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Fever

Occurs whenpathologic process causes body temperature to exceed normal range.

DuBois suggested that usual range ofnormal body temperature is 97–100.4°F (36.2–38.0°C)rectal or 96.8–99.3°F (36.0–37.4°C)oral. Rectal temperature tends to be 0.5–1.0°F greaterthan oral.

In normal circadian rhythm, maximaltemperature occurs between 5:00 and 7:00 P.M. and minimal temperatureoccurs between 2:00 and 6:00 A.M.

Many disorders associated with feverare discussed in other chapters.

Principal Causes of Acute Fever

1. Commoncauses
   1. Infectious
      1. Respiratorytract
         1. Upperrespiratory tract infection (common cold)
         2. Pharyngitis
         3. Tonsillitis
         4. Otitis media
         5. Herpes gingivostomatitis
         6. Herpangina
         7. Sinusitis
         8. Croup
         9. Bronchiolitis
         10. Bronchitis
         11. Pneumonia (viral, bacterial, Mycoplasma)
         12. Pertussis
      2. Gastrointestinal
         1. Gastroenteritis
         2. Appendicitis
         3. Hepatitis
      3. Genitourinary
         1. Urinary tract infection (includingpyelonephritis)
         2. Sexually transmitted diseases
      4. Musculoskeletal
         1. Septicarthritis
         2. Osteomyelitis
         3. Myositis
      5. Central nervous system
         1. Meningitis(viral, bacterial)
         2. Viral encephalitis
      6. Infections associated with prominentrash
         1. Roseola
         2. Hand-foot-mouth syndrome
         3. Varicella
         4. Erythema infectiosum (parvovirus B19)
         5. Measles
         6. Scarlet fever
         7. Meningococcemia
         8. Rocky mountain spotted fever
      7. Other
         1. Viral illnesses
         2. Septicemia/bacteremia
         3. Infectious mononucleosis
         4. Lymphadenitis
         5. Cellulitis/abscess
         6. Cat scratch disease
         7. Dental abscess
         8. Periorbital cellulitis
         9. Parotitis
   2. Noninfectious
      1. Drug reactions
      2. Vaccine reactions
      3. Trauma
      4. Burns
      5. Kawasaki disease
2. Uncommon causes
   1. Infectious
      1. Respiratorytract
         1. Viral
            1. Hantaviruspulmonary syndrome
         2. Bacterial
            1. Supraglottitis
            2. Bacterial tracheitis
            3. Abscess (peritonsillar, retropharyngeal,lateral pharyngeal)
            4. Tuberculosis
            5. Actinomycosis
            6. Nocardiasis
            7. Legionella
         3. Fungal
            1. Aspergillosis
            2. Blastomycosis
            3. Histoplasmosis
            4. Coccidioidomycosis
         4. Parasitic
            1. Pneumocystis carinii
      2. Gastrointestinal
         1. Amebiasis
         2. Pancreatitis
         3. Cholecystitis
         4. Cholangitis
         5. Peritonitis
         6. Intraabdominal abscess
      3. Genitourinary
         1. Epididymitis
         2. Orchitis
         3. Abscesses (perinephric, tuboovarian)
      4. Cardiac
         1. Acute rheumatic fever
         2. Myocarditis
         3. Pericarditis
         4. Endocarditis
      5. Central nervous system
         1. Brainabscess
      6. Other
         1. Viral
            1. Human immunodeficiency virus
            2. Rabies
         2. Bacterial
            1. Staphylococcal scalded skin syndrome
            2. Toxic shock syndrome
            3. Orbital cellulitis/abscess
            4. Borrelia (relapsing fever)
            5. Brucellosis
            6. Leptospirosis
            7. Plague
            8. Psittacosis (ornithosis)
            9. Rat-bite fever
            10. Syphilis
            11. Tularemia
            12. Tetanus
         3. Fungal
            1. Disseminated histoplasmosis
            2. Nonpulmonary blastomycosis
         4. Parasitic
            1. Malaria
            2. Ascariasis
            3. Toxocariasis (visceral larva migrans,ocular larva migrans)
            4. Toxoplasmosis
            5. Trichinosis
         5. Rickettsial
            1. Endemic typhus (murine)
            2. Epidemic typhus (louse-borne typhus)
            3. Q fever
            4. Rickettsial pox
            5. Ehrlichiosis
   2. Noninfectious
      1. Respiratory
         1. Pulmonary infarction
         2. Pulmonary embolism
      2. Gastrointestinal
         1. Pulmonaryinfarction
         2. Pulmonary embolism
      3. Intestinal obstruction
      4. Inflammatory bowel disease
      5. Cardiac
         1. Postpericardiotomy syndrome
      6. Hematologic
         1. Intravascular hemolysis
         2. Bleeding into a closed space
      7. Endocrine
         1. Thyrotoxicosis
         2. Diabetes insipidus
      8. Central nervous system
         1. Intracranialinjury and hemorrhage
         2. Spinal cord injury
         3. Hypothalamic and brain stem lesions
         4. Status epilepticus
      9. Neoplasia
         1. Leukemia
         2. Lymphoma
         3. Neuroblastoma
         4. Pheochromocytoma
      10. Connective tissue disorders
          1. Juvenilerheumatoid arthritis
          2. Systemic lupus erythematosus
          3. Polyarteritis nodosa
          4. Polymyositis
          5. Dermatomyositis
          6. Mixed connective tissue disease
      11. Poisonings
          1. Atropine
          2. Cocaine
          3. Salicylate
          4. Lysergic acid diethylamide
          5. Hydrocarbons
          6. Organophosphates
          7. Tricyclic antidepressants
          8. Amphetamines
          9. Phenothiazines
      12. Other
          1. Spider bites (black widow, brown recluse)
          2. Stevens-Johnson syndrome
          3. Heat-related illness
          4. Serum sickness
          5. Anhidrotic ectodermal dysplasia
          6. Familial dysautonomia
          7. Sarcoidosis
          8. Familial Mediterranean fever
          9. Factitious fever

