Fever in children

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Zaida Obeidat, M.D.

Synonyms and keywords: Fever in kids

Historical Perspective

• The history of fever are briefly reviewed by the Greeks as well as the views brought up in the Bible and widespread throughout the Middle Ages where fever and disease were interpreted as punishment for misbehavior.
• Later views are introduced, based on the rise of science and Harvey's discovery of the circulation of the blood which produced two rival camps, iatrochemists and iatrophysicists.
• Next are brought up as the contributions of tissue pathology, experiments defining the role of the CNS in regulating body temperature, the old correlation of fever with inflammation and the discovery of microbial agents of disease and bacterial pyrogens in the late nineteenth and early twentieth century
• Finally, work in the last 30 years is summarized, starting with the discovery of endogenous pyrogen (EP) and the recent finding that EP is probably similar to lymphocyte activating factor (LAF) and leukocytic endogenous mediator (LEM) which collectively as interleukin-1 IL-1 play a major role in both inflammation and immunity.

Classification

• Fever may be classified based on duration into:
  • Acute fever: (<7 days duration), if untreated it can become persistent or chronic, attributes to infectious disease such as upper respiratory tract infection (URTI) and malaria.
  • Sub-acute fever:(<2 weeks), seen in typhoid fever and intra-abdominal abscess.
  • Chronic fever: (>2 weeks), typical of chronic bacterial infections (tuberculosis TB), viral infections (HIV), cancers and connective tissue diseases.

• Fever also can be classified based on height of body temperature into:
  • Low grade fever
  • Moderate grade fever
  • High grade fever (attributes to Serious bacterial infections in infants)
  • Hyperpyrexia

• The height of fever may correlate with severity of illness, such as in dengue fever, shigellosis, and acute falciparum malaria.
• There are three major fever type: Sustained/continuous fever, intermittent fever and remittent fever.
  • Continuous or sustained fever does not fluctuate more than about 1°C (1.5°F) during 24hours, but never touches normal, characteristics of lobar and gram negative pneumonia, typhoid, acute bacterial meningitis, and urinary tract infection.
  • Fever with bradycardia (Faget’s sign or sphygmothermic dissociation)is characteristic of untreated typhoid, leishmaniasis, brucellosis, Legionnaire’s disease and psittacosis, and Yellow Fever.
  • Intermittent fever is defined as fever present only for several hours during the day. It can be seen in malaria, pyogenic infections, tuberculosis (TB), schistosomiasis, lymphomas, leptospira, borrelia, kala-azar, or septicemia.
  • Sources of continuous, intermittent or transient bacteraemia may lead to continuous, intermittent or transient fevers respectively. In malaria, depending on the specie of parasite, fever can occur with a periodicity of 24h (quotidian-due to plasmodium falciparum), 48h (tertian plasmodium ovale and vivax), or 72h (quartan Plasmodium malaria). The Pel-Epstein’s fever is an intermittent low grade fever characterised by 3—10 days of fever with subsequent a febrile periods of 3—10 days. It is thought to be a typical but rare manifestation of Hodgkin’s lymphoma.
  • Remittent fever is defined as fever with daily fluctuations exceeding 2◦C but at no time touches normal. Remittent fevers are often associated with infectious diseases such as infective endocarditis, rickettsiae infections, and brucellosis. Relapsing fevers refer to those that are recurring and separated by periods with low grade fever or no fever. Periodic or relapsing fevers are seen in malaria, lymphoma, borrelia, cyclic neutropenia, and rat-bite fever. Fever associated with night sweats has been described in infectious diseases such as TB, Nocardia, brucellosis, liver or lung abscess and sub-acute infective endocarditis, as well as in non-infectious diseases such as polyarteritis nodosa and cancers such as lymphomas.

