Rashmi Srivastava, MD Department of Child Health Fever in Infants and Children: Sepsis, Meningitis, and Occult Bacteremia Rashmi Srivastava, MD Department of Child Health

‘True’ Fever Occurs when IL-1, IL-6, TNF-ά or other cytokines are released from monocytes and macrophages in response to infection, tissue injury, drugs, and other inflammatory processes, increasing the body’s set point. The anterior hypothalamus maintains an inherent set point near 36ºC(98.6ºF). Normal circadian rhythm, which is highest(up to 2ºC, 3ºF) ~6pm and lowest at 6am. This accounts for increased volume of ER visits that peaks in the evening. Most true fevers follow this diurnal pattern.

‘False’ fever, aka hyperthermia Does not directly increase the body’s set point. CNS disease that directly affects the hypothalamus--ICH, infection. Diseases that increase the body’s production of heat--hyperthyroidism, malignant hyperthermia, salicylate overdose. Excess heat load--child left in a car or left next to a heater for too long. Defective heat loss mechanisms--burns, heat stroke, drugs that compromise blood flow and sweating mechanisms. Normal causes of temperature elevation include physical activity, ovulation, and environmental temperature.

Reliable Temperature Measurement All measurements are estimates of the body’s true core temp—central circulation=aorta and pulmonary artery. RECTAL—gold standard Esophageal—accurate but impractical Tactile and axillary—inaccurate, varies considerably with environmental temperature Tympanic—inaccurate in age <3 years

Benefits of fever The hypothalamus will not allow the temp to rise above 41.5ºC(107ºF). WBCs work best and kill the most bacteria at 38-40ºC(100.4-104ºF). Neutrophils make more superoxide anion, and there is more and increased activity of interferon. Coxsackie and polio virus replication is directly inhibited.

Fever without a source(FWS) 5 to 20% of febrile children have no localizing signs on PE and nothing in the history to explain the fever. By definition, less than 7 days. FWS(like fever) is most common in children younger than age 5, with a peak prevalence between 6 and 24 months of age. Those <6 months retain protective maternal antibodies against common organisms, while those 18-24 months old are more immune competent, and are at a lower risk of developing bacteremia

Diagnostic Assessment in Children Age is important as 1) etiologic pathogens, 2) clinical exam, and 3) immune system capacity changes as the newborn ages. Most break them into the first 2-4 weeks of life(neonatal), 1-3 months, and 3 to 36 months.

Infants 1 to 3 months Causes HSV(17% are 15 days to 6 weeks of age) Bacterial sepsis/meningitis Group B Strep, S. Pneumoniae, H. influenza, N. meningitidis, Enterobacteriaceae Bone and joint infections UTI Bacterial enteritis(esp Salmonella) Pneumonia Enterovirus sepsis/meningitis(July-October) The risk of bacteremia/meningitis is 3.3%, pneumonia, bone/joint infections and bacterial enteritis is 13.7% 30-50% of those who are ultimately diagnosed with bacterial meningitis have been seen by a physician within the prior week(usually 1-2 days before) and were diagnosed as having a trivial illness and discharged on oral antibiotics. These children may have had early meninigitis that was missed or occult bacteremia that progressed to meningitis.

Infants 1 to 3 months Infants who are toxic and febrile have a much higher risk of serious bacterial infection. They should be admitted, have a full sepsis workup, and given antibiotics/antiviralsAmpicillin and Cefotaxime. Infants who are nontoxic and febrile who meet all Rochester criteria can ‘safely’ be treated as an outpatient. Generally, 1-2.9% of children meeting these criteria will develop a serious bacterial infection, 0.7% bacteremia, 0.14% meningitis.

