Abstract
Purpose of review
Fever is a common complaint between children under 36 months of age. While most of febrile children are affected from viral infections, some infants can suffer from a serious bacterial infection (SBI). This article focuses on the child with fever without source (FWS) and the available diagnostic tools to estimate SBI risk and avoid unnecessary complementary tests and treatments, as well as their use in routine clinical practice in a Latin American country.
Recent findings
The combination of medical history, physical examination, and complementary tests continues to being very important to take decisions on febrile infant. Procalcitonin, C-reactive protein, and absolute neutrophil count are the most relevant complementary tests to help us perform actions on infants with FWS with good clinical appearance and without risk factors.
Summary
The evaluation and disposition of febrile infants is highly variable, particularly among infants between 29 and 60 days of age. If a child has bad appearance or the bacterial source of fever is definite, treatment needs to be started immediately. However, if febrile infant has FWS, has a good clinical appearance, and does not have risk factors in medical history, the complementary tests can be necessary to identify febrile infants with low SBI risk. The evaluation of SBI risk, and mainly of invasive bacterial infection—bacteremia and meningitis—, will continue to change according to new scientific researches; training and experience of physicians and availability of auxiliary tests; and, of course, sociocultural background. This is particularly important in low-resource settings; therefore, in children 1 to 2 months of age, it is preferable to establish a safer strategy to assess SBI risk and hospitalization should be considered.
Avoid common mistakes on your manuscript.
Introduction
Fever is one of the most frequent complaints in children under 3 years old in emergency department [1,2,3,4]. Parents and physicians can be concerned as it can be a serious problem that requires urgent evaluation, complementary tests and treatment. Fever may be associated with serious bacterial infections (SBI). Most of febrile children looks good and suffers from self-limited viral infections; others have bad appearance and suffer from a serious disease; and, finally, a small percentage has an occult SBI.
After asking about health history and physical examination, 1 in 5 of patients has fever without source (FWS) [5]. Within this percentage, a small group could suffer from an occult SBI such as urinary tract infection (UTI), pneumonia, occult bacteremia (OB) or, more rarely, bacterial meningitis.
Since the implementation of conjugate vaccines against Haemophilus influenzae type B (HibCV) and Streptococcus pneumoniae (PCV) the incidence of SBI has decreased. The impact has been greater, the incidence of bacteremia was not only reduced among vaccinated children but the unvaccinated population also benefited through the protection phenomenon known as “herd effect” [2, 4, 6]. But immunization coverage varies around the world. In 2017, in Argentina, there was 92% of infants younger than 1-year old who had 3 doses of HibCV [7] and 78% of PCV [8]; in Latin America, the percentage was 81% of PCV [8].
In high-resource settings, most infants with FWS who looks good and has normal complementary tests can be followed as outpatients, but this is more difficult in low-resource settings. In developing countries, such as Argentina and other Latin American countries, there is a high percentage of population that has low educational level and poor immediate access to health system. FWS, especially in younger children, should be addressed even more carefully in this sociocultural background.
Fever
In Argentina and other countries of Latin America, temperature is measured with a thermometer in axillary region. Non-rectal measurements would underestimate the fever register, although it is accepted that in the case of temperature ≥ 38 °C (100.4 °F) in a non-rectal measurement the diagnosis of fever should be recognized. Hyperpyrexia may be associated with a higher rate of SBI. Before the implementation of the PCV, the relation between SBI due to Streptococcus pneumoniae (especially in young children) and higher body temperature was described [2, 9,10,11,12,13,14,15]. We must also consider that hypothermia can be as important as fever during the evaluation of a child with a bad appearance since it can be associated with sepsis.
Approach to febrile child under 36 months of age
Whatever age or risk factors, the child with sepsis requires an intensive approach that include diagnostic test, antibiotic treatment, and hospitalization. If the patient has bad appearance or the physical examination is abnormal, this should be enough to initiate actions that can be adapted to medical history and complementary tests. On the other side, risk factors in medical history between well appearance patients (e.g., immunocompromised or recent surgery), often, by themselves, can define the beginning of medical actions. But in case of febrile child with good appearance and history without risk factors, the auxiliary tests could be necessary to define SBI risk. Then, we could do an evaluation in steps to determine the risk of suffering SBI. This approach must be dynamic, since according to the child’s appearance, we will sometimes take immediate actions after the physical examination while at other times we will ask about the medical history or wait for the results of complementary exams to define actions to follow.
If the first step (appearance and physical examination) is abnormal, it may be necessary to take diagnostic and therapeutic actions immediately. If it is normal, the second step (clinical history and risk factors) can by itself determine diagnostic and therapeutic actions. Finally, when first and second steps are normal, the third one (complementary tests) may be essential to determine SBI risk.
First step: Appearance and physical examination
Some signs and symptoms will guide us to determine severity and cause of illness. Tachypnea or bradypnea, tachycardia, cyanosis, dehydration, mottled skin, petechiae, poor peripheral perfusion, decreased muscle tone, lethargy, irritability, lack of eye contact, and poor interaction with parents should make us suspect of a serious infectious disease [11, 12, 16,17,18,19,20,21,22,23]. Children who look bad have a higher SBI risk than children who have good appearance. Similarly, febrile children who have obvious viral source (e.g., rhinitis, non-petechial rash, non-dysenteric diarrhea) have lower SBI risk than those with FWS [2, 10].
