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Fever Assit. Prof. Dr. Suat Biçer Yeditepe University, Faculty of Medicine Child Health and Pediatrics Department AMAÇLAR Çocukluk çağında ateş nedenleri konusunda bilgi sahibi olabilmek, Ne zaman ateş ciddi hastalık belirtisidir sorusunu yanıtlayabilmek, Ateşli çocuğa yaklaşım konusunda bilgi sahibi olmak, Yineleyen ateşte etiyolojik faktörler ve tedavi yöntemleri konusunda bilgi sahibi olmak, Ateşli çocuğa müdahale yöntemleri ve antipiretikler konusunda bilgi sahibi olmak. What is the definition of fever in children? ≥ 39°C > 39°C ≥ 40°C ≥ 38°C > 38°C > 37.9°C > 37°C ≥ 36.5°C > 36.5°C What is the definition of hyperpyrexia in children? The same definition for fever, ≥ 38°C > 39°C > 37.9°C > 37°C ≥ 36.5°C > 36.5°C ≥ 39°C > 38°C > 37.9°C > 37°C ≥ 36.5°C > 36.5°C > 40°C > 41°C Definition Fever is defined as a rectal temperature ≥38°C, and a value >40°C is called hyperpyrexia. Body temperature fluctuates in a defined normal range (36.6°C-37.9°C rectally), so that the highest point is reached in early evening and the lowest point is reached in the morning. Any abnormal rise in body temperature should be considered a symptom of an underlying condition. Where is regulated the body temperature? Body temperature is regulated by thermosensitive neurons located in the supraoptic and posterior hypothalamus that respond to changes in blood temperature as well as cold and warm receptors located in capillary and venous vessels. Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior hypothalamus that respond to changes in blood temperature as well as cold and warm receptors located in skin and muscles. Pathogenesis Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, regulation of extracellular fluid volume via arginine vasopressin, and behavioral responses, such as seeking a warmer or cooler environmental temperature. FEVER RESPONSE Infection, toksins, injury, inflamation, immunolojic reactions, Vasomotor area Monocyt, neutrophil, lymphocyt, endotel, glial, mesenchimal cells Increased set point Monoamins and Calcium cAMP Prostoglandin E2 Pyrojenic cytokins, IL-1, TNF, IFN, IL-6 Endotel Circulation Circumventricular area Which mechanisms can produce fever? Pyrogens, Heat production exceeding loss, Defective heat loss The first mechanism involves endogeneous and exogenous pyrogens that raise the hypothalamic temperature set point. Endogenous pyrogens include the cytokines interleukin 1 (IL)-1 and IL-6, tumor necrosis factor-α (TNF-α), and interferon (IFN)-β and IFN-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The best-studied lipid mediator is ................., which attaches to the ................. receptors in the ................. to produce the new temperature set point. The best-studied lipid mediator is prostaglandin (PG)E2, which attaches to the prostaglandin receptors in the hypothalamus to produce the new temperature set point. Exogenous pyrogens or substances that come from outside the body include mainly infectious pathogens and drugs. Microbes, microbial toxins, or other products of microbes are the most common exogenous pyrogens and stimulate macrophages and other cells to produce endogenous pyrogens. Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drugs. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens. Second and third mechanisms that leads to fever: Heat production exceeding heat loss is the second mechanism that leads to fever, with examples including salicylate poisoning and malignant hyperthermia. Defective heat loss is the third mechanism of fever genesis, for example, in children with ectodermal dysplasia or victims of severe heat exposure. What are the causes of fever? (organized into 4 main categories) 1- Infections Etiology 2- Inflammatory diseases 3- Neoplastic diseaes 4- Miscellaneous What are the most common causes of acute fever and hyperpyrexia? 1- Self-limited viral infections (common cold, gastroenteritis) 2- Uncomplicated bacterial infections (otitis media, pharyngitis, sinusitis) What is the limit of fever? 40°C 41°C 42°C 43°C 45°C The body temperature should not rise above potentially lethal levels (41.7°C) in the neurologically intact child unless extreme hyperthermic environmental conditions are present or other extenuating circumstances exist, such as underlying malignant hyperthermia or thyrotoxicosis. The pattern of the fever can provide clues to the underlying etiology. Viral infections typically are associated with a slow decline of fever over a week, whereas bacterial infections are associated with a prompt resolution of fever after effective antimicrobial treatment is employed. Although administration of antimicrobial agents can result in a very rapid elimination of bacteria, if tissue injury has been extensive, the inflammatory response and fever can continue for days after all microbes have been eradicated. Intermittent fever is an exaggerated circadian rhythm that includes a period of normal temperatures on most days; extremely wide fluctuations may be termed septic or hectic fever. Sustained fever is persistent and does not vary by more than 0.5°C/day. Remittent fever is persistent and varies by more than 0.5°C/day. Relapsing fever is characterized by febrile periods that are separated by intervals of normal temperature; tertian fever occurs on the first and third days (malaria caused by Plasmodium vivax), and quartan fever occurs on the first and fourth days (malaria caused by Plasmodium malariae). Diseases characterized by relapsing fevers should be distinguished from infectious diseases that have a tendency to relapse. Biphasic fever indicates a single illness with 2 distinct periods (camelback fever pattern); poliomyelitis is the classic example. A biphasic course is also characteristic of other enteroviral infections, leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola, and Lassa fevers). The term periodic fever is used narrowly to describe fever syndromes with a regular periodicity (cyclic neutropenia and PFAPA [periodic fever, aphthous stomatitis, pharyngitis, and adenopathy]) or more broadly to include disorders characterized by recurrent episodes of fever that do not follow a strictly periodic pattern (familial Mediterranean fever, Hibernian fever, TNF-receptor–associated periodic syndrome [TRAPS], hyper-IgD syndrome, the Muckle-Wells syndrome). Factitious fever, or self-induced fever, may be caused by intentional manipulation of the thermometer or injection of pyrogenic material. INFECTIOUS CAUSES Relapsing fever (Borrelia recurrentis) Acute rheumatic fever Q fever (Coxiella burnetii) Visceral leishmaniasis Typhoid fever (Salmonella