BASIC CONSIDERATIONS

Normal thermoregulation is controlled by a hypo­thalamic thermostat, i.e. thermosensitive neurons in pre-optic or anterior hypothalamus, which maintains the body temperature at optimal levels for normal metabolic activity.

Pathogenesis: Fever denotes resetting of body thermostat at higher temperature due to variety of factors. For example:

• Endogenous pyrogens, produced in response to infections or inflammations, e.g. cytokines interleukins (IF-1#946; and IL-6), tumor necrosis factor-#945; (TNF-#945;), interferon (IFN-#946; and #947;), stimulated leukocytes, etc.

• Exogenous pyrogens, e.g. microbes and microbial toxins, which either directly affect thermoregulation (endotoxins), or stimulate release of endogenous pyrogens by immunological reactions.

• Central causes, e.g. autonomic disturbances (Riley-Day syndrome), hyperthyroidism, etc.

• Inadequate heat-loss mechanisms, e.g. reduced sweating in atropine poisoning or ectodermal dysplasia.

Consequences: Fever is an adaptive response to a pyrogenic illness, which may be beneficial as well as detrimental. Elevated body temperature is known to decrease microbial multiplication and increase protective inflammatory response. On the other hand, adverse effects of fever include: (a) febrile seizures or fever- triggered epilepsy, (b) increased oxygen consumption (c) increased CO₂ production, and (d) metabolic acidosis/instability.

Clinically, Childhood fevers may be broadly divided into three categories:

a. Fevers with localizing signs,

b. Fevers without focus or localizing signs (Sec 10.1.2)

c. Prolonged pyrexia or pyrexia of unknown origin (Sec 10.1.3)

Fevers with localizing signs: Most acute febrile episodes in childhood are short duration, self-limiting and often associated with localizing signs, e.g. Coryza, cough, diarrhea, jaundice, dysuria, etc. Detailed history and examination is usually enough to arrive at the diagnosis and detailed investigations are unnecessary, except those relevant to the clinical diagnosis. However, sometimes localizing signs may be misleading and patient should be clinically evaluated in toto for underlying or associated health problems.

Fever without focus or localizing signs, generally defined as acute fever of lt;7 days duration, pose a diagnostic dilemma and require detailed evaluation to detect or exclude presence of serious bacterial infections (SBI) or occult bacteremia. Children with fever without focus are at higher risk of occult bacteremia or SBI if they have: (a) Age lt; 3 months, (b) immunocompromised state, c) presence of co-morbidities, e.g. severe malnutrition or chronic medical conditions, (c) ill or toxic appearance. Despite the initial impression of a fever without focus, many of these cases are found to have subtle signs on re-evaluation or develop them during the course of illness, to assist in the diagnosis.

Prolonged fever or pyrexia of unknown origin (PUO) is generally defined as: (a) fever lasting for gt;14 days, (b) fever documented in the hospital, and (c) no cause identified after one week of routine investigations in the hospital.

Diagnostic considerations in febrile children at the time of presentation include:

• Age of the child is a major determinant for the risk for serious bacterial infections or occult bacteremia. Ranging from as high as 30% in newborns to lt;5% in older infants or toddlers, as follows:

- A febrile newborn carries substantially high-risk of occult bacteremia (~30%) and serious bacterial infections (~7-10%), e.g.

- Post-neonatal young infants (1-3 months) with fever also have a substantial risk of occult bacteremia (10­15%), though not as high as in newborns. Localizing signs are often absent in these cases despite presence of serious bacterial infections. Many criteria have been developed to identify low-risk cases in this age group, e.g. Rochester criteria (Table 10.1) which has a negative predictive value of gt;98% for serious bacterial infection or bacteremia.

- Fever in older infants and toddlers (3-36 months) is usually viral except in presence of (a) high fever 39°C, (b) leukocytosis 15,000 cells/mm³ with neutrophilia, (c) elevated inflammatory markers, e.g. CRP, and (d) persistence beyond one week. Most of these cases have localizing signs and risk of occult bacteremia or SBI is lt; 5% in these cases, in absence of significant clinical abnormalities.

• Duration of fever: While short-duration fevers without focus are common and usually benign, persistent of fever beyond a week is a cause of concern and need detailed revaluation and investigations.

• Periodicity of fever is an important diagnostic clue in many febrile illnesses, as follows, though the course may be modified by antipyretics:

- Continuous fever with diurnal variation of lt;0.5°C, e.g. in pneumonia, urinary tract infection, etc.

TABLE 10.1: Rochester criteria for low-risk of serious infection in children 1-3 months age

Apparently well infant with normal examination and

• Total leukocyte count 5000-15000 cells/mm³ with absolute band cell count lt;1500 cells/mm³

• Urine lt; 10 WBC/HPF

• Stool lt; 5 WBC/HPF (in presence of diarrhea)

- Remittent fever with diurnal variation of gt;1°C but never touching the baseline, e.g. in enteric fever (step-ladder pattern), infective endocarditis, etc.

- Intermittent fever alternating with short afebrile periods, e.g.

- Relapsing or biphasic fever, i.e. reappearance of fever after an afebrile period of gt;2-3 days, e.g. in dengue, leptospirosis, Hodgkin disease (Pel- Epstein fever), etc.

- Single isolated spikes are usually benign, due to intra­venous infusions, invasive procedures, drugs and vaccinations.