Second step: History
History of fever, over-all health during fever-free time, pregnancy history, history of birth, previous diseases, receiving drugs as antibiotics, antipyretics or other medication, recently received vaccine, recent contact with infected people, immunizations, trips and signs, or symptoms are very relevant to guide clinical suspicion [2, 10, 12, 24].
Sometimes, isolated presence of some risk factors (e.g., immunocompromised) in child with fever can define diagnostic and therapeutic actions since it increases SBI risk [2, 9, 25].
Third step: Complementary tests
There are several tests to approach the diagnosis of SBI. None of them is 100% effective and sensitive, so a combination of them is needed for the diagnostic assessment.
White blood cell count
Most studies agree that white blood cell count (WBCC) ≤ 5000 or ≥ 15,000/mm3, absolute neutrophil count (ANC) ≥ 10,000/mm3, band neutrophil count (BNC) ≥ 1500/mm3 and BNC/ANC index ≥ 0.2 are associated with highest SBI risk. These last three values of neutrophils have higher sensitivity than the total WBCC. WBCC and ANC were predictors to determine the risk for SBI previous the introduction of PCV [2, 10, 12, 16, 17, 26,27,28, 29••]. Recently, ANC ≤ 4090/mm3 was associated with lower risk for SBI [30••].
C-reactive protein
Sensitivity and specificity vary according to the cut points used [31,32,33]. It can also rise in some viral infections. It increases about 12 h after the onset of fever. C-reactive protein (CRP) > 20 mg/L can be associate to bacterial infection.
Procalcitonine
It is best marker to differentiate between bacterial, viral and noninfectious causes of inflammation. It rises more rapidly than CRP and is more sensitive and specific as predictors of SBI than WBCC, ANC, and CRP. It increases rapidly and intensely in bacterial infection, correlating magnitude of ascent with severity of infection. Value < 0.5 ng/mL is normal [31, 33, 34, 35••, 36, 37], and some researchers consider a value < 0.3 ng/mL and less to improve sensitivity to define low SBI risk in younger children [30••, 35••, 37].
Neither procalcitonine (PCT), CRP, WBC, nor ANC is an absolute determinant by itself to define SBI risk.
Urine tests and culture
Diagnosis of UTI is made through urine culture but its result is not obtained immediately so it requires faster tests that approach the diagnosis. Detection of leukocytes ≥ 10/high-power field, bacteriuria, leukocyte esterase, and nitrites is good as these screening tests predict UTI [2, 10]. Although in our country it is common to use a technique of a medium jet after meticulous genital hygiene, the urethrovesical catheterization and suprapubic puncture are the methods of choice for urine culture, particularly in younger children [12, 17, 27, 38, 39].
Blood cultures
It is a gold standard for diagnosis of bacteremia. Blood cultures with contaminating microorganisms are even more frequent than those that develop true pathogenic organisms, which increase the probability of unnecessary complementary tests, antibiotic therapy, and hospitalizations [2, 10].
Lumbar puncture
To make the diagnosis of meningitis, a sample of cerebrospinal fluid (CSF) must be obtained, usually by lumbar puncture (LP). Absolute and differential count of white blood cells, red blood cells, Gram stain and glucose (in relation to the glycaemia value), and protein determinations should be performed. Occasionally other CSF tests may be necessary (e.g., latex agglutination in case of patients receiving antibiotics that inhibit microbial development). CSF culture and glucose determination can be modified if the patient received previous antibiotic therapy but not so quickly the cells.
Stools tests and culture
In case of diarrhea, stools tests can be performed. The presence of leukocytes ≥ 5/high-power field is considered abnormal [2, 10, 12].
Chest x-ray
If there are respiratory symptoms or signs (cough, cyanosis, tachypnea, rales, etc.), it should be performed [10, 12, 16, 27, 40]. WBCC > 20,000/mm3 can be a predictor of pneumonia in children without respiratory semiology. Also, chest x-ray should be performed in presence of high hyperthermia and several days elapsed of cough or fever [10, 27, 41].
Age-specific consideration
The immaturity of the immune system and the few signs and symptoms that the infant shows lead a greater SBI risk when the child is younger. Therefore, in order to assess febrile children, they are divided into three age groups: 0 to 28 days, 29 to 90 days, and 3 to 36 months. There is a current tendency to modify the last two groups to 29 to 60 days and 2 to 24 months.
Younger than 1 month
The risk of having a SBI is 12 to 28% in this group [2, 6, 10, 42,43,44]. The most frequent presentation is UTI, followed by bacteremia (2 to 3%) and meningitis [2, 4, 6, 10, 16, 42, 44]. Appearance and physical examination may be normal and auxiliary tests do not have adequate sensitivity among infants younger than 28 days, so they should be admitted and blood, CFS, and urine cultures are needed. Studies in neonates who tried to reproduce the criteria of low risk to suffer SBI reported a low but not tolerable percentage of SBI in groups of children considered to be at low risk [2, 9, 10, 16, 42,43,44,45,46,47]. The delay in diagnosis and treatment can increase morbidity and mortality.
Despite the presence of suggestive signs or even positive tests for viral infection, complementary tests and antibiotic treatment for a possible SBI should not be delayed. [2, 10, 48, 49•].
In conclusion, all infants of this age group should be hospitalized, since it is not possible to know who is having serious invasive disease [6, 9, 10, 16, 50].