Clinical Features and Diagnosis: Acute Fever

Common Causes

Infectious

Infectious causes of acute fever are listedbelow and discussed in other chapters.

Respiratorytract

Upperrespiratory tract infection (common cold)

Pharyngitis

Tonsillitis

Otitis media

Herpes gingivostomatitis

Herpangina

Sinusitis

Croup

Bronchiolitis

Bronchitis

Pneumonia (viral, bacterial, mycoplasma)

Pertussis

Gastrointestinal

Gastroenteritis

Appendicitis

Hepatitis

Genitourinary

Urinary tract infection (includingpyelonephritis)

Sexually transmitted diseases

Musculoskeletal

Septic arthritis

Osteomyelitis

Myositis

Central nervous system

Meningitis(viral, bacterial)

Viral encephalitis

Infections associated with prominentrash

Roseola

Hand-foot-mouth syndrome

Varicella

Erythema infectiosum (parvovirus B19)

Measles

Scarlet fever

Meningococcemia

Rocky Mountain spotted fever

Other

Viral illnesses

Septicemia/bacteremia

Infectious mononucleosis

Lymphadenitis

Cellulitis/abscess

Cat scratch disease

Dental abscess

Periorbital cellulites

Parotitis

Noninfectious

Drug Reactions

Hypersensitivityreactions are responsible for most cases of drug fever.

Although fever can occur without otherfindings, urticarial rash and peripheral eosinophilia make diagnosismore likely.

Vaccine Reactions

Reactionsto acellular pertussis vaccine can produce fever but are uncommon.

Within 7–10 days after administrationof live measles vaccine or measles, mumps, rubella (MMR) vaccine,fever can occur and is often associated with macular or papular rash.

Trauma

Crush injuries and fractures of large bonescan cause fever due to large amount of tissue damage and releaseof inflammatory mediators.

Burns

Fever may occur with severe burns, even inabsence of infection, because of fluid losses and resetting of thermoregulatorycenter. Severe sunburn also may cause fever.

Kawasaki Disease

Definedas vasculitis of unknown cause that usually occurs in children <5yrs of age.

Diagnostic criteria are absence ofany other disease process and presence of fever for ≥5 days associatedwith 4 of 5 signs:

Bilateral conjunctival injection

Cervical lymphadenopathy

Macular or papular rash primarily ontrunk

Mucous membrane involvement with dry,fissured lips, strawberry tongue, or pharyngeal injection

≥1 change in extremities, includingpalmar erythema, edema, and periungal or generalized desquamation

Lab findings include leukocytosis,pyuria, proteinuria, spinal fluid pleocytosis, elevation in serumaminotransferases, and increased erythrocyte sedimentation rate.

Chest radiograph may show small pleuraleffusions.

Platelet count may be normal at onset,but thrombocytosis usually occurs during second week of illness.

Complications include coronary arteryaneurysms, myocarditis, and myocardial infarction.