Infants 1 to 3 months Rochester Criteria/Low Risk Criteria Nontoxic—most critical and difficult Previously healthy, not low birth weight No focal bacterial infection on PE except Otitis Media WBC 5,000-15,000/mm3 (normal) Bands<1500/mm3 (normal) Normal urinalysis, including gram stain If diarrhea, must be non-bloody and WBC<5/hpf. If respiratory symptoms present, normal CXR Negative predictive value 98.9%

Infants 1 to 3 months If all of the criteria are met, then there are 2 options for outpatient management: 1) Blood, Urine Cultures, LP, Ceftriaxone 50mg/kg IM (to 1g), and return for reevaluation within 24 hours. 2) Blood, Urine Cultures and careful observation. Parents should have mature judgement, can return within 30 minutes and have a thermometer and a phone. IF NO LP IS DONE, DO NOT GIVE CEFTRIAXONE AS IT WILL COMPROMISE F/U IF THE PATIENT IS STILL FEBRILE

Infants 1 to 3 months Follow-up of low risk infants If all cultures negative: afebrile, well appearingCareful observation Blood cultures negative: well appearing, febrileCareful observation, may consider second dose of Ceftriaxone Blood culture positiveadmit for sepsis workup and parenteral antibiotics pending results Urine culture positive: if persistent feveradmit for sepsis workup, parenteral antibiotics pending results. If afebrile and welloutpatient antibiotics

Infants 3 to 36 months Infant sepsis syndrome: Age 3-36 months Fever>39ºC ANC>10,000 If a child meets all 3 criteria, he has a 3% risk for pneumococcemia. If untreated, 3% will progress to meningitis. Bacteremia risk peaks at 8-12 months Pneumococcal sepsis peaks at 1 year, then drops off Pneumococcal meningitis peaks at 3-5 months OM, sinusitis, pneumonia, response to antipyretics, and social status do not significantly alter risk. Other causes: HHV6(15%), UTI(girls 3%, boys 0.6%), menigococcemia(0.1%), Salmonella(0.2%), H. influenza(0.05%), Enterovirus(JulyOctober).

Infants 3 to 36 months UA with micro, CBC with differential, Blood Cultures LP if meningeal signs, not wanting to be held or moved, petechiae, purpura or toxic. Antimicrobials: OM or pneumonia: cover for pneumococcus, non-typable H. flu and Moraxella: amoxicillin+augmentin, ceftriaxone URI or no focus: cover for pneumococcus and menigococcus: amoxicillin(80-100mg/dg/day), ceftriaxone Pneumococcemia: promptly reassess, if well, should at least treat with 1 dose ceftriaxone. PCV-7 >97% protection, thus all pneumococcal sepsis will decrease by 90%. So CBC and antimicrobials for this age group is becoming less critical. Toxicity assessment: loss of alertness, decreased activity, irritability, higher fever, sustained fever, anorezia, vomiting, pallor, grunting, and maternal worry.

Occult Bacteremia 5% of children with FWS have OCCULT BACTEREMIA The presence of a positive blood culture in kids who look well enough to be treated as outpatients and in whom the positive results are not anticipated.

Occult Bacteremia Streptococcus pneumonia is responsible for 2/3 to ¾ of all cases. Peak prevalence between 6 and 24 months Association with high fever(39.4ºC or 103ºF) High WBC count(>15,000) Absence of evident focal soft tissue infection. Neisseria meningitidis, Haemophilus influenzae type b, and salmonellae account for most of the remaining cases.

Risk of Occult Bacteremia Low Risk Age >3yr Temp <39.4ºC WBC >5000 and <15,000 High Risk <2yr >40ºC(104ºF) <5000 or >15,000 Hx of contact with H. Flu or N. meningitidis OB has a low prevalence, so even though WBC is a sensitive and specific screening test, it has a low PPV. So the test does not discriminate between children who have FWS who are bacteremic and those who are not. Therefore, blood culture is the gold standardstill has a high number of false positives, take 24-48hrs, and most cases of occult pneumococcal bacteremia clear without treatment.

Occult Bacteremia Empiric antibiotics should be targeted against S. pneumoniae, N. meningitidis, and H. influenza Amoxicillin Augmentin, Bactrim, 2nd or 3rd gen Cephalosporins Single dose Ceftriaxone 50-75mg/kg Followup is essential!