Since Streptococcus group B begun to search in pregnant women and intrapartum treatment have been performed, its incidence in early sepsis decreased [45, 51]. Escherichia coli is the most common germ today, especially in UTI. Other bacteria are Staphylococcus spp., Streptococcus spp., and Gram-negative; Listeria monocytogenes and Streptococcus pneumoniae are rare.
Antibiotic therapy can include intravenous ampicillin 100 mg/kg/day (200 to 400 mg/kg/day in meningitis) associated with gentamicin 5–7.5 mg/kg/day. Another therapeutic option is intravenous ampicillin and cefotaxime 150 mg/kg/day (300 mg/kg/day in meningitis) [52]. Ampicillin has activity against Listeria monocytogenes as well as on Streptococcus group B, Enterococcus faecalis and some Escherichia coli; gentamicin or cefotaxime on the resistant Escherichia coli [53,54,55]. Ceftriaxone is generally not used in this age group because it competes with bilirubin for albumin binding sites and causes hyperbilirubinemia.
If the patient presents history of previous hospitalization, intravenous vancomycin 40 mg/kg/day (60 mg/kg/day in meningitis) associated with amikacin 15 mg/kg/day due to hospital-acquired infections (Staphylococcus spp., Pseudomonas spp., etc.) is recommended.
Herpes simplex virus infection should be suspected if there are risk factors (skin vesicles, scalp during fetal monitoring, premature rupture of membranes, seizures, lethargy, pleocytosis in the CSF, etc.); it is recommended to prescribe intravenous acyclovir 60 mg/kg/day [4, 6, 9, 45].
Currently, since the decrease of bacterial infections after the second and third week of life, some authors propose only observation, no antibiotics, in children older than 21 days without risk factors in history and with normal physical examination and normal auxiliary tests [29].
The suggested approach to febrile infant younger than 1 month of age is shown in Fig. 1.
Febrile infant younger than 1 month of age with FWS.
One to three months
Also, in this age group, physical examination may be insufficient even for invasive bacterial infections (IBI), such as meningitis and bacteremia. About 5 to 10% of infants under 3 months of age with FWS has SBI, and between 0.5 and 2% of these children are affected by bacterial meningitis [56]. In the last decades, the way we approach febrile infants of this age group has been changed.
The identification of viral infection decreases but does not eliminate SBI risk [2, 4, 6, 10, 48, 57,58,59,60]. The most frequent coinfection with the viral infection is UTI [6, 48].
Of course, in this group, UTI is also the most frequent SBI [4, 6, 9, 22] and it is diagnosed in 4–16% of infants under 3 months of age with FWS. There is evidence that supports ambulatory approach of children older than 2 months with UTI, with good general condition and assured follow-up, without performing blood cultures or lumbar puncture [2, 10, 56, 61,62,63].
In spite of this, it is known that this age group also has a higher bacteremia risk and bacterial meningitis although infant has good appearance [6]. Since bacterial meningitis is less frequent, the utility of LP is discussed [6, 29••, 64,65,66, 67•, 68••, 69••, 70]. Although it has been recognized that abnormal, low, or high WBCC increases risk of bacteremia and meningitis [2, 10, 71], neither the clinical examination nor WBCC alone is absolutely reliable to rule out IBI in this age group. Therefore, LP should be strongly considered, especially if antibiotic is prescribed [6, 71]. In febrile infant between 30 and 90 days of age, it is described that the abnormal urine test has a high negative predictive value for meningitis, so the LP would not be routinely necessary if it also has low SBI risk according to clinical criteria and auxiliary tests [29••].
Between infants who meet criteria of low SBI risk, ambulatory management could be considered. Empiric antibiotic treatment in this group should be avoided, especially if blood cultures and LP were not performed, so as not to impair evaluation during follow-up.
Especially in this age group, the evaluation of risk of SBI and IBI will continue to change according to the progress of scientific research and the availability of auxiliary tests ranging from C-reactive protein to procalcitonin through panels to quickly find out viral or bacterial microorganism.
Sociocultural aspects of the patient’s environment are very important factors to decide the way of follow-up. So, today, we cannot establish a single recommendation for febrile infant 1 to 3 months.
At present, there is a clear tendency to treat febrile infants between 2 and 3 months of age as those who belong to the age group of 3 to 36 months [6].
Patients who do not meet the low risk criteria for SBI could receive intravenous ceftriaxone 50 mg/kg/day (100 mg/kg/day in meningitis), and it could be associated with ampicillin 200–300 mg/kg/day if suspected infection by Listeria monocytogenes and vancomycin 60 mg/kg/day for resistant Gram-positive cocci or Enterococcus spp.
The suggested approach to febrile infant 1 to 3 months of age is shown in Fig. 2.
Febrile infant 1 to 3 months of age with FWS.
Three to thirty-six months
There are less difficulties to evaluate a child of this age, since they generally interact better with the surrounding environment. Although good appearance does not completely rule out an SBI, it is unlikely to occur [2, 6, 10, 72, 73]. The prevalence of occult bacteremia (OB) among this group is between 0.5 and 2% [9, 74]. The use of clinical observation scales can be more useful in this group but the problem lies in the difficulty of detecting occult SBI.
In this group, a body temperature of ≥ 39 °C is used as the cutoff line to initiate a more extensive evaluation because increases OB risk due to pneumococcus and UTI [2, 9,10,11, 16, 43, 75,76,77].