2-D echocardiography may reveal coronaryartery aneurysms within 1–2 cm of origin of coronary arteriesfrom aorta.

Uncommon Causes

Infectious

Many infections in this category, as listedbelow, are discussed in other chapters.

Respiratorytract

Viral(hantavirus pulmonary syndrome)

Bacterial [supraglottitis,bacterial tracheitis, abscess (peritonsillar, retropharyngeal, lateral pharyngeal),tuberculosis, actinomycosis, nocardiasis, Legionella]

Fungal (aspergillosis, blastomycosis,histoplasmosis, coccidioidomycosis)

Parasitic (P. carinii)

Gastrointestinal

Amebiasis

Pancreatitis

Cholecystitis

Cholangitis

Peritonitis

Intraabdominal abscess

Genitourinary

Epididymitis

Orchitis

Abscesses (perinephric, tuboovarian)

Cardiac

Acute rheumatic fever

Myocarditis

Pericarditis

Endocarditis

Central nervous system (brain abscess)

Other

Viral (HIV, rabies)

Bacterial [staphylococcalscalded skin syndrome, toxic shock syndrome, orbital cellulitis/abscess,Borrelia (relapsing fever), brucellosis, leptospirosis, plague,psittacosis (ornithosis), rat-bite fever, syphilis, tularemia, tetanus]

Fungal (disseminated histoplasmosis,nonpulmonary blastomycosis)

Parasitic [malaria, ascariasis,toxocariasis (visceral larva migrans, ocular larva migrans), toxoplasmosis,trichinosis]

Rickettsial [endemic typhus(murine), epidemic typhus (louse-borne typhus), Q fever, rickettsialpox, ehrlichiosis]

Hantavirus Pulmonary Syndrome

Can occurafter exposure to infected rodents (most commonly, deer mouse),their saliva, or excreta.

Characterized by acute onset of fever,headache, myalgia, cough, vomiting, and diarrhea followed by developmentof hypotension and noncardiogenic pulmonary edema. Leukocytosiswith immature granulocytes, thrombocytopenia, and elevated Hct arefrequent findings.

Reverse-transcriptase polymerase chainreaction or enzyme immunoassay can detect viral antigen from clinicalsamples. Diagnosis also can be confirmed serologically.

Borrelia (Relapsing Fever)

Caused byspirochetes of Borrelia. Infected ticks (Ornithodoros species) andlice (P. humanus) are sources of human infections. Most cases inU.S. are transmitted by ticks, which become infected by feedingon rodents and other small mammals.

Incubation period of 7–10days is followed by fever, headache, chills, myalgia, and arthralgia,which may last up to 1 wk. Transient macular rash, petechiae ofskin, jaundice, and hepatosplenomegaly may occur.

Complications include pneumonia, myocarditis,and meningitis. After 5- to 10-day interval, relapse occurs withfever and same clinical findings as described above.

Spirochetes can be seen by dark-fieldmicroscopy and in Wright-stained smears of peripheral blood. Positiveblood culture is also diagnostic.

Brucellosis

Transmittedby direct contact with infected animals (goats, sheep, cows, swine)or by ingestion of contaminated milk or milk products produced bythem.

Onset can be acute or insidious, withfever, headache, abdominal pain, arthralgia, myalgia, weight loss,lymphadenopathy (especially cervical and axillary), and hepatosplenomegaly.Prolonged fever without any other findings sometimes occurs.

Complications include meningitis, osteomyelitis,and endocarditis.

Organism can sometimes be culturedfrom blood, urine, spinal fluid, bone marrow, or lymph node. Ifthese cultures are negative, diagnosis depends on serologic findings.Serum agglutination test with antibody titer ≥1:160 or 4-foldincrease in agglutination titer on serial samples is diagnostic.

Leptospirosis

L. interrogansinfects humans through contact with animal urine in contaminated foodor water. Incubation period is 2–20 days.

Acute illness usually consists of fever,headache, chills, malaise, myalgia, vomiting, lymphadenopathy, andabdominal pain. Hepatic (hepatomegaly, jaundice, liver failure),renal (azotemia, renal failure), and CNS dysfunction (aseptic meningitis,alteration in consciousness) may follow.

Diagnosis confirmed by positive blood,urine, or spinal fluid cultures; 4-fold increase in serial agglutinationtiters; or visualization of spirochete by dark-field microscopyof urine.