Body temperature	°C	°F
Normal	37-38°C	98.6-100.4°F
Mild/low grade fever	38.1-39°C	100.5-102.2°F
Moderate grade fever	39.1-40°C	102.2-104.0°F
High grade fever	40.1-41.1°C	104.1-106°F
Hyperpyrexia	>41.1°C	>106.0°F

Pathophysiology

• The development of the pyrexia is similar to the normal thermoregulatory processes that follow exposure to cold temperatures.
• The thermal balance point in fever is reset to a higher level such that normal peripheral and central body temperatures are now sensed as cold temperature signals by the thermoregulatory circuitry.
• Fever is different from heat stroke and hyperthermia where body temperature is increased without an equivalent increase of the thermal balance point.

The role of pyrogens and cryogens

• The initiation, manifestations and regulation of pyrexia are dependent on the pyrogenic and anti-pyretic properties of numerous exogenous and endogenous substances.
• Pyrogens directly or indirectly lead to pyrexia and cryogens prevent extortionate temperature elevation.
• The [[balance][] in the interactivity between pyrogens and cryogens is control the height and duration of the pyrexia.

Pryogens

• Pyrogens are classified into exogenous and endogenous pyrogens based on their site of production.
• Exogenous pyrogens are part or whole micro organisms (lipopolysaccharide (LPS) in gram negative cell wall) or products of micro organisms as toxins.
• Endogenous pyrogens include muramyl dipeptidase and enterotoxins of Staphylococcus aureus and group A and B Streptococcus (superantigens).
• Endogenous pyrogens are mainly pyrogenic cytokines including interleukins (IL-6, IL-1), interferon gamma (INF-a) and ciliary neurotropic factor (CNTF) and tumor necrosis factor (TNFa).

Cryogens

• Cyrogens include cytokines(IL-10), hormones (a-melanocyte stimulating hormone, corticotrophin and corticotrophin releasing hormone) and neuroendocrine products (neuropeptide Y, bombesin, and thyroliberin), and cytochrome P-450.
• The antipyretic effect induced by inhibiting synthesis of pyrogenic cytokines (glucocorticoids), cytokine receptors blockade (IL-1 receptor antagonist), and increasing heat loss by enhancing sensitivity of warm sensitive neurons (bombesin).

The pathophysiological mechanisms for the injurious effects of a fever, classified as follows:

• Direct cellular damage:
  • Membrane, mitochondrial and DNA damage
  • Stimulation of excitotoxic mechanisms
  • Protein denaturation
  • Cell death
• Local effects:
  • Cytokine stimulation
  • Inflammatory response
  • Vascular stasis
  • Extravasation
  • Oedema
• Systemic effects:
  • Endotoxaemia
  • Gut bacterial translocation

Causes

Common conditions that can cause fevers include:

• Upper respiratory tract infections (URTI)
• Flu
• Ear infections
• Roseola
• Tonsillitis
• Urinary tract infections (UTI)
• Chickenpox and Pertussis (Whooping cough)

Fever in children can sometimes associated with more serious signs and symptoms, such as:

• Dyspnea
• Vomiting
• Rash
• Seizures

Serious bacterial infections include:

• Meningitis
• Septicaemia
• Pneumonia

Causes of undiagnosed fever in children include:

• Infection
  • Viruses
  • Pyogenic Infection
  • Salmonella Infection
  • Brucellosis
  • Tuberculosis
• Collagen Vascular Diseases
• Neoplasm

Differential diagnoses for fever in children

Cause	Differential Diagnosis
Infectious; Bacterial or mycobacterial	Brucellosis, dental abscess, endocarditis, non-tuberculous mycobacteria (eg, Mycobacterium chelonae), occult bacterial infection, recurrent bacterial infections, relapsing fever (Borrelia spp other than Borrelia burgdorferi), Yersinia enterocolitica
Parasitic	Malaria (eg, Plasmodium vivax, Plasmodium ovale)
Inflammatory or Immunologic	Behçet syndrome, inflammatory bowel disease (eg, Crohn disease), hereditary fever syndromes (eg, FMF), juvenile dermatomyositis, PFAPA syndrome, sarcoidosis, systemic lupus erythematous, systemic juvenile idiopathic arthritis (Still disease), vasculitis (eg, polyarteritis nodosa)
Malignant	Leukemia, lymphoma
Other	Benign giant lymph node hyperplasia (Castleman disease), CNS abnormalities (eg, hypothalamic dysfunction), drug fever, factitious fever, IgG4-related disease, immunodeficiency syndromes with recurrent infections

