Fever in Infants

Field: Medicine (Health Sciences)

A 7-month-old infant is brought to the emergency department by his mother with a fever. She did not have a thermometer at home, but he felt warm. He threw up milk 30 minutes prior to arrival, but has had three wet diapers in the past 12 hours. He has been in previously good health, and was the product of a full-term delivery with a birth weight of 7 pounds, 12 ounces. There are no sick contacts at home, but he spends two afternoons each week in day care. At the time of arrival to the ED, his temperature was 39.4°C (102.9°F). He appears sluggish at first, but perks up somewhat after 100 mg acetaminophen (given in triage, based upon 15 mg/kg). There is no rash, and, in fact, no physical findings indicative of a source for fever. After an observation period during which he tolerates apple juice by mouth, he is discharged home, at which time his repeat temperature is 38.1°C (100.6°F). The mother is given instructions to return to the emergency department if there is any failure to tolerate PO fluids over the next four hours, any decreased urine output, or any alteration in behavior. The mother is much relieved that the temperature is down, understands the instructions, and agrees to follow-up with her pediatrician in two days (Monday) when the office opens. Unfortunately, the baby does not tolerate feedings within four hours. He returns to the emergency department six hours later, at 4 a.m. Sunday. He is more lethargic, and now has a rash on his face and trunk. After cultures and antibiotics, the child is transferred to a local childrens' hospital 20 miles away. Blood cultures are positive for Neisseria meningitidis; cerebrospinal fluid is normal. He has a stormy course, during which he loses eight fingers, and both legs below the knee. The mother brings suit against the emergency physician for the first visit. Definition of Fever Whether temperature is the most important, or even second, third, or fourth most important vital sign, is a moot point. It is a source of concern for parents now and for the foreseeable future. There has to be a line in the sand drawn somewhere, and that line generally is a temperature higher than 100.4°F or 38°C in someone who has been resting. This is assuming a rectal temperature; axillary and TM temperatures are unreliable in young children.Table: The Yale Observation ScoreFever is present in 19 to 30 percent of encounters in an office-based pediatric practice, and accounts for 10 to 20 percent of pediatric visits to emergency departments. Any busy community emergency department sees this every day. Bacteremia is present in two to three percent of febrile infants under 3 months, in approximately 10 percent of febrile infants 1 to 2 months of age, and in approximately 13 percent of febrile infants under 1 month of age. The primary drivers of recommendations for testing and treatment of children with fever without a clear source have been meningitis, meningococcemia, and sepsis. Most children with fever have a benign outcome, and even most bacterial illnesses such as gastroenteritis, urinary tract infections, sinusitis, or even pneumonia, are not immediately life-threatening. Meningococcemia, meningitis, and sepsis are relatively rare, but the lethality and morbidity is so high that there is a large volume of literature and effort to detect those rare cases. This article focuses on bacteremia in infants who otherwise look well. For purposes of this discussion, assume that the following states are not present (immunocompromised patients): sickle cell disease, asplenia, complement/properidin deficiency, agammaglobulinemia, AIDS, congenital heart disease (endocarditis), central venous line, and malignancy. Standard of Care If there is a standard of care, it certainly is not being practiced uniformly. In one report, fewer than half of infants with a temperature higher than 39°C received any laboratory testing. In one pediatric practice, nine percent of those diagnosed with viral illness were prescribed antibiotics. A major reason for many physicians — pediatricians and emergency physicians alike — not practicing in a uniform manner is that truly serious disease in febrile children is rare. The estimated incidence of bacterial meningitis is 33 per 100,000 population in the United States per year, and for bacterial meningitis or meningococcemia combined: 0.06 percent (15 in 26,970 child years). Doctors could turn away a lot of febrile children at the door unseen to follow up at their primary care physician's office during bankers' hours before ever getting burned on a case. The extensive literature on the subject is an effort to ferret out those rare cases to allow zero tolerance for infectious disasters in infants. Meningococcemia presents a major challenge because of its rarity and its lethality. Occult Bacteremia Occult bacteremia (OB) by definition is identified bacteremia in patients without clinical evidence of sepsis (shock, purpura), and no clear foci of infection or toxic appearance. This occurs in 1.6 to 3 percent of children with temperatures higher than 39°C and no obvious source, and less than one percent if an identifiable source such as gingivostomatitis, croup, varicella, bronchiolitis is present on physical examination. The incidence of OB is higher (8–15%) in children 3 to 36 months of age with a white blood count (WBC) greater than 15,000/mm3, an absolute band count (ABC) greater than 1500, or an absolute neutrophil count (ANC) greater than 10,000. Expect that 2.8 percent of febrile infants (>39°C) under 24 months who look clinically well and have no site of infection detectable on physical examination will have positive blood cultures. Historically, the most common bacterial infections causing bacteremia in infants were due to S. pneumonia, Hemophilus influenzae, and rarely N. meningitidis. With the elimination of perhaps 95 percent of H. influenzae due to immunization and the prospect of elimination of 90 percent of pneumococcal infections with the newer vaccine, it has been claimed that OB is a thing of the past. We can all breathe easier about avoiding court cases for missed diagnoses in febrile kids as long as we can pick up meningitis on examination and judicious use of lumbar puncture. Don't count on it. Plaintiffs' attorneys will always bring up this argument. Even if you cannot know that the child will have a positive blood culture until 24 hours have passed and most hospitals do not have observation areas to watch all of these febrile infants, meningococcemia is treatable. How many entities of any sort can actually be cured pharmacologically except infectious disease? Would this child have all of his fingers and toes today if he had been treated earlier pending culture results? Interest in this question dates at least from 1983 from a study in which 96 children with temperatures higher than 40°C, WBCs greater than 15,000, or ESR greater than 30 were randomized to receive antibiotics (50) or no antimicrobials (46). There were 10 of 96 with positive blood cultures, five in each group. The five untreated patients were unimproved at 24 hours, and two developed meningitis. Four of five treated for bacteremia showed improvement at the first follow-up visit. Since then, it has been shown through meta-analyses that antibiotics reduce the rate of subsequent meningitis in patients with OB (already only 2.8% of the original group of febrile children) eight- to 10-fold. On the other hand, perhaps five percent (3–6%) of untreated pneumococcal OB develop meningitis. If we never treated any febrile child who looks well otherwise, only approximately one in 1000 would develop meningitis. We could lower that rate to one in 10,000 if we treated every febrile infant who looks well. 0f course, it would be a very short period of time before ceftriaxone or other antibiotics selected out superbugs that could only be killed with flame throwers. The Natural History of OB This is not completely understood, but most children do well. In one retrospective analysis of 382 children with pneumococcal OB, 17 percent of untreated children had persistent bacteremia at follow-up, and one developed meningitis. Because pneumococcal OB is the most common cause of OB, most children do well, and the vaccine will eliminate 90 percent of cases at any rate. Some claim that bacteremia will not be a source of worry within a short period of time. Meta-analyses for untreated OB due to pneumococcus indicates 2.7 to 5.8 percent risk for meningitis. Four percent risk decreases to approximately 0.4 percent if parenteral antibiotics given. Salmonella bacteremia accounts for three to seven percent of cases of OB, and most have diarrhea. The most common complication if untreated is persistent bacteremia at follow-up (45–68% of the time). In two retrospective analyses of 40 cases and 54 cases respectively, one child in the first study developed osteomyelitis; none developed meningitis. Serious complications are rare under 3 months of age. N meningitidis accounts for approximately 1.6 percent (4 of 252) cases of OB. What about Meningococcus? Severe morbidity and death in children with this condition are common. It is the pathogen with the highest frequency of adverse outcomes. Twenty-five to 50 percent present with occult disease, and are discharged after outpatient evaluation. There are two large series documenting risk of OB caused by N. meningitidis. Overall it occurs in 0.025 percent of children 3 to 36 months of age with temperature higher than 39°C: two of 6680 patients in one series, two of 9465 in another. Six reports on outcomes of meningococcal OB indicate that meningitis developed in six of 12 left untreated, two of seven given oral antibiotics, and none of four given parenteral antibiotics. Retrospective analyses of 113 children with unsuspected meningococcal disease indicate that 42 percent developed meningitis, four percent died, three percent