrolled and clinical data were prospectively and carefully gathered. Serious bacterial infections occurred in 7% of the 269 patients who were RSV positive and in 12.5% of the 979 RSV-negative patients. No bacterial meningitis was seen in RSV-positive patients. Three episodes of bacteremia (all in infants < 20 days of age) or 1.1% of blood cultures done in RSV-positive patients were documented (versus a 2.3% occurrence of positive blood cultures in RSV-negative patients). Fourteen of 261 urine cultures or 5.4% were positive (10.1% were positive in the RSV-negative group). The occurrence of serious bacterial infection was 10.1% in RSV-positive children ≤ 28 days and 5.5% (all urinary tract infection) in children >28 days. Thus the authors state that a sepsis workup is indicated in infants ≤ 28 days even if an RSV infection is documented and the presence of RSV does not obviate the need for urine culture in infants > 28 days.
21. Titus MO, Wright SW: Prevalence of serious bacterial infections in febrile infants with respiratory syncytial virus infection. Pediatrics 2003; 112:282-284. This was a retrospective analysis of 174 febrile infants who were positive for RSV; they were seen over a 4-year period at one institution. They were matched by gender and age to 174 control subjects who were also admitted to the hospital, were febrile but were RSV negative. Only 2 of the 174 RSV positive patients had serious bacterial illnesses, both urinary tract infections; in the control group, 22 patients had SBI (12.6%) including meningitis (1), bacteremia (4), and urinary tract infection (17). The occurrence of SBI, 1.2%, in RSV-positive infants was lower than that of Levine et al., but this study was retrospective and from one institution. The authors do recommend that urine cultures be obtained on all febrile infants with RSV infections.
22. Melendez E, Harper MB: Utility of sepsis evaluation in infants 90 days of age or younger with fever and clinical bronchiolitis. Pediatr Infect Dis J 2003; 22:1053-1056. This retrospective report focused on febrile infants ≤ 90 days of age with fever and bronchiolitis but in whom the RSV status was not documented. It was from a single institution over a 5-year period. The authors identified 329 infants. None of the 309 blood cultures, none of 199 spinal fluid culture, and 6 (or 2%) of the urine cultures grew a pathogen. All six infants with urinary tract infection were ≥ 33 days of age and only one had an abnormal urinalysis. Although no RSV screening was done, the no (or low occurrence) of bacteremia and meningitis and the documentation of positive urine cultures was similar to reports cited previously [20,21,22] but the occurrence of urinary tract infection only in infants ≥ 33 days of age is dissimilar.
23. Pantell RH, Newman TB, Bernzweig J, et al. Management and outcomes of care of fever in early infancy. JAMA 2004; 291:1203-1212. This report summarizes the assessment over a three year period of 3066 consecutively enrolled febrile infants up to 90 days of age in 219 practices in 44 states. The study was done within the Pediatric Research in Office Settings (PROS) network of the American Academy of Pediatrics. Although the clinical assessment was standardized, testing, antibiotic use and hospitalization were at the discretion of the examining physician. Many patients had 1 or several follow up visits after the initial evaluation. Bacteremia/bacterial meningitis, the outcome measure, occurred in 63 children. Three clinical factors - ill appearance, age <25 days and temperature ≥38.6°C - would have identified all but 4 of these 63 children. Despite a selective testing and treating strategy, practitioners started antibiotic therapy at the initial visit in 61 of 63 (96.8%) infants with bacteremia/bacterial meningitis, similar to the proportion of infants (95.2%) with bacteremia/meningitis who would have been identified if published guidelines were followed. These results, which may not be generalizable to patients seen in a pediatric emergency department, demonstrate the importance of experienced clinical judgment and follow-up in managing febrile infants in pediatric practice.
24. Baker MD, Bell LM, Avner JR: Outpatient management without antibiotics of fever in selected infants. N Engl J Med 1993; 329:1437-1446.