• CNS—central nervous system; FMF—familial Mediterranean fever; IgG4—immunoglobulin G4; PFAPA—periodic fever, aphthous stomatitis, pharyngitis, and adenitis.

Epidemiology and Demographics

• Following the widespread use of immunizations against Streptococcus pneumoniae and Haemophilus influenzae b, incidence of fever caused by infection due to these organisms has been decreased.
• Since 1990, rates of invasive Hib infection (including meningitis) in children 5 years and younger have declined by more than 99%.
• In 2005, the incidence of fever caused by invasive pneumococcal infection in children declined by 77% from 1998.

Age

• Fever caused by urinary tract infections (UTIs) are the most common source of serious bacterial infection in children younger than 3 months, commonly from E.coli or Klebsiella species.
• According to a case series, fever caused by pneumonia is the most common serious bacterial infection in children 3 to 36 months of age, followed by UTI.

Natural History, Complications and Prognosis

• Any abnormal increase body temperature in a child should be estimated as a potential symptom of an underlying condition.
• Fever occurs when the body temperature increase by an alteration of the hypothalamic temperature set-point due to exposure to endogenous pyrogens.
• Hyperthermia occurs when the body temperature increase due to failure of thermoregulation, whether by increased heat absorption, heat production and/or reduced ability to dissipate it.
• Hyperthermia may have severe consequences on the body, since hyperthermia does not represent a controlled physiologic phenomenon.
• Hyperthermia is less common in children, compared to fever.
• Most cases of hyperthermia occurs due to environmental hyperthermia, caused by massive heat exposure, which overcomes the body’s thermoregulation, such as in the case of “forgotten baby syndrome” involving children left in cars during hot season.
• Heat stroke is described as a core temperature ≥40 °C along with central nervous system dysfunction due to environmental heat exposure.
• Young children have less efficient heat dissipation mechanisms, compared to older children and adults.
• Other predisposing factors include:
  • Excessive fluids loss or that negatively affect water-electrolyte balance (e.g., gastrointestinal illness, diabetes insipidus, diabetes mellitus, cystic fibrosis, diuretics, fever)
  • Conditions associated with suboptimal sweating (spina bifida, familial dysautonomia, hypo/anhidrotic ectodermal dysplasia, Crisponi syndrome, Fabry disease)
  • Diminished thirst/water intake (cognitive impairment, young children)
  • Hypothalamic dysfunction
  • Anorexia nervosa
  • Obesity
• Apart from environmental heat exposure, hyperthermia may be directly caused by conditions resulting in abnormal thermoregulation or increased heat production.
• Central nervous system conditions involving injury to the hypothalamus (either congenital or acquired) may lead to temperature dysregulation and hyperthermia (sometimes called neurogenic or central fever).
• Other causes include status epilepticus, thyrotoxicosis, and genetic syndromes associated with abnormal thermoregulation.
• Intoxication from hyperthermia-inducing drugs may result in severe hyperthermia; involved drugs include stimulating/sympathomimetic drugs (cocaine, methamphetamine, MDMA), anticholinergic drugs (e.g., antihistamines, tricyclic antidepressants), serotoninergic drugs (serotonin syndrome), and salicylates
• Neuroleptic malignant syndrome is a severe idiosyncratic reaction to antipsychotic agents, but also antiemetic agents such as metoclopramide, characterized by altered mental status, muscular rigidity, movement disorders, hyperthermia and autonomic dysfunction.
• Malignant hyperthermia is a rare genetic disorder associated with several forms of congenital myopathy and triggered by succinylcholine or inhalational anesthetics agents; clinical features include rapid onset of extremely high temperature (38.5–46 °C), usually heralded by masseters spasm, muscle rigidity, metabolic acidosis, and hemodynamic collapse. Specific treatment, with discontinuation of involved anesthetics, muscular relaxation with sodium dantrolene, and correction of metabolic acidosis, has dramatically reduced the mortality, once as high as 70%, to less than 5%.