typhi) Lyme disease (Borrelia burgdorferi) Syphilis (Treponema pallidum) Malaria Tuberculosis Babesiosis Histoplasmosis Respiratory viral infections Coccidioidomycosis Blastomycosis Melioidosis (Pseudomonas pseudomallei) Lymphocytic choriomeningitis (LCM) infection Dengue fever Yellow fever Leptospirosis Brucellosis NONINFECTIOUS CAUSES Behçet disease Crohn disease Weber-Christian disease (panniculitis) Leukoclastic angiitis Sweet syndrome Systemic lupus erythematosus PERIODIC FEVER SYNDROMES Familial Mediterranean fever Cyclic neutropenia Periodic fever, aphthous stomatitis, pharyngitis, adenopathy (PFAPA) Hyper IgD syndrome Hibernian fever (tumor necrosis factor super-family IgAassociated syndrome [TRAPS]) Muckle-Wells syndrome The double quotidian fever (or fever that peaks twice in 24 hours) is classically associated with inflammatory arthritis. In general, a single isolated fever spike is not associated with an infectious disease. Such a spike can be attributed to the infusion of blood products and some drugs, as well as to some procedures, or to manipulation of a catheter on a colonized or infected body surface. Temperatures in excess of 41°C are most often associated with a noninfectious cause. Causes for very high temperatures (>41°C) include central fever (resulting from central nervous system (CNS) dysfunction involving the hypothalamus), malignant hyperthermia, malignant neuroleptic syndrome, drug fever, or heatstroke. Hypothermia Temperatures that are lower than normal (<36°C) can be associated with sepsis but are more commonly related to cold exposure, hypothyroidism, or overuse of antipyretics. Clinical Features The clinical features of fever can range from no symptoms at all to extreme malaise. Children might complain of feeling hot or cold, display facial flushing, and experience shivering. Fatigue and irritability may be evident. Parents often report that the child looks ill or pale and has a decreased appetite. The underlying etiology also produces accompanying symptoms. Although the underlying etiologies can manifest in varied ways clinically, there are some predictable features. For instance, fever with petechiae in an illappearing patient indicates the high possibility of life-threatening conditions such as meningococcemia, Rocky Mountain spotted fever, or acute bacterial endocarditis. Changes in heart rate, most commonly tachycardia, accompany fever. Relative tachycardia, when the pulse rate is elevated out of proportion to the temperature, is usually due to noninfectious diseases or infectious diseases in which a toxin is responsible for the clinical manifestations. Relative bradycardia (temperature-pulse dissociation), when the pulse rate remains low in the presence of fever, can accompany typhoid fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of fever also may be a result of a conduction defect resulting from cardiac involvement with acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis. Evaluation Most acute febrile episodes in a normal host can be diagnosed by a careful history and physical examination and require few, if any, laboratory tests. Because infection is the most likely etiology of the acute fever, the evaluation should initially be geared to discovering an underlying infectious cause. The details of the history should include the onset and pattern of fever and any accompanying signs and symptoms. The patient often displays signs or symptoms that provide clues to the cause of the fever. Exposures to other ill persons at home, daycare, and school should be noted, along with any recent travel or medications. The past medical history should include information about underlying immune deficiencies or other major illnesses and receipt of childhood vaccines. In the acutely febrile child, the physical examination should focus on any localized complaints, but a complete head-to-toe screen is recommended, because clues to the underlying diagnosis may be found. For example, palm and sole lesions may be discovered during a thorough skin examination and provide a clue for infection with coxsackievirus. Vital signs should include pulse oximetry, because hypoxia indicates lower respiratory tract disease. EVALUATION OF ACUTE FEVER Thorough history: onset, other symptoms, exposures (daycare, school, family, pets, playmates), travel, medications, other EVALUATION OF ACUTE FEVER underlying disorders, immunizations Physical examination: complete, with focus on localizing symptoms Laboratory studies on a case-by-case basis: • Rapid antigen testing • Nasopharyngeal: respiratory viruses • Throat: group A streptococcus • Stool: rotavirus • Throat culture • Blood: complete blood count, blood culture, C-reactive protein, sedimentation rate • Urine: urinalysis, culture • Stool: hemocult, culture • Cerebrospinal fluid: cell count, glucose, protein, Gram stain, culture Chest radiograph or other imaging studies on a case-by-case basis If a fever has an obvious cause, then the evaluation is complete, no further testing is advised, and care is tailored to the underlying diagnosis with as-needed re-evaluation. If the cause of the fever is not apparent, then further diagnostic testing should be considered on a caseby-case basis. The history of presentation and abnormal physical examination findings guide the evaluation. The child with respiratory symptoms and hypoxia can require a chest radiograph or rapid antigen testing for RSV or influenza. The child with pharyngitis can benefit from rapid antigen detection testing for group A Streptococcus and a throat culture. Dysuria, back pain, or history of vesicoureteral reflux should prompt a urinalysis and urine culture, and bloody diarrhea should prompt a stool culture. A complete blood count and blood culture should be considered in the ill-appearing child, along with cerebrospinal fluid studies if the child has neck stiffness. Well-defined high-risk groups require a moreextensive evaluation on the basis of age, associated disease, or immunodeficiency status and might warrant prompt antimicrobial therapy before a pathogen is identified. Treatment Although fear of fever is a common parental worry, evidence is lacking to support the belief that high fever can result in brain damage or other bodily harm, except in rare instances of febrile status epilepticus and heat stroke. Treating fever in self-limiting illnesses for the sole reason of bringing the body temperature back to normal is not necessary in the otherwise healthy child. Most evidence suggests that fever is an adaptive response and should be treated only in selected circumstances. In humans, increased temperatures are associated with