Plague

Y. pestisis responsible for plague. Most common form is bubonic plague, whichis usually transmitted by bites of infected fleas and uncommonlyby contact with infected tissues and fluids of wild rodents (e.g.,prairie dogs, ground squirrels, chipmunks, hares, rabbits, and rats).

Characterized by fever and painfulregional adenopathy, usually involving cervical, inguinal, or axillarylymph nodes (buboes).

Less common forms include pneumonicplague (cough, fever, dyspnea, hemoptysis), septicemic plague (fever,hypotension, coagulopathy), and meningeal plague (fever, headache,photophobia, seizures).

Positive fluorescent antibody testof sputum, lymph node aspirate, blood, or spinal fluid is presumptiveevidence of infection. Serologic tests also may confirm diagnosis.Positive sputum, lymph node, blood, or spinal fluid cultures aredefinitive.

Psittacosis (Ornithosis)

C. psittacicauses psittacosis, which is transmitted from parrots and otherrelated species (parakeets, finches, cockatoos), and ornithosis,which is acquired from turkeys, pigeons, ducks, chickens, and otherfowl. Transmission is by inhalation of organisms from infected bird'senvironment. Incubation period is usually 1–2 wks.

Affected individuals have acute respiratorytract infection with fever and nonproductive cough.

Chest radiograph usually shows interstitialpneumonia. Usual method of diagnosis is serologic, with 4-fold increasein complement fixation antibody titer. With compatible clinicalpicture, single complement fixation titer ≥1:32 is also considereddiagnostic.

Rat-Bite Fever

May followrodent bite, usually that of rat.

2 different organisms, S. moniliformis,which is more common in U.S., and S. minus, which is more commonin Japan, can cause this infection.

Clinical features include fever, chills,headache, muscle pain, and rash (macular, papular, or petechial).

Migratory polyarthritis/arthralgiasoccur in some cases of S. moniliformis infection. Complicationsinclude pneumonia, meningitis, myocarditis, pericarditis, endocarditis,and soft tissue or solid organ abscesses. Positive culture fromsite of bite, blood, or joint fluid confirms diagnosis.

With S. minus infection, the bite maybe followed by ulceration, lymphadenopathy, and rash composed ofpurple or red plaques. Diagnosis of S. minus may be confirmed byobservation of organisms by dark-field microscopy in wet mountsof blood, exudate of lesion, and lymph nodes.

Syphilis

T. pallidumcauses syphilis, which may be congenital or acquired. See Chap. 36, Jaundice, fordiscussion of congenital syphilis.

Acquired syphilis almost always occursby sexual transmission.

Incubation period is 10–90days.

In primary stage, ≥1 painless ulcer(chancres) occurs on skin or mucous membranes at site of inoculation,usually on genitalia.

During secondary stage, which occurs1–2 mos later, generalized macular or papular rash appears,usually involving palms and soles. Fever, malaise, headache, arthralgia,generalized adenopathy, splenomegaly, and condyloma lata also canoccur.

Tertiary stage occurs several yearsto decades later and is characterized by aortitis or gummatous changesof skin, bones, or viscera.

Neurosyphilis can occur at any stage.

Nontreponemal reagin antibody test(rapid plasma reagin card test) and VDRL slide test, which measureimmunoglobulins directed against cardiolipin antigen, are usefulscreening tests.

Any positive test result should beconfirmed by 1 treponemal test.

Specific treponemal antibody serologictests include fluorescent treponemal antibody absorption test (FTA-ABS),which usually remains positive for life, even with successful therapy.

Microscopic dark-field exam of lesionscraping or lymph node aspirate that shows spirochetes or positivedirect fluorescent antibody test of lesion exudate or tissue isalso diagnostic.

Diagnosis of CNS involvement is establishedby positive CSF VDRL or FTA-ABS tests. CSF pleocytosis and increasedCSF protein concentration also may be found.

Tularemia

Source ofinfection with F. tularensis is infected animal or carcass, usuallyrabbit. Infection is acquired by ingestion of contaminated meator water, handling infected animals, or bites by dog ticks or deerflies that have come into contact with infected animal.

Fever, chills, headache, and myalgiaare usual findings. Common presentation is ulceroglandular syndromewith painful, swollen, ulcerating papule and inflamed lymph nodesthat may drain spontaneously.

Other syndromes are glandular (absenceof skin or mucous membrane involvement); oculoglandular (conjunctivitisand preauricular lymph node involvement); oropharyngeal (exudativepharyngitis); typhoidal (fever and hepatosplenomegaly); and pneumonic(cough).