Fever is the most common reason for increased body temperature in pediatric clinical practice. The most common causes of fever in children are infections; non-infectious causes include immune-mediated, inflammatory, and neoplastic conditions. When a cause for fever cannot be identified by history and physical examination it is called “fever without source” (FWS). In industrialized countries, a minority of children with FWS will have a serious bacterial infection (SBI) (mainly urinary tract infection (UTI), less commonly pneumonia, sepsis, or meningitis), while the majority will have mild, self-resolving viral illnesses.

• Signs and symptoms of a viral upper respiratory infection do not reliably exclude the possibility of an associated SBI, given the possibility of co-infections. In a study of children 2 to 36 months with FWS, at least one virus (most frequently adenovirus, human herpesvirus-6, enterovirus, and parechovirus) could be identified in 76% of children in whom no other explanation for the fever was found, but also in 40% of children with SBI. Therefore, detection of viral pathogens cannot be considered a discriminating factor.

Prognosis

• There is an association with a greater likelihood of serious bacterial infection (SBI) for temperatures >39 °C.
• In a prospective cohort study on more than 12,800 children presenting with febrile illness, fever >39 °C was associated with an increased risk of SBI, especially in infants under 6 months.
• In a prospective series of 103 children with a temperature >41 °C, almost 50% had an SBI.
• Temperatures above 41 °C have also been associated with a higher risk of meningitis.
• Children with SBI may also have a normal temperature or be hypothermic.

Diagnosis

Symptoms

• Fever is often characterised by:
  • Chills
  • Rigors
  • Sweating
  • Headache
  • Malaise
  • Anorexia

Physical Examination

• Initial history and physical examination in infants and young children with fever is aim to identify serious illness. Immunocompromised patients (cancer, asplenia, or HIV infection) need more evaluation and treatment.
• Benign causes of fever such as vaccination in the past 24 hours are reassuring. Teething is rarely associated with a fever of more than 100.4°F
• A meta-analysis of febrile children older than one month has identified red flags associated with a high likelihood of serious infection.

• Clinical Red Flags for Serious Infection in Children Older than One Month
• Global assessments
  • Parental concerns
  • Physician instinct
• Child behavior
  • Changes in crying pattern
  • Drowsiness
  • Inconsolability
  • Moaning
• Circulatory/respiratory
  • Crackles
  • Cyanosis
  • Decreased breath sounds
  • Poor peripheral circulation
  • Rapid breathing
  • Shortness of breath
• Other factors
  • Decreased skin elasticity
  • Hypotension
  • Meningeal irritation
  • Petechial rash
  • Seizures
  • Unconsciousness

Laboratory Findings

• History and physical examination cannot identify all children with serious bacterial infections, hence sensible use of imaging and laboratory testing is valuable.

Urinalysis and urine culture

• Urinalysis is a key factor in the evaluation of fever in infancy and early childhood because UTI is a common cause of serious bacterial infection. *Urine sample should be obtained for all children younger than 24 months with unexplained fever. It may be obtained by catheterization or suprapubic aspiration.
• In children with voluntary urine control, a clean catch method (urination into a specimen container after cleaning the area around the urethra) may be used.
• Cultures of specimens collected in a urine bag may have an 85 percent false-positive rate, and urine dipstick testing has a 12 percent false-negative rate.
• All specimens should be sent for formal urinalysis and culture.
• UTI rates vary with patient sex and age.
• In the first three months of life, UTIs are more common in boys than in girls, and much more common in uncircumcised boys. After three months of age, UTIs are more common in girls.