decreased microbial replication and an increased inflammatory response. • Increases neutrophil migration, • Antibacterial agents such as released from neutrophils superoxide anion production increases. • Increases the production of interferon • Enhances the antiviral and antitumor activity of interferon. • Activation of T-helper cells, and cytotoxic activity of expression increases. • Promotes the release of lactoferrin. Accelerate the killing of intracellular bacteria. Increases the bactericidal activity of antimicrobial agents. Although fever can have beneficial effects, it also - increases Fever can exacerbate; - cardiac insufficiency in patients with heart disease or - oxygen consumption, - carbon dioxide production, - cardiac output chronic anemia (e.g., sickle cell disease), - pulmonary insufficiency in patients with chronic lung disease, - metabolic instability in patients with diabetes mellitus or inborn errors of metabolism. Basal metabolic rate leads to a six-fold increase, Body temperature increase from 38 to 41 ⁰ C with increasing oxygen consumption by 20%, The oxygen affinity of hemoglobin is reduced, Degrees above the normal body temperature of a need to keep the increase in the basal metabolic rate of 10-12.5%. Children between the ages of 6 mo and 6 yr are at increased risk for simple febrile seizures. Children with idiopathic epilepsy also often have an increased frequency of seizures associated with a fever. Fever with temperatures <39°C in healthy children generally does not require treatment. However, as temperatures become higher, patients tend to become more uncomfortable, and treatment of fever is then reasonable. If a child is included in one of the high-risk groups or if the child's caregiver is concerned that the fever is adversely affecting the child's behavior and causing discomfort, treatment may be given to hasten the Other than providing symptomatic relief, antipyretic therapy does not change the course of infectious diseases. Encouraging good hydration is the first step to replace fluids that are lost related to the increased metabolic demands of fever. Antipyretic therapy is beneficial in high-risk patients who have chronic cardiopulmonary diseases, metabolic disorders, or neurologic diseases and in those who are at risk for febrile seizures. Hyperpyrexia (>40°C) indicates greater risk of hypothalamic disorders or CNS hemorrhage and should be treated with antipyretics. Some studies have shown that hyperpyrexia may be associated with a significantly increased risk of serious bacterial infection, but other studies have not substantiated this relationship. High fever during pregnancy may be teratogenic. Acetaminophen at a dose of 10-15 mg/kg/dose every 4 hr and ibuprofen in children older than 6 months at a dose of 5-10 mg/kg/dose every 8 hours are the most commonly employed antipyretics. Antipyretics reduce fever by reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibuprofen). To reduce fever most safely, the caregiver should choose one type of medication and clearly record the dose and time of administration, so overdosage does not occur, especially if multiple caregivers are involved in the management. Physical measures such as tepid baths and cooling blankets are not considered effective to reduce fever. Evidence is also scarce for the use of complementary and alternative medicine interventions. Fever due to specific underlying etiologies resolves when the condition is properly treated. Examples include administration of intravenous immunoglobulin to treat Kawasaki disease or the administration of antibiotics to treat bacterial infections. Fever without a Focus Fever without a focus refers to a rectal temperature of 38°C or higher as the sole presenting feature. The terms “fever without localizing signs” and “fever of unknown origin” (FUO) are subcategories of fever without a focus. Fever without Localizing Signs Fever of acute onset, with duration of <1 wk and without localizing signs, is a common diagnostic dilemma in children <36 mo of age. The etiology and evaluation of fever without localizing signs depends on the age of the child. Traditionally, 3 age groups are considered: neonates or infants to 1 mo of age, infants >1 mo to 3 mo of age, and children >3 mo to 3 yr of age. In 1993, practice guidelines were published to aid the clinician in evaluating the otherwise healthy 0 to 36 mo old with fever without a source. However, with the advent and extensive use of the conjugate Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccines, the rates of infections with these 2 pathogens have decreased substantially. As a consequence, modifications to the 1993 guidelines have been advocated as described later. Children in high-risk groups require a moreaggressive approach and consideration of a broader differential diagnosis. FEBRILE PATIENTS AT INCREASED RISK FOR SERIOUS BACTERIAL INFECTIONS RISK GROUP DIAGNOSTIC CONSIDERATIONS IMMUNOCOMPETENT PATIENTS Neonates (<28 days) Sepsis and meningitis caused by group B streptococcus, Escherichia coli, Listeria monocytogenes; neonatal herpes simplex virus infection, enteroviruses Infants 1-3 mo Serious bacterial disease in 10-15%, including bacteremia in 5%; urinary tract infection Occult bacteremia in <0.5% of children immunized with both Infants and children 3-36 Haemophilus influenzae type b and pneumococcal conjugate mo vaccines; urinary tract infections Hyperpyrexia (>40°C) Meningitis, bacteremia, pneumonia, heatstroke, hemorrhagic shock-encephalopathy syndrome Fever with petechiae Bacteremia and meningitis caused by Neisseria meningitidis, H. influenzae type b, and Streptococcus pneumoniae IMMUNOCOMPROMISED PATIENTS Sickle cell disease Sepsis, pneumonia, and meningitis caused by S. pneumoniae, osteomyelitis caused by Salmonella and Staphylococcus aureus Asplenia Bacteremia and meningitis caused by N. meningitidis, H. influenzae type b, and S. pneumoniae Complement or properdin deficiency Sepsis caused by N. meningitidis Agammaglobulinemia Bacteremia, sinopulmonary infections AIDS S. pneumoniae, H. influenzae type b, and Salmonella infections Congenital heart disease Infective endocarditis; brain abscess with right-to-left shunting Central venous line Staphylococcus aureus, coagulase-negative staphylococci, Candida Malignancy Bacteremia with gram-negative enteric bacteria, S. aureus, and coagulase-negative staphylococci; fungemia with Candida and Aspergillus Neonates Neonates who experience fever without focus are a challenge to evaluate because they display limited signs of infection, making it difficult to clinically distinguish between a serious bacterial infection and