Positive culture or 4-fold increasein serum agglutinin titer is diagnostic.

Malaria

Sporozoaof genus Plasmodium cause malaria, which occurs in many tropicaland subtropical countries. Bite by infected female Anopheles mosquitotransmits infection. 4 known types of malaria are caused by differentspecies and have the following incubation periods:

P. falciparum,9–14 days

P. vivax, 12–17 days

P. ovale, 16–18 days

P. malariae, 18–40 days

P. falciparum and P. vivax infectionsare most common, whereas P. falciparum infection is most serious.Mixed infections with more than 1 type also occur.

Typical symptoms are fever with chills,sweats, and headache. Fever usually occurs every other day withP. vivax, P. falciparum, and P. ovale infections, and every thirdday with P. malariae infection. Vomiting, diarrhea, cough, and abdominalpain are other manifestations. Significant hemolysis produces pallorand jaundice. Hepatosplenomegaly may occur with chronic infection.

Clinical syndromes that may occur withP. falciparum infection include

Febrile illness without specific or localizingsigns

Severe anemia

Respiratory failure ± pulmonaryedema

Renal failure secondary to acute tubularnecrosis

Cerebral malaria with seizures andalteration of consciousness

Vascular collapse and shock associatedwith adrenal insufficiency

P. vivax and P. ovale may cause anemiaand hypersplenism, whereas nephrotic syndrome may be associatedwith P. malariae infection. Any type can cause congenital malaria,which is characterized by fever, irritability, and lethargy.

Analysis of thick and thin blood smearsusing Wright or Giemsa stain identifies parasite and confirms diagnosis.

Ascariasis

Infectionwith roundworm A. lumbricoides is usually asymptomatic, but diarrhea, vomiting,and abdominal pain sometimes occur. Larval migration through lungcan cause transient pneumonitis associated with fever and eosinophilia.

Adult worms, which are whitish brownin color and 15–30 cm (males) or 20–40 cm (females)long, sometimes pass through rectum.

Identification of ova by microscopicidentification of stool or adult worm is diagnostic.

Toxocariasis (Visceral Larva Migrans, Ocular Larva Migrans)

Dog roundwormT. canis and cat roundworm T. cati cause toxocariasis.

Ingestion of infective eggs from soilcauses human infection, which is most common in toddlers.

Although infection can be asymptomatic,with eosinophilia as its only manifestation, other findings includefever, cough, macular or papular rash, and hepatosplenomegaly. Pneumonia,myocarditis, and encephalitis are rare complications. Ocular invasionusually occurs without other evidence of infection.

Enzyme immunoassay for serum Toxocaraantibodies available through CDC is both sensitive and specificfor visceral larva migrans and less sensitive for ocular larva migrans.Liver biopsy also may detect larvae, but yield is low.

Trichinosis

Infectionwith nematode T. spiralis is acquired by eating undercooked meat(usually pork) containing encysted larvae.

Fever, diarrhea, vomiting, and abdominalpain follow in 1–7 days. During next 2–8 wks,fever, myalgia, urticarial rash, and hemorrhages (conjunctival andsubungual) may develop. Eosinophilia as high as 70% alsomay occur. Most serious complication is myocarditis.

Identification of larvae in suspectmeat is fastest way to diagnose. Diagnosis also can be made by visualizinglarvae in muscle biopsy or by increase in paired acute and convalescentantibody titers.

Endemic Typhus (Murine)

Murine typhuscaused by R. mooseri is primarily infection of rats. Transmissionto humans occurs by bite of infected rat or inhalation of infectedrat excreta 1–2 wks after exposure. Infection occurs insoutheastern U.S. and is more common during summer months.

Fever, headache, and myalgia are usualfindings. Macular or papular rash occurs about 1 wk into illness,which lasts 2–3 wks.

Diagnosis is usually confirmed by serologictests.

Epidemic Typhus (Louse-Borne Typhus)

Humans areonly known reservoir of R. prowsekii, which causes epidemic typhus.

Infection is transmitted by infectedbody louse feces, usually through skin abrasion. Crowding, poorpersonal hygiene, and poverty are factors that contribute to itsoccurrence.

Usual incubation period is 1–2wks.

Begins with sudden onset of fever,chills, headache, and myalgia. Macular or papular rash appears in3–7 days and is followed by petechial or hemorrhagic rash.Face, palms, and soles are usually spared. In severe cases pneumonia,renal failure, and alteration in consciousness may occur.