Urinary infection
It is the most common cause of occult SBI [9, 13, 16, 22, 78,79,80,81]. Fever is usually the only sign of UTI in young children. It is described that approximately 5% of febrile children < 12 months suffer from UTI, more frequent in women and with higher temperatures [6, 10, 34].
Sometimes, UTI can still occur along with other infections such as diarrhea or rhinitis or a febrile post-vaccinal syndrome. In younger children, the urine test may be normal, so a sample should always be taken for urine culture. The most frequent bacteria are Escherichia coli, Klebsiella spp., and Proteus spp.
In Latin America, where the circumcision is not usual in most of population, it would be convenient to rule out UTI in all febrile children < 2 years who present at least two of the following risk factors: age < 12 months, duration of fever ≥ 24 h, temperature ≥ 39 °C (102.2 ° F), no other probable infectious source, and history of UTI or known uropathy [2, 6, 10, 22].
Initial antibiotic treatment will depend on antibiotic sensitivity of the most frequent pathogens; in Argentina, it can start with oral cephalexin 50–100 mg/kg/day or trimethoprim-sulfamethoxazole 6–12 mg/kg/day or amoxicillin-clavulanic acid 40 mg/kg/day. Duration of treatment will be 7 to 14 days. Children < 2–3-month old, bad appearance or oral intolerance, or due to sociocultural factors that do not allow ambulatory follow-up, will be admitted [82].
Occult bacteremia
It is the presence of pathogenic bacterium in blood cultures taken from a child in which a bacterial infection is not suspected from medical history, physical examination, and some complementary tests. Implementation of immunizations has changed etiology of bacteremia [2, 4, 6, 9]. In pre PCV era, bacteremia by Streptococcus pneumoniae was the most frequent, between 6 and 24 months of age [2, 10, 83, 84]; higher hyperthermia; WBC ≥ 15,000/mm3; and ANC ≥ 10,000/mm3 are associated with a higher risk of OB [43, 83, 84]. The second most common cause of bacteremia has been Escherichia coli and that it is usually associated with UTI [4, 6, 55, 71, 85]. Salmonella spp. causes between 4 and 8% of the OB, and occurs most frequently with temperatures ≥ 39 °C (102.2 ° F) and suffering from diarrhea [6, 16, 83,84,85]. Streptococcus pyogenes, Enterococcus spp., Neisseria meningitidis, Haemophilus influenzae no type B, Escherichia coli, Moraxella Catarrhalis, Salmonella spp., and Staphylococcus aureus arise as more frequent causes of OB [4, 16, 55, 74, 85,86,87]. Although infections by Neisseria meningitidis are less frequent causes of bacteremia, patients look usually bad and it is associated with high rates of morbidity and mortality; also, blood cultures should be performed and intravenous antibiotics should be administered to febrile children with risk factors for meningococcal infection (contacts with patients with meningococcal disease, outbreaks of meningococcal disease, and fever and petechiae below the nipple region) [6, 9, 88].
In countries where HibCV and PCV are mandatory and there is good vaccine coverage in the population, according to the association between UTI and bacteremia due to Escherichia coli, the low relative frequency of bacteremia due to other germs and the limited value of the usual complementary tests to predict non-pneumococcal bacteremia, the empirical diagnostic, and therapeutic actions to be taken in febrile children who received ≥ 2 doses of anti-Hib and anti-pneumococcal conjugate vaccines are questioned [6].
If a febrile infant has abnormal blood complementary tests or risk factors, blood cultures and initiate intravenous antibiotic (ceftriaxone 50 mg/kg/day) should be performed; optionally, it can be admitted and be observed without antibiotics.
All febrile children who underwent blood cultures will be cited in 24 h for clinical control and blood culture reading. If the patient presents bacteremia due to Streptococcus pneumoniae but at the time of control the child has good appearance and no fever can be managed as outpatient after receiving intravenous antibiotic, while if persistently, febrile child should be hospitalized, blood cultures be repeated, and LP be performed. Patients with bacteremia by Neisseria meningitidis and Haemophilus influenzae type B should be hospitalized to perform LP and intravenous antibiotic therapy. And hospitalization, repeat blood cultures, perform LP, and intravenous antibiotic therapy in bacteremia by Salmonella spp. and Escherichia coli should be considered [2, 10].
Occult pneumonia
The most frequent etiology of pneumonia at this age is viruses, then Streptococcus pneumoniae, and Chlamydia trachomatis. Mycoplasma pneumoniae and Staphylococcus aureus are uncommon in this age group but are arising more commonly as causes of pneumonia. Like pneumococcal bacteremia and meningitis, pneumonia also became less frequent because of immunizations. It is usual for bacterial respiratory infections to be preceded by viral infections of the respiratory tract. But, in fact, neither signs, symptoms, blood tests, nor radiological findings can reliably distinguish between bacterial and non-bacterial etiology. There is consensus in Argentina to treat pneumonia of probable bacterial etiology in children > 3–6 months with good general condition like outpatients with oral amoxicillin 80–100 mg/kg/day for 10 days. Children younger than 3–6 months or with risk factors to severe pneumonia need to be admitted. Azithromycin or other macrolides can be used when there is suspicion of the infection by Chlamydia trachomatis or Mycoplasma pneumoniae. Children younger than 3–6 months with bad appearance, moderate-to-severe respiratory distress, hypoxemia, complicated pneumonia, suspicion or confirmation of a more virulent etiology (e.g., Staphylococcus aureus), difficulty feeding or oral intolerance, lack of response to antibiotic treatment in 48–72 h, rapid progression of the disease in 48–72 h, or other risk factors for severe disease should be admitted. Treatment can include ampicillin 200 mg/kg/day (or ceftriaxone 80 mg/kg/day or cefotaxime 100 mg/kg/day). Clindamycin 30 mg/kg/day or vancomycin 40–60 mg/kg/day is added for suspected community-acquired methicillin-resistant Staphylococcus aureus infection. Sociocultural factors are causes of admission too [6, 89,90,91].