self-limited viral illness. Immature immune responses in the first few months of life also increase the significance of fever in the young infant. In general, neonates who have a fever and do not appear ill have a 7% risk of having a serious bacterial infection. Serious bacterial infections include occult bacteremia, meningitis, pneumonia, osteomyelitis, septic arthritis, enteritis, and urinary tract infections. Although neonates with serious infection can acquire community pathogens, they are mainly at risk for late-onset neonatal bacterial diseases (group B streptococci, Escherichia coli, and Listeria monocytogenes) and perinatally acquired herpes simplex virus (HSV) infection. Practice guidelines recommend that if a neonate has had a fever recorded at home by a reliable parent, the patient should be treated as a febrile neonate. If excessive clothing and blankets encasing the infant are suspected of falsely elevating the body temperature, then the excessive coverings should be removed and the temperature retaken in 15 to 30 minutes. If body temperature is normal after the covers are removed, then the infant is considered afebrile. Owing to the unreliability of physical findings and the presence of an immature immune system, all febrile neonates should be hospitalized; blood, urine, and cerebrospinal fluid (CSF) should be cultured, and the child should receive empirical intravenous antibiotics. CSF studies should include cell counts, glucose and protein levels, Gram stain, and culture; HSV and enterovirus polymerase chain reaction should be considered. Stool culture and chest radiograph may also be part of the evaluation. Combination antibiotics such as ampicillin and cefotaxime are recommended. Acyclovir should be included if HSV infection is suspected owing to the presence of CSF pleocytosis or known maternal history of genital HSV, especially at the time of delivery. 1 Month to 3 Months The large majority of children with fever without localizing signs in the 1-3 mo age group likely have a viral syndrome. In contrast to bacterial infections, most viral diseases have a distinct seasonal pattern: respiratory syncytial virus and influenza A virus infections are more common during the winter, whereas enterovirus infections usually occur in the summer and fall. Although a viral infection is the most likely etiology, fever in this age group should always suggest the possibility of serious bacterial disease. Organisms to consider include group B streptococcus, L. monocytogenes, Salmonella enteritis, E. coli, Neisseria meningitidis, S. pneumoniae, Hib, and Staphylococcus aureus. Pyelonephritis is more common in uncircumcised infant boys and infants with urinary tract anomalies. Other potential bacterial diseases in this age group include otitis media, pneumonia, omphalitis, mastitis, and other skin and soft tissue infections. Ill-appearing (toxic) febrile infants ≤3 mo of age require prompt hospitalization and immediate parenteral antimicrobial therapy after cultures of blood, urine, and CSF are obtained. Ampicillin (to cover L. monocytogenes and enterococcus) plus either ceftriaxone or cefotaxime is an effective initial antimicrobial regimen for ill-appearing infants without focal findings. This regimen is effective against the usual bacterial pathogens causing sepsis, urinary tract infection, and enteritis in young infants. However, if meningitis is suspected because of CSF abnormalities, vancomycin should be included to treat possible penicillin-resistant S. pneumoniae until the results of culture and susceptibility tests are known. Many academic institutions have investigated the optimal management of low-risk patients in this age group with fever without a focus. The use of viral diagnostic studies (enteroviruses, respiratory viruses, rotavirus, and herpesvirus) in combination with the Rochester Criteria or similar criteria can enhance the ability to determine which infants are at high risk for serious bacterial infections. Febrile infants in whom a virus has been detected are at low or no risk of a serious bacterial infection. Well-appearing infants 1-3 mo of age can be managed safely using low-risk laboratory and clinical criteria as indicated in Table, if reliable parents are involved and close follow-up is assured. LOW RISK CRITERIA IN 1-3 MONTHS OLD WITH FEVER BOSTON CRITERIA nfants are at low risk if they appear well, have normal physical examination, have a caretaker reachable by elephone, and laboratory tests are as follows: • • • CBC: <20,000 WBC/mm3 Urine: negative leukocyte esterase CSF: leukocyte count less than 10 × 106/L, • CBC: <15,000 WBC/mm3; band: total neutrophil ratio <0.2 Urine: <10 WBC/HPF; no bacteria on Gram stain CSF: <8 WBC/mm3; no bacteria on Gram stain Chest radiograph: no infiltrate Stool: no RBC; few to no WBC PHILADELPHIA PROTOCOL nfants are at low risk if they appear well, have a normal physical examination, and laboratory tests are as follows: • • • • PITTSBURGH GUIDELINES Infants are at low risk if they appear well, have a normal physical examination, and laboratory tests are as follows: • • • • • CBC: 5,000-15,000 WBC; peripheral absolute band count <1500/mm3 Urine (enhanced urinalysis): 9 WBC/mm3 and no bacteria on Gram stain CSF: 5 WBC/mm3 and negative Gram stain; if bloody tap, then WBC : RBC ≤ 1 : 500 Chest radiograph: no infiltrate Stool: 5 WBC/HPF with diarrhea ROCHESTER CRITERIA Infants are at low risk if they appear well, have a normal physical examination, and laboratory findings are as follows: • • • CBC: 5,000-15,000 WBC/mm3; absolute band count ≤1500/mm3 Urine: <10 WBC/HPF at 40× Stool: <5 WBC/HPF if diarrhea Infants 1-3 mo of age with fever who appear generally well; who have been previously healthy; who have no evidence of skin, soft tissue, bone, joint, or ear infection; and who have a peripheral white blood cell (WBC) count of 5,000-15,000 cells/µL, an absolute band count of <1,500 cells/µL, and normal urinalysis and negative culture (blood and urine) results are unlikely to have a serious bacterial infection. The negative predictive value with 95% confidence of these criteria for any serious bacterial infection is >98% and for bacteremia is >99%. Among serious bacterial infections, pyelonephritis is the most common and may be seen in well-appearing infants who have fever without a focus or in those who appear ill. Urinalysis may be negative in infants <2 mo of age with pyelonephritis. Bacteremia is present in <30% of infants with pyelonephritis. The decision to obtain CSF studies in the wellappearing 1-3 mo old infant depends on the decision to administer empirical antibiotics. If close observation without antibiotics is planned, a lumbar puncture may be deferred. If the child deteriorates clinically, a full sepsis evaluation should be performed, and intravenous antibiotics should be administered. If empirical antibiotics are initiated, CSF studies should be obtained, preferably before administering antibiotics. 