Diagnosis may be confirmed by isolationof organism, visualization of rickettsiae in tissues, detectingrickettsiae by polymerase chain reaction, or by serologic testing.

Q Fever

Caused byC. burnetii, which infects cattle, sheep, goats, and rodents.

Human infection follows inhalationof infected dust from exposure to hides or products of conceptionof these animals.

Incubation period is 10–20days.

Acute onset of fever, chills, headache,and weakness are characteristic. Hepatosplenomegaly and weight lossoften occur. Persistent cough may signify pneumonia. High, spikingfever may continue for 1–3 wks, with gradual resolution.Major manifestations of chronic disease are hepatitis and endocarditis.

Immunofluorescence, complement fixation,enzyme immunoassay, and immune adherence hemagglutination antibodytests are used diagnostically.

Rickettsial Pox

Definedas mild illness caused by R. akari.

House mice harbor this organism, whichis transmitted to humans by mites.

Incubation period is 2–7 daysfollowing attachment of infected mite.

Mite bite produces red papule, whichforms vesicle that ulcerates. Fever, headache, chills, sweats, myalgia,and papular/vesicular eruption follow in 1–3 days.

During acute stage, organism may beisolated from blood. Serologic tests are also diagnostic.

Ehrlichiosis

Consistsof at least 2 distinct diseases: human monocytic ehrlichiosis causedby E. chaffeensis and human granulocytic ehrlichiosis caused byan unnamed Ehrlichia species. Both are transmitted by tick vectors.

Both resemble Rocky Mountain spottedfever, with fever, headache, malaise, chills, and myalgia. Macularor papular rash that occasionally can be petechial occurs commonlywith monocytic form and rarely with granulocytic form.

Lab findings include anemia, thrombocytopenia,increased liver aminotransferases, and CSF pleocytosis with predominanceof lymphocytes.

Diagnosis may be confirmed by serologicmethods or by polymerase chain reaction of DNA from a clinical sample.

Noninfectious

Many uncommon noninfectious causes, as listedbelow, are discussed in other chapters.

Respiratory

Pulmonaryinfarction

Pulmonary embolism

Gastrointestinal

Intestinal obstruction

Inflammatory bowel disease

Cardiac (postpericardiotomy syndrome)

Hematologic

Intravascular hemolysis

Bleeding into closed space

Endocrine

Thyrotoxicosis

Diabetes insipidus

Central nervous system

Intracranialinjury and hemorrhage

Spinal cord injury

Hypothalamic and brain stem lesions

Status epilepticus

Neoplasia

Leukemia

Lymphoma

Neuroblastoma

Pheochromocytoma

Connective tissue disorders

Juvenile rheumatoidarthritis

Systemic lupus erythematosus

Polyarteritis nodosa

Polymyositis

Dermatomyositis

Mixed connective tissue disease

Poisonings

Atropine

Cocaine

Salicylate

Lysergic acid diethylamide

Hydrocarbons

Organophosphates

Tricyclic antidepressants

Amphetamines

Phenothiazines

Other

Spider bites (black widow, brown recluse)

Stevens-Johnson syndrome

Heat-related illness

Serum sickness

Anhidrotic ectodermal dysplasia

Familial dysautonomia

Sarcoidosis

Familial Mediterranean fever

Factitious fever

Central Nervous System

Increasedtemperature may occur with intraventricular hemorrhage as well assubdural hematoma or effusion. CT is diagnostic.

Absence of effective control mechanismsof temperature regulation sometimes results from spinal cord injury.In such cases, significant increase in environmental temperatureproduces hyperpyrexia.

Any hypothalamic or brainstem lesionmay damage hypothalamic temperature-regulating center and producehyperpyrexia. Hypoxic-ischemic encephalopathy and brain tumors arecommon examples.

Prolonged status epilepticus may resultin autonomic changes with associated increase in temperature.

Neoplasia

Fever in children with cancer usually occursbecause of underlying disease process, infection, or effects oftreatment. Important factor in determining risk of serious infection,especially bacterial infection, is neutropenia (absolute neutrophilcount <500 cells/mm³).

Other

Spider Bites

Bite ofbrown recluse spider (L. reclusa) can cause severe local reaction,with fever, pain, and swelling followed by blister formation andnecrosis. Spider is brown, 10–15 mm long, with 6 eyes arrangedin an arc.