Meningitis
Although meningitis is a severe and invasive infection, is not recommended routinely perform During evaluation of a febrile child between 3 and 36 months of age who presents a normal neurological examination because bacterial meningitis decreased markedly since implementation of the HibCV and PCV, LP will be performed in individual cases based on history and physical examination. Ceftriaxone 100 mg/kg/day if the child has meningitis is recommended.
The suggested approach to febrile infant 3 to 36 months of age is shown in Fig. 3.
Febrile infant 3 to 36 months of age with FWS.
Conclusions
The challenge in febrile infant continues to identify and treat SBI, optimize the use of diagnostic tools, rationalize the use of antibiotics and hospitalizations, and minimize iatrogenic complications.
No history nor finding of the physical examination or complementary tests in children under 3-year old with FWS are enough to predict 100% for SBI risk. However, the combination of low risk background, good appearance, and normal value of complementary tests can identify most febrile children of this age with low risk for SBI.
New researches are taking other pathways to better identify the risk for SBI; it is proposed that analysis of host expression patterns in response to infections may provide an alternative diagnostic approach [92••].
The evaluation of SBI risk, and mainly of IBI—bacteremia and meningitis—, will continue to change according to the progress of scientific research; environment in which the patient is assisted; training and experience of the physicians and availability of auxiliary tests; and, of course, sociocultural background of the patient’s environment.
At present, there is a clear tendency to approach febrile infants between 2 and 3 months of age as those who belong to the age group of 3 to 36 months (according age of patient, experience of attending physician, available resources, and sociocultural factors).
On the other hand, since characteristics of population and conformation of the health system in Argentina and other Latin American countries, here it seems preferable to approach a strategy of greater security to assess the SBI risk (i.e., admit, observe, and strongly consider lumbar puncture) in children between 1 and 2 months. However, it is likely that individually, the institutions modify their care protocols according to their own characteristics and that of the population they attend, in order to reduce the variation in care.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Bilkis MD, Vásquez M, González FC, et al. Estudio multicéntrico de la urgencia pediátrica. Arch Argent Pediatr. 2006;104(4):301–8 Arch Argent Pediatr, págs. 301–8.
Ishimine P. The evolving approach to the young child who has fever and no obvious source. Emerg Med Clin N Am. 2007;25(4):1087–115. https://doi.org/10.1016/j.emc.2007.07.012.
Nawar EW, Niska RW, Xu J. National Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Adv Data. 2007 Jun 29;386:1–32.
Arora R, Mahajan P. Evaluation of child with fever without source review of literature and update. Pediatr Clin N Am. 2013;60:1049–62.
Machado BM, Cardoso DM, de Paulis M, de Ulhoa Escobar AM, Gilio AE. Fever without source: evaluation of a guideline. J Pediatr (Rio J). 2009;85(5):426–32.
Ishmine P. Risk stratification and management of the febrile young child. Emerg Med Clin N Am. 2013;31:601–26.
Ministerio de Salud y Desarrollo Social de Republica Argentina. Organización Panamericana de la Salud. Organización Mundial de la Salud. Indicadores básicos Argentina 2018. www.paho.org/arg/index.php?option=com_content&view=article&id=160:datos-estadistic.
Organización Panamericana de la Salud. Organización Mundial de la Salud. Inmunización en las Américas. Resumen 2018. Inmunización integral de la familia. Familia, promoción de la salud y curso de vida. www.paho.org/hq/index.php?option=com_docman&view=down.
Wing R, Dor M, McQuilkin P. Fever in the pediatric patient. Emerg Med Clin N Am. 2013;31:1073–96.
Ishimine P. Fever without source in children 0 to 36 months of age. Pediatr Clin N Am. 2006;53:167–94.
Kuppermann N, Fleisher GR, Jaffe DM. Predictors of occult pneumococcal bacteremia in young febrile children. Ann Emerg Med. 1998;31:679–87.
Slater M, Krug SE. Evaluation of the infant with fever without source: an evidence based approach. Emerg Med Clin North Am. 1999;17:97–126.
Álvarez Rodríguez A, Ortiz Silva O, Hernández MN. Validación de nuevos parámetros predictivos de infecciones bacterianas severas en niños febriles menores de 36 meses de edad. Rev Cubana Pediatr. 1999;71(4):197–204.
Stanley R. Pagon, Bachur R. Hyperpyrexia among infants younger than 3 months. Pediatr Emerg Care. 2005;21(5):291–4.
Trautner BW, Caviness AC, Gerlacher GR, et al. Prospective evaluation of true risk of serious bacterial infection in children who present to the emergency department with hyperpyrexia. Pediatrics. 2006;118(1):34–40.
Baraff LJ. Management of infants and young children with fever without source. Pediatric Annals. 2008;37:673–9.
Baraff LJ, Bass JW, Fleisher GR, Klein JO, GH MC Jr, Powell KR, et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. Ann Emerg Med. 1993;22(7):1198–210. https://doi.org/10.1016/s0196-0644(05)80991-6:s.n.
Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med. 1993;329:1437–41.
Jaskiewicz JA, McCarthy CA, Richardson AC, et al. Febrile infants at low risk for serious bacterial infection—an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. Pediatrics. 1994;94:390–6.
Van den Bruel A, Haj-Hassan T, Thompson M, Buntinx F, Mant D. Diagnostic value of clinical features at presentation to identify serious infection in children in developed countries: a systematic review. Lancet. 2010;375(9717):834–45.
Thompson M, Coad N, Harnden A, Mayon-White R, Perera R, Mant D. How well do vital signs identify children with serious infections in paediatric emergency care? Arch Dis Child. 2009;94(11):888–93.
Trainor J, Stamos JK. Fever Without a localizing source. Pediatric Annals. 2011;40(1):21–5.
Pantell RH, Newman TB, Bernzweig J, Bergman DA, Takayama JI, Segal M, et al. Management and outcomes of care of fever in early infancy. JAMA. 2004;291:1203–12.
Rino P, Vidal C. Lactante febril. In: Manual de Emergencias y Cuidados Críticos. Comité Nacional de Terapia Intensiva. Sociedad Argentina de Pediatría. FUNDASAP Ediciones; 2009. p. 465–73.
Paganini HR. Fiebre sin foco en el lactante entre 3 y 36 meses de edad. In: Infectología Pediátrica 2007. 1st ed. Buenos Aires: Científica Interamericana; 2007. p. 232–6.
Jaffe DM, Fleisher GR. Temperature and total white blood cell count as indicators of bacteremia. Pediatrics. 1991;87:670–4.
American College of Emergency Physicians Clinical Policies Committee; American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530–45.
Kuppermann N. Occult bacteremia in young febrile children. Pediatr Clin North Am. 1999;46:1073–109.
•• Gomez B, Mintegi S, Bressan S, et al. Validation of the “Step-by-Step” Approach in the management of young febrile infants. Pediatrics. 2016;138(2):e20154381 Prospective study. They validated a tool for the management of infants with FWS and confirmed superior accuracy in identifying febrile infants under 3 months of age with low risk for IBI, compared with the Rochester criteria and the Lab-score.
Kuppermann N, Dayan PS, Levine DA, et al. Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network (PECARN). A clinical prediction rule to identify febrile infants 60 days and younger at low risk for serious bacterial infections. JAMA Pediatr. 2019. https://doi.org/10.1001/jamapediatrics.2018.5501 s.n. Prospective, observational, and multicentric study. They validated a prediction rule to identify febrile infants younger than 60 days of age with low risk for SBI. They included urine test, ANC, and procalcitonin levels.
Galetto-Lacour A, Gervaix A. Identifying severe bacterial infection in children with fever without source. Expert Review of Anti-infective Therapy. 2010;8(11):1231–7.
Sanders S, Barnett A, Correa-Velez I, Coulthard M, Doust J. Systematic review of the diagnostic accuracy of C-reactive protein to detect bacterial infection in nonhospitalized infants and children with fever. J. Pediatr. 2008;153(4):570–4.
Galetto-Lacour A, Zamora SA, Gervaix A. Bedside procalcitonin and C-reactive protein tests in children with fever without localizing signs of infection seen in a referral center. Pediatrics. 2003;112(5):1054–60.
Van den Bruel A, Thompson MJ, Haj-Hassan T, Stevens R, Moll H, Lakhanpaul M, Mant D. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ. 2011;342:d3082.: s.n.
•• Milcent K, Faesch S, Gras-Le Guen C, et al. Use of procalcitonin assays to predict serious bacterial infection in young febrile infants. JAMA Pediatr. 2016;170(1):62–9 Prospective cohort study. It evaluates the utility PCT assay in infants with FWS between 7 and 91 days to identify IBS and IBI and concludes that PCT test is better than CRP for identifying IBI in febrile infant and both tests have similar results in detecting IBS.
Olaciregui I, Hernandez U, Munoz JA, Emparanza JI, Landa JJ. Markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin. Arch. Dis. Child. 2009;94(7):501–5.
Tamsut England J, Del Vecchio MT, Aronoff SC. Use of serum procalcitonin in evaluation of febrile infants: a meta-analysis of 2317 patients. The Journal of Emergency Medicine. 2014;47(6):682–8.
Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months: s.n. Pediatrics. 2011;128(3):595–610. https://doi.org/10.1542/peds.2011-1330 Epub 2011 Aug 28.
Subcommittee on Urinary Tract Infection. Committee on Quality Improvement. American Academy of Pediatrics. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Published corrections appear in Pediatrics 2000;105(1 pt 1):141. Pediatrics. 1999;103(5 pt 1):1052 and Pediatrics 1999;104(1 pt 1):118]. Pediatrics 1999;103(4 pt 1):84352.: s.n.
Bramson RT, Meyer TL, Silbiger ML, Blickman JG, Halpern E. The futility of the chest radiograph in the febrile infant without respiratory symptoms. Pediatrics. 1993;92(4):524–6.
Murphy CG, van de Pol AC, Harper MB, Bachur RG. Clinical predictors of occult pneumonia in the febrile child. Acad Emerg Med. 2007;14(3):243–9.
Kadish HA, Loveridge B, Tobey J, Bolte RG, Corneli HM. Applyning outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr. 2000;39:81–8.