3 Months to 36 Months of Age Approximately 30% of febrile children in the 3-36 mo age group have no localizing signs of infection. Viral infections are the cause of the vast majority of fevers in this population, but serious bacterial infections do occur and are caused by the same pathogens listed for patients 1-3 mo of age, except for the perinatally acquired infections. S. pneumoniae, N. meningitidis, and Salmonella account for most cases of occult bacteremia. Hib was an important cause of occult bacteremia in young children before universal immunization with conjugate Hib vaccines and remains common in underdeveloped countries that have not implemented these vaccines. Risk factors indicating increased probability of occult bacteremia include temperature ≥39°C, WBC count ≥15,000/µL, and elevated absolute neutrophil count, band count, erythrocyte sedimentation rate, or Creactive protein. The incidence of bacteremia and/or pneumonia or pyelonephritis, among infants 3-36 mo of age increases as the temperature (especially >40°C) and WBC count (especially >25,000) increase. However, no combination of laboratory tests or clinical assessment is completely accurate in predicting the presence of occult bacteremia. Socioeconomic status, race, sex, and age (within the range of 3-36 mo) do not appear to affect the risk for occult bacteremia. Without therapy, occult bacteremia due to pneumococcus can resolve spontaneously without sequelae, can persist, or can lead to localized infections such as meningitis, pneumonia, cellulitis, pericarditis, osteomyelitis, or suppurative arthritis. The pattern of sequelae may be related to host factors and the offending organism. In some children, the occult bacteremic illness can represent the early signs of serious localized infection rather than a transient disease state. Hib bacteremia is characteristically associated with a higher risk for localized serious infection than is bacteremia due to S. pneumoniae. Hospitalized children with Hib bacteremia often develop focal infections, such as meningitis, epiglottitis, cellulitis, pericarditis, or osteoarticular infection, and spontaneous resolution of bacteremia is rare. Among patients with pneumococcal bacteremia (occult or focal), spontaneous resolution occurs in 30-40%, with a higher rate of spontaneous resolution among wellappearing children. Important bacterial infections among children 336 mo of age with localizing signs include otitis media, sinusitis, pneumonia (not always evident without a chest x-ray), enteritis, urinary tract infection, osteomyelitis, and meningitis. Treatment of toxic-appearing febrile children 3-36 mo of age who do not have focal signs of infection includes hospitalization and prompt institution of antimicrobial therapy after specimens of blood, urine, and CSF are obtained for culture. Consensus practice guidelines published in 1993 recommended that children 3-36 mo of age who have a temperature of <39°C and do not appear toxic be observed as outpatients without performing diagnostic tests or administering antimicrobial agents. For nontoxic-appearing infants with a rectal temperature of ≥39°C, options include obtaining a blood culture and administering empirical antibiotic therapy (ceftriaxone, a single dose of 50 mg/kg, not to exceed 1 g); if the WBC count is >15,000/µL, obtaining a blood culture and beginning empirical antibiotic therapy; or obtaining a blood culture and observing as outpatients without empirical antibiotic therapy, with return for re-evaluation within 24 hr. Guidelines for managing febrile children 3-36 mo of age who have received both Hib and S. pneumoniae conjugate vaccines have not been established, but careful observation without empirical administration of antibiotic therapy is generally prudent. Because fully vaccinated young children are at a much lower risk of occult bacteremia and meningitis as the cause of acute fever without localizing signs, some advocate that the only laboratory tests needed in this age group when temperature is >39°C are a urinalysis and urine culture for circumcised boys <6 mo of age and uncircumcised boys and all girls <24 mo of age. Regardless of the management option , the family should be instructed to return immediately if the child's condition deteriorates or new symptoms develop. GROUP MANAGEMENT MANAGEMENT OF FEVER WITHOUT LOCALIZING SIGNS Any toxic-appearing child 0-36 mo and temperature ≥38°C Hospitalize, broad cultures plus other tests,* parenteral antibiotics Child <1 mo and temperature ≥38°C Hospitalize, broad cultures plus other tests,* parenteral antibiotics Child 1-3 mo and temperature ≥38°C Two-step process 1) Determine risk based on history, physical examination, and laboratory studies. Low risk: Uncomplicated medical history, Normal physical examination, Normal laboratory studies Urine: negative leukocyte esterase, nitrite and <10 WBC/HPF Peripheral blood: 5,000-15,000 WBC/mm3; <1,500 bands or band : total neutrophil ratio <0.2 Stool studies if diarrhea (no RBC and <5 WBC/HPF) CSF cell count (<8 WBC/mm3) and negative Gram stain Chest radiograph without infiltrate 2) If child fulfills all low-risk criteria, administer no antibiotics, ensure follow-up in 24 hr and access to emergency care if child deteriorates. Daily follow-up should occur until blood, urine, and CSF cultures are final. If any cultures are positive, child returns for further evaluation and treatment. If child does not fulfill all low-risk criteria, hospitalize and administer parenteral antibiotics until all cultures are final and definitive diagnosis determined and treated. GROUP Child 3-36 mo Reassurance that diagnosis is likely self-limiting viral infection, but and temperature advise return with persistence of fever, temperatures >39°C, and 38-39°C new signs and symptoms Child 3-36 mo and temperature >39°C Two-step process: 1) Determine immunization status 2) If received conjugate pneumococcal and H. influenzae type b vaccines, obtain urine studies (urine WBC, leukocyte esterase, nitrite, and culture) for all girls, all boys <6 mo old, all uncircumcised boys <2 yr, all children with recurrent urinary tract infections If did not receive conjugate pneumococcal and H. influenzae type b vaccines, manage according to the 1993 Guidelines (see Baraff et al. Pediatrics 1993;92:1-12) Empirical antibiotic therapy for