Female black widow spider (L. mactans)has red ventral spot and variable red dorsal spots. Usual lengthis about 2 cm, and bite produces twin red fang marks in skin. Injectionof venom produces pain and swelling at site of bite. Vomiting, fever,and intense abdominal pain may occur within 30 mins.

History and identification of spiderconfirm diagnosis.

Serum Sickness

Occurs 1–2wks after exposure to animal serum (e.g., diphtheria antitoxin;botulism antitoxin types A, B, and E; and antivenoms for snake orspider bites). Accelerated reaction may occur within 1–5days in individuals who have had previous exposure.

Clinical manifestations include fever;macular, papular, erythematous, or urticarial rash; localized orgeneralized adenopathy; hepatosplenomegaly; vomiting; abdominalpain; arthralgia or arthritis; and generalized edema. Usually self-limitedillness and lasting few days to few weeks.

Factitious Fever

Sometimes parent or guardian fabricates andreports persistent fever in child. Clues to this diagnosis are

Lack oftachycardia, flushing, sweating, or warm skin at time of fever

Rapid appearance and disappearanceof high fever in child who is otherwise well

Absence of fever when nurse or physiciantakes temperature

Wide discrepancy between oral and rectaltemperatures when taken simultaneously.

In any of these situations, consider Munchausensyndrome by proxy.

Diagnostic Approach: Acute Fever

Most acutefevers are caused by infection, usually viral or bacterial.

Common infections should be consideredbefore less common ones, unless clinical findings suggest otherwise.

Best guide to accurate diagnosis ishistory and physical exam.

Clinical Findings

Age of child,height of fever, compromised host defenses, and associated findings (e.g.,rash, painful extremity, abdominal pain, jaundice, generalized lymphadenopathy,hepatomegaly, or splenomegaly) are important factors in diagnosisof any child who presents with fever.

Important historical information includesany history of contact with other ill individuals, foreign travel,previous immunizations, drug exposure, history of pica, and exposureto animals or birds.

History of pica suggests toxoplasmosis or toxocariasis(visceral larva migrans).

History of tick exposure suggests RockyMountain spotted fever, relapsing fever, or Lyme disease.

History of exposure to animals or birdssuggests diseases caused by rats (plague, rat-bite fever, leptospirosis);hamsters (lymphocytic choriomeningitis encephalitis); rabbits (tularemia);cattle, goats, and dogs (brucellosis); cats (cat scratch disease,toxoplasmosis); and birds (psittacosis).

Age

Risk ofserious bacterial illness (e.g., septicemia and meningitis) varieswith age and is greatest during immediate neonatal period, especiallyin premature infants.

Clinical findings may be nonspecific,including poor feeding, decreased activity, fever, or hypothermia.

In such infants, CBC with differentialand blood, urine, and spinal fluid cultures should be performed.

Gram-stained smear of spinal fluidshould be performed and antigen studies considered.

Chest radiograph should be performedwith history of respiratory symptoms.

Stool culture should be performed withhistory of diarrhea.

Height of Fever

In infants,incidence of serious bacterial infection is higher in those withrectal temperature >41°C compared with those withlower temperature.

Preschool and school-aged childrenoften have high fever that persists for several days and is notassociated with localizing findings. Such children do not appearvery ill and usually have self-limited viral infections.

Continued observation with close follow-upusually clarifies many of these problems.

Whatever the height of fever, assessmentof toxicity and level of functioning is crucial in diagnosis andmanagement.

Compromised Host Defenses

Children with impaired host defenses dueto primary or secondary immunodeficiency disorders are at risk fordevelopment of serious infection caused by wide range of infectiveagents, including bacteria (S. aureus, gram-negative enteric organisms),viruses (cytomegalovirus, VZV), protozoa (P. carinii), and fungi(Candida and Aspergillus species).

Associated Physical Findings

Fever and Rash

Macularor papular rashes occur with viral infection (enteroviruses, herpesvirus6, measles virus, rubella virus, parvovirus B19, Epstein-Barr virus),bacterial infection (scarlet fever, meningococcemia, toxic shocksyndrome, typhoid fever, rat bite fever, leptospirosis), rickettsialinfection (Rocky Mountain spotted fever), Kawasaki disease, anddrug reactions (most commonly penicillins and sulfonamides).

Erythematous rashes occur with viralinfection (parvovirus B19), bacterial infection (scarlet fever,toxic shock syndrome, staphylococcal scalded skin syndrome), Kawasakidisease, and reactions to same drugs causing macular or papularrashes.