Avner JR, Baker MD. Management of fever in infants and children. Emerg Med Clin North Am. 2002;20:4967.
Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med. 1999;153(5):508–11.
Geskey J. Neonatal fever in the term infant evaluation and management strategies. Current Pediatrics Reviews. 2008;4:N2.
Ferrera PC, Bartfield JM, Snyder HS. Neonatal fever: utility of the Rochester criteria in determining low risk for serious bacterial infections. Am J Emerg Med. 1997;15(3):299–302.
Chiu CH, Lin TY, Bullard MJ. Identification of febrile neonates unlikely to have bacterial infections. Pediatr Infect Dis. 1997;16(1):59–63.
Levine DA, Platt SL, Dayan PS, Macias CG, et al. Multicenter RSV-SBI Study Group of the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. Pediatrics. 2004;113:1728–34.
• Bonadio W, Huang F, Nateson S, et al. Meta-analysis to determine risk for serious bacterial infection in febrile outpatient neonates with RSV infection. Pediatr Emerg Care. 2016;32(5):286–9 This study evaluated febrile infants ≤ 28 days of age who received outpatient sepsis evaluation and nasopharyngeal aspirate antigen testing for respiratory syncytial viral (RSV) infection. Rates of SBI were not significantly different between febrile infants ≤ 28 days of age with and without RSV infection.
Schwartz S, Raveh D, Toker O, Segal G, Godovitch N, Schlesinger Y. A week-by-week analysis of the low-risk criteria for serious bacterial infection in febrile neonates. Arch Dis Child. 2009;94(4):287–92. https://doi.org/10.1136/adc.2008.138768 Epub 2008 Oct 31.
Chancey RJ, Jhaveri R. Fever without localizing signs in children: a review in the post-Hib and postpneumococcal era. Minerva Pediatrica. 2009;61(5):489–501.
Bruno M, Ellis A. Consenso para el uso adecuado de antibióticos en el niño menor de 36 meses con fiebre sin foco de infección evidente. Arch Argent Pediatr. 2017;115(Supl 2):S27–37.
Biondi EA, Byington CL. Evaluation and management of febrile, well-appearing young. infants. Infect Dis Clin North Am. 2015;29(3):575–85.
Byington CL, Rittichier KK, Bassett KE, Castillo H, Glasgow TS, Daly J, et al. Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. Pediatrics. 2003;111(5 Pt 1):964–8.
Greenhow TL, Hung YY, Herz AM, Losada E, Pantell RH. The changing epidemiology of serious bacterial infections in young infants. Pediatr Infect Dis J. 2014 Jun;33(6):595–9.
Ruiz Contreras J, Albañil Ballesteros MR. Abordaje del niño con fiebre sin foco. Lúa Ediciones: Curso de Actualización Pediatría. Madrid; 2015.
Kuppermann N, Bank DE, Walton EA, Senac MO Jr, McCasli Kuppermann N, Bank DE, et al. Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis. Arch Pediatr Adolesc Med. 1997;151:1207–14.
Greenes DS, Harper MB. Low risk of bacteremia in febrile children with recognizable viral syndromes. Pediatr Infect Dis J. 1999;18:258–61.
Byington CL, Enriquez FR, Hoff C, et al. Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. Pediatrics. 2004;113:1662–6.
Swaminathan A, Hom J. Do febrile infants aged 60 to 90 days with bronchiolitis require a septic evaluation? Ann Emerg Med. 2012;60(5):605–6. https://doi.org/10.1016/j.annemergmed.2012.02.014 Epub 2012 Apr 19.
Dayan PS, Hanson E, Bennett JE, et al. Clinical course of urinary tract infections in infants younger than 60 days of age. Pediatr Emerg Care. 2004;20:85–8.
Hoberman A, Wald ER, Hickey RW, et al. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Pediatrics. 1999;104:79–86.
Schanadower D, Kuppermann N, et al. Febrile infants with urinary tract infections at very low risk for adverse events and bacteremia. Pediatrics. 2010;126(6):1072–83.
Paquette K, Cheng MP, McGillivray D, Lam C, Quach C. Is a lumbar puncture necessary when evaluating febrile infants (30 to 90 days of age) with an abnormal urinalysis? Pediatr Emerg Care. 2011;27(11):105761.
Galetto-Lacour A, Zamora SA, Andreola B, et al. Validation of a laboratory risk index score for the identifi cation of severe bacterial infection in children with fever without source. Arch Dis Child. 2010;95:968–73. https://doi.org/10.1136/adc.2009.176800.
Velasco R, Benito H, Mozún R, Trujillo J, Merino P, Mintegi S. on behalf of the Group for the Study of Febrile Infant of the RISeuP-SPERG Network.. Febrile young infants with altered urinalysis at low risk for invasive bacterial infection. A Spanish Pediatric Emergency Research Network’s Study: Pediatr Infect Dis J. 2015 Jan;34(1):17–21. https://doi.org/10.1097/INF.0000000000000482.
• Velasco R, Gómez B, Hernández-Bou S, Olaciregui I, de la Torre M, González A, et al. Validation of a predictive model for identifying febrile young infants with altered urinalysis at low risk of invasive bacterial infection. s.l. Eur J Clin Microbiol Infect Dis. 2017;36(2):281–4. https://doi.org/10.1007/s10096-016-2798-2 Retrospective multicenter study. They evaluated febrile infants younger than 3 months of age with altered urine test with low SBI risk.