well-appearing children <36 mo of age who have not received Hib and S. pneumoniae conjugate vaccines and who have a rectal temperature of >39°C and a WBC count of >15,000/µL is strongly recommended. If blood cultures are obtained and S. pneumoniae is isolated from the blood, the child should return to the physician as soon as possible after the culture results are known. If the child appears well, is afebrile, and has a normal physical exam, a second blood culture should be obtained and the child should be treated with 7-10 days of oral antimicrobial therapy. If the child appears ill and continues to have fever with no identifiable focus of infection at the time of follow-up, or if H. influenzae, or N. meningitidis is present in the initial blood culture, the child should have a repeat blood culture, be evaluated for meningitis (including lumbar puncture), and receive treatment in the hospital with appropriate intravenous antimicrobial agents. If the child develops a localized infection, therapy should be directed toward the likely pathogens. Fever of Unknown Origin The classification of FUO is best reserved for children with fever documented by a health care provider and for which the cause could not be identified after 3 wk of evaluation as an outpatient or after 1 wk of evaluation in the hospital We apologize for any inconvenience to the environment. (Çevreye verdiğimiz rahatsızlık nedeniyle özür dileriz) SUMMARY OF DEFINITIONS AND MAJOR FEATURES OF THE FOUR SUBTYPES OF FEVER OF UNKNOWN ORIGIN FEATURE CLASSIC FUO HEALTH CARE– ASSOCIATED IMMUNE-DEFICIENT FUO HIV-RELATED FUO FUO Definition >38.0°C, >3 wk, ≥38.0°C, >1 wk, not ≥38.0°C, >1 wk, negative >2 visits or 1 wk in present or incubating cultures after 48 hr hospital on admission ≥38.0°C, >3 wk for outpatients, >1 wk for inpatients, HIV infection confirmed Patient location Community, clinic, Acute care hospital Hospital or clinic or hospital Community, clinic, or hospital HIV (primary infection), typical and atypical Cancer, infections, Health care– mycobacteria, CMV, inflammatory associated infections, Majority due to infections, but lymphomas, conditions, postoperative cause documented in only 40- toxoplasmosis, Leading causes undiagnosed, complications, drug 60% cryptococcosis, immune habitual reconstitution fever hyperthermia inflammatory syndrome (IRIS) FEATURE CLASSIC FUO History emphasis HEALTH CARE– ASSOCIATED FUO Travel, contacts, animal and insect Operations and exposure, procedures, medications, devices, anatomic immunizations, considerations, family history, drug treatment cardiac valve disorder Fundi, oropharynx, temporal artery, abdomen, lymph Wounds, drains, Examination nodes, spleen, devices, sinuses, emphasis joints, skin, nails, urine genitalia, rectum or prostate, lower limb deep veins IMMUNE-DEFICIENT FUO HIV-RELATED FUO Stage of chemotherapy, drugs administered, underlying immunosuppressive disorder Drugs, exposures, risk factors, travel, contacts, stage of HIV infection Skin folds, IV sites, lungs, perianal area Mouth, sinuses, skin, lymph nodes, eyes, lungs, perianal area FUO Etiology The many causes of FUO in children are infections and rheumatologic (connective tissue or autoimmune) diseases . Neoplastic disorders should also be seriously considered, although most children with malignancies do not have fever alone. The possibility of drug fever should be considered if the patient is receiving any drug. Drug fever is usually sustained and not associated with other symptoms. Discontinuation of the drug is associated with resolution of the fever, generally within 72 hr, although certain drugs, such as iodides, are excreted for a prolonged period with fever that can persist for as long as 1 mo after drug withdrawal. Most fevers of unknown or unrecognized origin result from atypical presentations of common diseases. In some cases, the presentation as an FUO is characteristic of the disease, such as juvenile idiopathic arthritis, but the definitive diagnosis can be established only after prolonged observation because initially there are no associated or specific findings on physical examination and all laboratory results are negative or normal. In general, the systemic infectious diseases most commonly implicated in children with FUO are salmonellosis, tuberculosis, rickettsial diseases, syphilis, Lyme disease, cat-scratch disease, atypical prolonged presentations of common viral diseases, infectious mononucleosis, cytomegalovirus (CMV) infection, viral hepatitis, coccidioidomycosis, histoplasmosis, malaria, and toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and rat-bite fever. AIDS alone is not usually responsible for FUO, although febrile illnesses often occur in patients with AIDS as a result of opportunistic infections Juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are the connective tissue diseases associated most commonly with FUO. Inflammatory bowel disease, rheumatic fever, and Kawasaki disease are also commonly reported as causes of FUO. If factitious fever (inoculation of pyogenic material or manipulation of the thermometer by the patient or parent) is suspected, the presence and pattern of fever should be documented in the hospital. Prolonged and continuous observation, which can include electronic or video surveillance, of patients is imperative. FUO lasting >6 mo is uncommon in children and suggests granulomatous or autoimmune disease. Repeat interval evaluation, including history, physical examination, laboratory evaluation, and roentgenographic studies is required. Diagnosis The evaluation of FUO requires a thorough history and physical examination supplemented by a few screening laboratory tests and additional laboratory and radiographic tests as indicated by the history or abnormalities on examination or initial screening. History The age of the patient is helpful in evaluating FUO. Children >6 yr of age often have a respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis), JIA, or, rarely, leukemia. Adolescent patients are more likely to have tuberculosis, inflammatory bowel disease, autoimmune processes, or lymphoma, in addition to the causes of FUO found in younger children. A history of unusual dietary habits or travel as early as the birth of the child should be sought. Malaria, histoplasmosis, and coccidioidomycosis can re-emerge years after visiting or living in an endemic area. It is important to identify prophylactic immunizations and precautions taken by the patient against ingestion of contaminated water or food during foreign travel. A medication history should be pursued rigorously. This history should elicit information about over-the-counter preparations and topical agents, including eye drops, that may be associated with atropine-induced fever. The genetic background of a patient also is important. Ancestry from the Mediterranean should suggest the possibility of familial Mediterranean fever (FMF). Both FMF and hyperimmunoglobulin D syndrome are inherited as autosomal-recessive disorders. Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) and Muckle-Wells syndrome are inherited as autosomal dominant traits. Physical examination A complete is essential to find any physical clues to the underlying diagnosis. The child's general appearance, including sweating during fever, should be noted. The continuing absence of sweat in the presence of an elevated or changing body temperature suggests dehydration due to vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should suggest anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to atropine. EXAMPLES OF SUBTLE PHYSICAL FINDINGS HAVING SPECIAL SIGNIFICANCE IN PATIENTS WITH FEVER OF UNKNOWN ORIGIN BODY SITE PHYSICAL FINDING DIAGNOSIS Head Sinus tenderness Sinusitis Temporal artery Nodules, reduced pulsations Temporal arteritis Ulceration Disseminated histoplasmosis Tender tooth Periapical abscess Choroid tubercle Disseminated granulomatosis* Petechiae, Roth's spot Endocarditis Thyroid Enlargement, tenderness Thyroiditis Heart Murmur Infective or marantic endocarditis Abdomen Enlarged iliac crest lymph nodes, splenomegaly Lymphoma, endocarditis, disseminated granulomatosis* Perirectal fluctuance, tenderness Abscess Prostatic tenderness, fluctuance Abscess Testicular nodule Periarteritis nodosa Epididymal nodule Disseminated granulomatosis Lower extremities Deep venous tenderness Thrombosis or thrombophlebitis Skin and nails Petechiae, splinter hemorrhages, subcutaneous nodules, clubbing Vasculitis, endocarditis Oropharynx Fundi or conjunctivae Rectum Genitalia A careful ophthalmic examination is important. Red, weeping eyes may be a sign of connective tissue disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a febrile patient may be a clue to measles, coxsackievirus infection, tuberculosis, infectious mononucleosis, lymphogranuloma venereum, and cat-scratch disease. In contrast, bulbar conjunctivitis in a child with FUO suggests Kawasaki disease or leptospirosis. Petechial conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests sarcoidosis, JIA, SLE, Kawasaki disease, Behçet disease, and vasculitis. Chorioretinitis suggests CMV, toxoplasmosis, and syphilis. Proptosis suggests an orbital tumor, thyrotoxicosis, metastasis (neuroblastoma), orbital infection, Wegener granulomatosis, or pseudotumor. The ophthalmoscope should also be used to examine nailfold capillary abnormalities that are associated with connective tissue diseases such as juvenile dermatomyositis and systemic scleroderma. Immersion oil or lubricating jelly is placed on the skin adjacent to the nailbed, and the capillary pattern is observed with the ophthalmoscope set on +40. FUO is sometimes caused by hypothalamic dysfunction. A clue to this disorder is failure of pupillary constriction due to absence of the sphincter constrictor muscle of the eye. This muscle develops embryologically when hypothalamic structure and function also are undergoing differentiation. Fever resulting from familial dysautonomia may be suggested by lack of tears, an absent corneal reflex, or a smooth tongue with absence of fungiform papillae. Tenderness to tapping over the sinuses or the upper teeth suggests sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the immune system. Fever blisters are common findings in patients with pneumococcal, streptococcal, malarial, and rickettsial infection. These lesions also are common in children with meningococcal meningitis (which usually does not manifest as FUO) but rarely are seen in children with meningococcemia. Fever blisters also are occasionally seen with Salmonella or staphylococcal infections. Hyperemia of the pharynx, with or without exudate, suggests infectious mononucleosis, CMV infection, toxoplasmosis, salmonellosis, tularemia, Kawasaki disease, or leptospirosis. The muscles and bones should be palpated carefully. Point tenderness over a bone can suggest occult osteomyelitis or bone marrow invasion from neoplastic disease. Tenderness over the trapezius muscle may be a clue to subdiaphragmatic abscess. Generalized muscle tenderness suggests dermatomyositis, trichinosis, polyarteritis, Kawasaki disease, or mycoplasmal or arboviral infection. Rectal examination can reveal perirectal lymphadenopathy or tenderness, which suggests a deep pelvic abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should be obtained; occult blood loss can suggest granulomatous colitis or ulcerative colitis as the cause of FUO. Repetitive chills and temperature spikes are common in children with septicemia (regardless of cause), particularly when associated with kidney disease, liver or biliary disease, infective endocarditis, malaria, brucellosis, rat-bite fever, or a loculated collection of pus. The general activity of the patient and the presence or absence of rashes should be noted. Hyperactive deep tendon reflexes can suggest thyrotoxicosis as the cause of FUO. The laboratory evaluation of the child with FUO and whether the evaluation will occur in the inpatient or outpatient realm are determined on a case-by-case basis. Hospitalization may be required for laboratory or radiographic studies that are unavailable or impractical in an ambulatory setting, for more-careful observation, or for temporary relief of parents’ anxiety. The tempo of diagnostic evaluation should be adjusted to the tempo of the illness; haste may be imperative in a critically ill patient, but if the illness is more chronic, the evaluation can proceed in systematic fashion and can be carried out in an outpatient setting. If there are no clues in the patient's history or on physical examination that suggest a specific infection or area of suspicion, it is unlikely that diagnostic studies will be helpful. In that common scenario, continued surveillance and repeated re-evaluations of the child should be employed to detect any new clinical findings. Although ordering a large number of diagnostic tests in every child with FUO according to a predetermined list is discouraged, certain studies should be considered in the evaluation. A complete blood cell count with a differential white blood cell count and a urinalysis should be part of the initial laboratory evaluation. An absolute neutrophil count of <5,000/µL is evidence against indolent bacterial infection other than typhoid