• Severity of fever may be divided into:

- Malignant hyperpyrexia (gt;41°C), contrary to popular perception, is usually non-infective in origin, e.g. heat-stroke, pontine hemorrhage, drugs/ poisonings, hypothalamic dysfunction, neuroleptic syndrome, etc.

- Moderatefever (38-41°C) in most infectious illnesses.

- Low-grade fever (lt;38°C) in TB, malignancies,viral infections, etc.

- Hypothermia (lt;35°C) is an important indicator of serious infections in newborns and immuno­compromised children.

- Significant mismatch between core and skin temperature (gt;1°) indicates impending shock.

• Circadian rhythm, e.g. evening-rise temperature in tuberculosis or malignancies.

• Inter-febrile clinical state: Absence of ill-look between febrile episodes indicates viral etiology or malaria. In bacterial infections, child continues to betoxic or lethargic, even during afebrile phase.

• Pattern of defervescence:

- Sudden defervescence (by crisis) with profuse sweating, e.g. malaria, roseola infantum.

- Gradual defervescence over 48-72 hours (by lysis), e.g. enteric fever or other bacterial infections.

• Presence of co-existing features: For example,

- Chills and rigors usually indicate—malaria, uri­nary tract infection, pneumococcal pneumonia, septicemia, amebic hepatitis, infective endocarditis.

- Bradycardia is common in enteric fever, brucellosis and factitious fevers.

- Localizing signs, e.g. rash (Ch 10.1.3), jaundice (hepatitis), lymphadenitis (viral infections, malignancy), altered sensorium or seizures (CNS infections), respiratory distress (respiratory infections), splenomegaly (malaria, kala-azar), dysuria (urinary tract infections), heart disease (infective endocarditis), osteo-articular pain (osteomyelitis, arthritis, rheumatic disorders), etc.

- H/O vaccination, as fever is a common side effect of many vaccines given in this age group though rarely lasts for more than 24-48 hours.

Management of febrile child depends on the severity of the illness at the time of presentation, possible clinical diagnosis and underlying risk of occult bacteria or serious bacterial infections, apart from symptomatic antipyretic therapy.

Consensus Guidelines on Evaluation and Management of the Febrile Child presenting to the Emergency Department in India (2017) as well as IAP standard treatment guidelines 2022 suggest that:

• All febrile newborns need hospitalization and complete investigative workup which includes complete blood count (CBC), C-reactive protein (CRP), peripheral blood smear (PS) (band form, toxic granules, vacuolization, immature/total ratio ), blood and urine culture, urine analysis (UA), lumbar puncture (LP), and chest X-ray (CXR) is mandatory. Stool should be examined for pus cell and red blood cell (RBC) only if change in frequency of stool is present. First negative septic screen in an active febrile newborn is not the indication for discharge.

All ill-appearing newborns should be started on empirical intravenous antibiotics immediately on hospitalization, including ampicillin (100-200 mg/ kg/d q8hr) and gentamicin (7.5 mg/kg/d q8hr), after collection of cultures.

• Young infants (1-3 months), if apparently active except fever, should be observed in the emergency room, along with CBC, PS and urine analysis and culture (after catheterization) and blood culture in all cases. Chest X-ray is indicated if temperature 39°C, leucocyte count 20,000/mm³ or respiratory signs are present. Lumbar puncture is indicated only in sick- looking child.

All sick-looking children of this age group should be hospitalized and started on empirical intravenous antibiotics immediately on hospitalization, including Ceftriaxone (100 mg/kg/d q12hr) or (75 mg/kg/d q12hr), dose depending on the presence or absence of meningeal involvement.

Apparently well children of this age group should be managed symptomatically and may be hospitalized for observation or asked to follow-up after 24 hours, for further treatment, if required.

• Children aged 3 months - 3 years do not need urgent investigations, if apparently well and have no localizing signs, except urine microscopy, if have fever gt;24 hours and past history of UTI. However, sick- looking children of this age must be investigated with CBC, PS, urine analysis and culture, blood culture in all cases and chest skiagram and CSF in selected cases. Rapid tests for malaria, dengue and enteric fever may be done in endemic areas.

While sick-looking children of this age group should be hospitalized and started on empirical intra­venous Ceftriaxone, other apparently well children may be managed symptomatically with follow-up after 24 hours, for further treatment, if required.

• Febrile children gt;3 years are unlikely to have serious bacterial infections in absence of thelocalizing signs and need detailed workup only in presence of: (a) prolonged pyrexia, (b) immunocompromised state, (c) co-morbidities, or (d) nosocomial risk factors. Investigations in these cases should directed on clinical suspicion, though rapid tests for malaria, dengue and enteric fever may be done in endemic areas. Treatment is these cases should be directed on clinical grounds.

Antipyretic therapy includes: (a) hydrotherapy, i.e. tepid water sponging to bring down high fever, and (b) pharmacotherapy. Paracetamol (PO10-15 mg/kg/ dose) is the safest antipyretic in children, though others, e.g. Ibuprofen (PO 5-10 mg/kg) or Mefenamic acid (PO 5-7 mg/kg) may be used in selected cases. IV paracetamol may be given in babies with intractable vomiting or altered senosrium as 7.5 mg/kg (lt;10 kg) or 15 mg/kg in children gt;10 kg. Nimesulide and Aspirin are not recommended as antipyretics in children due to potential risk of hepatotoxicity and Reye's syndrome, respectively. No antipyretics are necessary in low-grade fevers lt;38°C.

10.1.1