25. Bonsu BK, Harper MB: Identifying febrile young infants with bacteremia: is the peripheral white blood cell count an accurate screen? Ann Emerg Med 2003; 42:216-225. In this retrospective review the authors studied the value of the peripheral white blood count to detect bacteremia in febrile infants 0 to 89 days of age. They reviewed 3810 infants and 38 or 1% had bacteremia. In a careful analysis, the study documented that the odds of bacteremia were increased only modestly at WBC values < 5000 and ≥ 15,000 per cu mm. The authors state that the WBC alone should not be used to determine whether a blood culture should be done on febrile infants.
26. Byington CL, Rittichier KK, Bassett KE, et al. Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. Pediatrics 2003; 111:964-968. This comprehensive report of 1298 infants ≤ 90 days of age with fever seen at a single institution emergency department over a nearly 3-year period noted that 105 had serious bacterial infections and 56 or 53% of the pathogens identified were resistant to ampicillin. These data led the authors to several conclusions about choosing antibiotic coverage; for example, at their institution, in the infant < 60 days of age with suspected bacterial meningitis ampicillin is still used to cover Group B streptococcus and Enterococcus but a cephalosporin along with the more traditional gentamicin is added to cover potentially resistant organisms. The authors speculated that the use of intrapartum antibiotics, most often ampicillin, in 30% of mothers in their geographic area may be the cause of this resistance phenomenon.
27. Ciftci E, Ince E, Dogru U: Pyrexia of unknown origin in children: a review of 102 patients from Turkey. Ann Trop Paediatr 2003, 23:259-263. This report on fever of unknown origin in children at a Pediatric Unit in Ankara, Turkey outlined the diagnoses in 102 patients who were evaluated. The diagnostic approach outlined in the article is of interest to readers. Infections were the most common cause (N = 45). The types of infections, such as brucellosis in 8 patients and enteric fever in 9 patients, were of interest. The occurrence of Familial Mediterranean in 8 patients was also of interest. Unlike reports in the United States, biopsy/aspiration of tissue were helpful in the diagnosis of a significant number of patients, N = 27.
28. Okwara FN, Obimbo EM, Wafula EM, Murila FV: Bacteraemia, urinary tract infection and malaria in hospitalised febrile children in Nairobi: is there an association? East Afr Med J 2004; 81:47-51. The study reported on 264 febrile children admitted to a teaching hospital in Nairobi, Kenya who had no focus of infection at admission. One hundred and fifty-eight had malarial parasitemia. Thirty-two children had bacteremia and 38 had urinary tract infection. The prevalence of bacteremia and urinary tract infection was similar in those with and without malarial parasitemia. The occurrence of malarial parasitemia in children with fever of unknown cause is notable. The authors speculate that the high occurrence of bacteremia may be related to malnutrition and to HIV infection, which is present in 220,000 children in their country but was not tested for in this study.
29. La Regina M, Nucera G, Diaco M, et al. Familial Mediterranean fever is no longer a rare disease in Italy. Eur J Hum Genet 2003; 11:50-56. This study from Italy reported on 71 patients in whom a new diagnosis of Familial Mediterranean Fever (FMF) was made based on clinical findings and/or genetic analysis. The study included both adults and children and makes many useful points about the manner in which this entity presented in children; for example, 8 patients with FMF who presented as children had a history of appendectomy without disappearance of episodes of abdominal pain.
30. Silpapojakul K, Varachit B, Silpapojakul K: Paediatric scrub typhus in Thailand: a study of 73 confirmed cases. Trans R Soc Trop Med Hyg 2004; 98:354-359. This is an excellent review of the epidemiologic, clinical, and laboratory characteristics as well as the treatment of 73 patients with scrub typhus seen at a pediatric unit in a General Hospital in Thailand over a 17-year period. The authors nicely related clinical findings to the pathophysiologic aspects of the disease, especially the fact that it is a vasculitis caused by a rickettsial endotheliopathy. They effectively contrast the findings in scrub typhus with those of dengue hemorrhagic fever and leptospirosis.