Mintegi S, Gomez B, Martinez-Virumbrales L, Morientes O, Benito J. Outpatient management of selected young febrile infants without antibiotics. Arch Dis Child. 2017;102(3):244–9. https://doi.org/10.1136/archdischild-2016-310,600 Prospective study. It assessed the accuracy for low SBI risk (good appearance, infants older than 21 days of age, no leukocyturia, ANC ≤ 10,000/mm3, CRP ≤ 20 mg/L, PCT < 0.5 ng/mL, and no clinical deterioration during stay in ED (< 24 h) to decide outpatient management without LP or antibiotic treatment.
Aronson PL, Wang ME, Shapiro ED, et al. Febrile Young Infant Research Collaborative. Risk stratification of febrile infants ≤60 days old without routine lumbar puncture. s.l. Pediatrics, 2018;142(6):pii: e20181879. https://doi.org/10.1542/peds.2018-1879 Case-control study. It concluded that the modified Philadelphia criteria had high sensitivity for IBI without routine LP. Infants discharged from ED without LP require close follow-up because some infants with bacteremia were classified as low-risk.
Martinez E, Mintegi S, Vilar B, et al. Prevalence and predictors of bacterial meningitis in young infants with fever without a source. Pediatr Infect Dis J. 2015;34:494–8.
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(2):216–25.
McCarthy PL, Sharpe MR, Spiezel SZ, et al. Observation scales to identify serious illness in febrile children. Pediatrics. 1982;70:802–9.
Teach SJ, Fleisher GR. Efficacy of an observation scale in detecting bacteremia in febrile children three to thirsty-six months of age, treated as outpatients: Occult Bacteremia Study Group. J Pediatr. 1995;126(6):877–81.
Wilkinson M, Bulloch B, Smith M. Prevalence of occult bacteremia in children aged 3 to 36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era. Acad Emerg Med. 2009;16(3):220.5.
Shaw KN, Gorelick M, McGowan KL, et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics. 1998;102(2):16.
Gorelick MH, Shaw KN. Clinical decision rule to identify febrile young children girls at risk for urinary tract infection. Arch Pediatr Adolesc Med. 2000;154(4):386–90.
Hoberman A, Chao HP, Keller DM, Hickey R, Davis HW, Ellis D. Prevalence of urinary tract infection in febrile infants. J Pediatr. 1993;123(1):17–23.
Goh PL, Lee SW, Wong EH. Predictors of serious bacterial infection in children aged 3 to 36 months with fever without source. Singapore Med J. 2006;47(4):276–80.
Torregrosa C, García RC, Sciarotta J, Vay C, Caíno S, Ellis A. Factores asociados a riesgo de infección bacteriana grave en niños bajo 24 meses de edad, internados por fiebre sin foco aparente. Rev Chil Infect. 2010;27(4):308–14.
Manzano S, Bailey B, Gervaix A, Cousineau J, Delvin E, Girodias J. Markers for bacterial infection in children with fever without source. Arch Dis Child. 2011;96:440–6.
Shaikh N, Morone NE, Bost JE, Farrell MH. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J. 2008 Apr;27(4):302–8. https://doi.org/10.1097/INF.0b013e31815e4122.
de Nefrología C. Sociedad Argentina de Pediatría. Nuevas recomendaciones frente a las actuales controversias en infección urinaria. Arch Arg Ped. 2015;6:579–81.
Lee G, Harper M. Risk of bacteriemia for febrile young children in the post-Haemophilus influenzan type b era. Arch Pediatr Adolesc Med. 1998;152:624–8.
Alpern ER, Alessandrini EA, Bell LM et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics 2000;106(3):505–11. .
Herz AM, Greenhow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3- to 36-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J. 2006.
Waddle E, Jhaveri R. Outcomes of febrile children without localizing signs after pneumococcal conjugate vaccine. Arch Dis Child. 2009;94(2):144–7.
Mintegi S, Benito J, Sanchez J, et al. Predictors of occult bacteremia in young febrile children in the era of heptavalent pneumococcal conjugated vaccine. Eur J Emerg Med. 2009;16(4):199–205.
Kaplan SL, Schutze GE, Leake JA, et al. Multicenter surveillance of invasive meningococcal infections in children. Pediatrics. 2006;118(4):e979–84. 145.
Comités de Neumonología, Infectología y Medicina Interna, Sociedad Argentina de Pediatría. Recomendaciones para el manejo de las infecciones respiratorias agudas bajas en menores de 2 años. Arch Arg Ped. 2015;113(4):373–4 www.sap.org.ar/index.p.
Bradley JS, Byington CL, Shah SS, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis. 2011;53(7):e25–76.
Harris M, Clark J, Coote N, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011;66(Suppl 2):ii1–23. 208.
•• Mahajan P, Kuppermann N, Mejias A, et al. Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger.. s.l. JAMA. 2016;316(8):846–57. https://doi.org/10.1001/jama.2016.9207 Prospective case-control study. They compared RNA biosignatures with routine complementary tests and Yale Observation Scale to distinguish bacterial infections in infants younger than 2 months of age.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Pedro Rino declares that he has no conflict of interest.
Eugenia Hernández declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Pediatrics in South America
Rights and permissions
About this article
Cite this article
Rino, P., Hernández, E. The Febrile Infant. Curr Treat Options Peds 5, 431–447 (2019). https://doi.org/10.1007/s40746-019-00184-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40746-019-00184-1