Blood cell counts and blood culture

• White blood cell (WBC) counts and absolute neutrophil counts have been used to point out serious bacterial infection, including occult bacteremia.
• Blood cell counts have higher value in neonates than in older children.
• WBC counts lower than 5,000 per mm3 (5 × 109 per L) or more than 15,000 per mm3 (15 × 109 per L) had a PPV of 44% for serious bacterial infection, and an absolute neutrophil count of more than 10,000 per mm3 (10 × 109 per L) had a PPV of 71% according to a study of neonates up to 28 days of age.
• Current guidelines recommend a complete blood count with differential and blood culture for infants three months or younger with fever.

Stool testing

• Diarrhea with fever in neonates and young infants submit systemic illness therefore stool culture and fecal WBC counts are supported.

Inflammatory markers

• The clinical value of C-reactive protein levels in recognizing serious infection in neonates, infants, and young children is being explored.
• C-reactive protein (CRP) level of 2 mg per dL (19 nmol per L) or greater has better sensitivity, specificity, and predictive value than a WBC count of greater than 15,000 per mm3 or less than 5,000 per mm3.
• Elevated levels of procalcitonin (another marker of inflammation and bacterial infection) also appear to have better sensitivity, specificity, and predictive value than WBC counts.

Lumbar puncture

• Vaccination against S. pneumoniae and Hib has greatly reduced the incidence of meningitis limiting the need for lumbar puncture.
• Fever with clinical signs of meningitis such as nuchal rigidity, petechiae, or abnormal neurologic findings in neonates, infants and young children is indication for lumbar puncture.
• In children older than 3 months, the test is not suggested unless neurologic signs are present.
• Two guidelines recommended a lumbar puncture for well-appearing, previously healthy young infants with no focal signs of infection, a WBC count between 5,000 and 15,000 per mm3, and no pyuria or bacteriuria on urinalysis.
• Although low peripheral WBC counts (less than 5,000 per mm3) are more often associated with meningitis than with bacteremia, WBC counts should not be used alone to determine which infants need lumbar puncture.

Electrocardiogram

There are no ECG findings associated with fever in children.

X-ray

• Chest X ray is recommended in all neonates with unexplained fever.
• Chest X ray is also recommended for young children older than one month revealing respiratory symptoms and for patients with a fever of more than 102.2°F (39°C) and a WBC count of more than 20,000 per mm3 (20 × 109 per L).

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with fever in children.

CT scan

There are no CT scan findings associated with fever in children.

MRI

There are no MRI findings associated with fever in children.

Treatment

Medical Therapy

• Fever plays a physiologic role in response to infection, inhibiting bacterial growth and viral replication, and enhancing the immune response.
• There is no evidence that use of antipyretics prolongs illness in children
• Antipyretic treatment should be reserved for distressed children, aiming at improving the child’s wellbeing rather than achieving normothermia.
• Antipyretic treatment has not been shown to prevent recurrence of febrile seizures.
• Response to antipyretics cannot predict the severity of the underlying illness, since children with bacterial and viral illnesses have a similar response to antipyretics [134]. However, evaluating if the child’s conditions markedly improve with antipyretic treatment may be useful to discern whether it was related to fever or to the severity of the underlying illness.
• In children with inherited metabolic and mitochondrial diseases, catabolic stressors should be avoided, and both fever and underlying infections should be treated
• Fever may increase metabolic and oxygen consumption; therefore, aggressive treatment may be more important in children with a limited cardiopulmonary or metabolic reserve, and it is recommended in patients recovering from cardiac arrest.
• Ibuprofen and acetaminophen are the only drugs approved for treatment of fever in children and they are generally considered to be equally safe and effective for reducing temperature and relieving discomfort.
• Combination therapy with acetaminophen plus ibuprofen seems to be slightly more effective in reducing body temperature compared with monotherapy alone