developed extremity necrosis. Other problems included pneumonia, septic shock, and seizures. Other retrospective analyses show that nine of 33 (27%) with unsuspected meningococcal OB treated with empiric antibiotics developed meningitis or died, versus 28 of 50 (56%) untreated patients. In fact, there was no difference in the percent of patients with WBCs greater than 15,000 between patients without bacteremia and those with occult meningococcal bacteremia, making laboratory diagnosis in the emergency department very difficult. Consider the possibility of contact and local outbreaks. Documentation Infant observation scores have been used to evaluate behavior and likelihood of having bacterial illness. The most common is the Yale Observation Score, summarized in the table. The problems with the Yale Observation Score and identification of OB, however, are numerous. It does not reliably identify bacteremic patients in emergency departments. The median score was 6 for groups of children with or without bacteremia. Sensitivity of the score greater than 10 decreased from 68 percent before to 21 percent after defervescence of febrile children. Because any child, septic or not, can have his temperature lowered without indicating whether he is actually sick, we should not want to use a behavioral scale that is temperature-dependent. The bottom line for appearance is that toxic appearance implies: Lethargy, poor or absent eye contact, failure of child to recognize parents, failure to interact with persons or objects in the environment. Poor perfusion of the extremities: acrocyanosis, mottling, capillary refill greater than 2 seconds. Hypo- or hyperventilation, cyanosis. Presence of Petechiae By definition, petechiae are larger than 3 mm in diameter and reddish-purple in color. The most common cause is not meningococcemia or even bacterial illness but viral infections (enterovirus, adenovirus, EBV, RSV, rubella). Obviously, of more concern is that they may be caused by H. influenzae type B, meningococcus, rickettsial illness, or Henoch Schoelein Purpura. A child is unlikely to have invasive bacterial disease if petechiae are only above the nipple line. When in doubt, hospitalize, perform an lumbar puncture, and institute antibiotics. Bacteremia by definition requires the presence of a positive blood culture, something we do not have the luxury of keeping around long enough to do us or patients any good, at least while they are under our care. Most of the positives have some degree of contaminants. In one large study from Childrens' Hospital of Pennsylvania, 258 of 711 positives contained only true pathogens. Of 10,200 drawn over four years, only nine were positive for N. meningitidis. Fever Phobia There is a lot of misinformation out there about fever, much of it propagated by the medical profession itself. Insurance companies are more likely to pay out and view a pediatric visit as a true emergency if they see the word “fever” somewhere. A poll in 1992 of Massachusetts pediatricians showed that 65 percent believed that fever itself could be dangerous to a child. Specifically, a temperature higher than 104°F degrees could lead to seizures, brain damage, or death. Dehydration was cited as a risk by 23 percent. The literature suggests that fever lower than 107°F (a theoretical value based on enzyme physiology) does not lead to these complications. Do not expect a jury to be sympathetic if a serious bacterial infection is missed in the ED and the parent dutifully brought in her child because of fever. There was poor objective documentation of the child's behavior by any observation scale other than that the child looked well. No rash was mentioned, either negatively or positively. No laboratory tests were ordered (more on that later). What the emergency physician had going for him was the extreme rarity of the disease and the paucity of symptoms on the original visit. It also helped that the Yale Observation Score is good at detecting meningitis but not at detecting bacteremia. The presentation of a child lacking lower extremities and fingers did not play well with the jury. Experts on either side gave conflicting opinions on standard of care for diagnostic work-up of the febrile child without source. The case was settled before jury verdict for $600,000. Bottom Lines Meningococcemia is rare and lethal. It will continue to cause morbidity and mortality after children are vaccinated for pneumococcus and H. influenza. Parents will still worry, perhaps inordinately, about fever, no matter how unusual meningitis is currently or how much rare it become in the future. The tolerance for complications in children in this society is so close to zero that worry about OB will not go away. There is no uniform standard of care for the diagnostic work-up of the febrile child, but the medical profession is getting close. Most of the time febrile children do well, no matter how bereft of current knowledge the EP (or pediatrician) may be.