fever. Conversely, in patients with a polymorphonuclear leukocyte count of >10,000/µL or a nonsegmented polymorphonuclear leukocyte count of >500/µL a severe bacterial infection is highly likely. Direct examination of the blood smear with Giemsa or Wright stain can reveal organisms of malaria, trypanosomiasis, babesiosis, or relapsing fever. ESR An erythrocyte sedimentation rate (ESR) of >30 mm/hr indicates inflammation and the need for further evaluation for infectious, autoimmune, or malignant diseases. An ESR of >100 mm/hr suggests tuberculosis, Kawasaki disease, malignancy, or autoimmune disease. A low ESR does not eliminate the possibility of infection or JIA. CRP C-reactive protein is another acute-phase reactant that becomes elevated and returns to normal more rapidly than the ESR. Experts may prefer to check 1 of the 2 because there is no evidence that measuring both the ESR and C-reactive protein in the same patient with FUO is clinically useful. Blood cultures should be obtained aerobically. Anaerobic blood cultures have an extremely low yield and should be obtained only if there are specific reasons to suspect anaerobic infection. Multiple or repeated blood cultures may be required to detect bacteremia associated with infective endocarditis, osteomyelitis, or deep-seated abscesses. Polymicrobial bacteremia suggests factitious selfinduced infection or gastrointestinal (GI) pathology. The isolation of leptospires, Francisella, or Yersinia can require selective media or specific conditions not routinely used. Urine culture should be obtained routinely. Tuberculin skin testing should be performed with intradermal placement of 5 units of purified protein derivative (PPD) that has been kept appropriately refrigerated. Radiographic examination of the chest, sinuses, mastoids, or GI tract may be indicated by specific historical or physical findings. Radiographic evaluation of the GI tract for inflammatory bowel disease may be helpful in evaluating selected children with FUO and no other localizing signs or symptoms. Examination of the bone marrow can reveal leukemia; metastatic neoplasm; mycobacterial, fungal, or parasitic diseases; and histiocytosis, hemophagocytosis, or storage diseases. If a bone marrow aspirate is performed, cultures for bacteria, mycobacteria, and fungi should be obtained. Serologic tests can aid in the diagnosis of infectious mononucleosis, CMV infection, toxoplasmosis, salmonellosis, tularemia, brucellosis, leptospirosis, cat-scratch disease, Lyme disease, rickettsial disease, and, on some occasions, JIA. The clinician should be aware that the reliability and sensitivity and specificity of these tests vary; for instance, serologic tests for Lyme disease outside of reference laboratories have been generally unreliable. Radionuclide scans may be helpful in detecting abdominal abscesses as well as osteomyelitis, especially if the focus cannot be localized to a specific limb or multifocal disease is suspected. Gallium citrate (67Ga) localizes inflammatory tissues (leukocytes) associated with tumors or abscesses. 99mTc phosphate is useful for detecting osteomyelitis before plain roentgenograms demonstrate bone lesions. Granulocytes tagged with indium (111In) or iodinated IgG may be useful in detecting localized pyogenic processes. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a helpful imaging modality in adults with an FUO and can contribute to an ultimate diagnosis in 30-60% of patients. Echocardiograms can demonstrate the presence of a vegetation on the leaflets of heart valves, suggesting infective endocarditis. Ultrasonography can identify intra-abdominal abscesses of the liver, subphrenic space, pelvis, or spleen. Total body CT or MRI (both with contrast) permits detection of neoplasms and collections of purulent material without the use of surgical exploration or radioisotopes. CT and MRI are helpful in identifying lesions of the head, neck, chest, retroperitoneal spaces, liver, spleen, intra-abdominal and intrathoracic lymph nodes, kidneys, pelvis, and mediastinum. CT or ultrasound-guided aspiration or biopsy of suspicious lesions has reduced the need for exploratory laparotomy or thoracotomy. MRI is particularly useful for detecting osteomyelitis if there is concern about a specific limb. Diagnostic imaging can be very helpful in confirming or evaluating a suspected diagnosis but rarely leads to an unsuspected cause, and in the case of CT scans, the child is exposed to large amounts of radiation. Biopsy is occasionally helpful in establishing a diagnosis of FUO. Bronchoscopy, laparoscopy, mediastinoscopy, and GI endoscopy can provide direct visualization and biopsy material when organspecific manifestations are present. When employing any of the more-invasive testing, the risk:benefit ratio for the patient must always be taken into consideration before proceeding further. The ultimate treatment of FUO is tailored to the underlying diagnosis. Fever and infection in children are not synonymous; antimicrobial agents should not be used as antipyretics, and empirical trials of medication should generally be avoided. An exception may be the use of antituberculous treatment in critically ill children with suspected disseminated tuberculosis. Empirical trials of other antimicrobial agents may be dangerous and can obscure the diagnosis of infective endocarditis, meningitis, parameningeal infection, or osteomyelitis. After a complete evaluation, antipyretics may be indicated to control fever and relieve symptoms. Prognosis Children with FUO have a better prognosis than do adults. The outcome in a child depends on the primary disease process, which is usually an atypical presentation of a common childhood illness. In many cases, no diagnosis can be established and fever abates spontaneously. In as many as 25% of cases in whom fever persists, the cause of the fever remains unclear, even after thorough evaluation. FEATURE CLASSIC FUO Imaging, Investigation biopsies, sedimentation emphasis rate, skin tests Observation, outpatient temperature chart, Management investigations, avoidance of empirical drug treatments Time course Months of disease Tempo of Weeks investigation HEALTH CARE– ASSOCIATED FUO IMMUNE-DEFICIENT FUO HIV-RELATED FUO Imaging, bacterial CXR, bacterial cultures cultures Blood and lymphocyte count; serologic tests; CXR; stool examination; biopsies of lung, bone marrow, and liver for cultures and cytologic tests; brain imaging Depends on situation Antimicrobial treatment protocols Antiviral and antimicrobial protocols, vaccines, revision of treatment regimens, good nutrition Weeks Days Weeks to months Days Hours Days to weeks