Petechial and purpuric rashes occurwith congenital viral infection (rubella virus, cytomegalovirus),other viral infection (enteroviruses, Epstein-Barr virus, arboviruses),bacterial infection (group A Streptococcus, N. meningitidis, S.pneumoniae, N. gonorrhoeae, S. aureus, H. influenzae type b, P. aeruginosaand other gram-negative enteric bacteria), rickettsial infection(Rocky Mountain spotted fever), and parasitic infection (toxoplasmosis).

Vesicular rashes occur with viral infection(herpes simplex virus, varicella-virus infection, enteroviruses)and bacterial infection (bullous impetigo, staphylococcal scaldedskin syndrome).

See Chap.60, Skin Lesions and Rashes.

Fever and Painful Extremity

Infectiousor inflammatory causes

Cellulitis

Septic arthritis

Osteomyelitis

Transient synovitis

Skin/soft tissue abscess

Thrombophlebitis

Acute rheumatic fever

Vaccine immunization

Other causes

Neoplasia (leukemia, osteogenic sarcoma,Ewing sarcoma, metastatic neuroblastoma)

Collagen vascular disease (juvenilerheumatoid arthritis, systemic lupus erythematosus)

Kawasaki disease

Serum sickness

Arthritis associated with inflammatorybowel disease

See Chap.37, Limp.

Fever and Abdominal Pain

Infectiousand inflammatory causes

Nonspecific viral illness

Gastroenteritis

Urinary tract infection

Pneumonia

Appendicitis

Intraabdominal abscess

Hepatitis

Peritonitis

Cholecystitis

Cholangitis

IBD

Pelvic inflammatory disease

Pancreatitis

Generalized vasculitis

Other causes

Neoplasia (leukemia, Hodgkin disease,non-Hodgkin lymphoma, neuroblastoma, hepatic malignancies)

Diabetic ketoacidosis

Black widow spider bite

See Chap.2, Abdominal Pain.

Fever and Jaundice

Most commoncause of fever and unconjugated hyperbilirubinemia in neonates is septicemia.Causes of fever and conjugated hyperbilirubinemia in neonates include

Viral infection(rubella virus, cytomegalovirus, herpes simplex virus, VZV, enteroviruses,hepatitis B virus)

Bacterial infection (septicemia, syphilis)

In infancy and childhood, fever andconjugated hyperbilirubinemia may be due to

Viral infection (hepatitis A, B, C,D, E; enteroviruses; herpes simplex virus; Epstein-Barr virus; cytomegalovirus

Bacterial infection (septicemia, cholecystitis,cholangitis, liver abscess, leptospirosis, brucellosis)

Rickettsial infection (Q fever)

Fungal infection (histoplasmosis)

Parasitic infection (amebiasis, malaria,visceral larval migrans)

Drug reactions

Neoplasia (hepatic malignancies, non-Hodgkinlymphoma)

See Chap.36, Jaundice.

Fever and Generalized Lymphadenopathy

Infectiouscauses

Viralinfection (rubella virus, measles virus, Epstein-Barr virus, cytomegalovirus, VZV,hepatitis A virus, HIV)

Bacterial infection (pyogenic infectionfrom S. aureus, group A Streptococcus, H. influenzae type b, S.pneumoniae; tuberculosis; brucellosis; tularemia; salmonellosis;leptospirosis; syphilis)

Fungal infection (histoplasmosis)

Parasitic infection (toxoplasmosis,malaria)

Noninfectious causes

Neoplasia(leukemia, non-Hodgkin lymphoma, metastatic neuroblastoma)

Langerhans histiocytosis

Collagen vascular disease (juvenilerheumatoid arthritis, systemic lupus erythematosus)

Drug reactions

Serum sickness

Chronic granulomatous disease

Sarcoidosis

See Chap.38, Lymphadenopathy.

Fever with Hepatomegaly, Splenomegaly, or Hepatosplenomegaly

Causes offever and hepatomegaly

Hepatitis (A, B, C, D, E)

Primary liver abscess

Amebiasis

Primary liver malignancies

Causes of fever and splenomegaly

Viral infection(rubella virus, cytomegalovirus, herpes simplex virus, enteroviruses, Epstein-Barrvirus)

Bacterial infection (septicemia, endocarditis,tularemia, plague, salmonellosis, splenic abscess)

Rickettsial infection (Rocky Mountainspotted fever)

Parasitic infection (malaria, toxoplasmosis)

Infectious causes of fever and hepatosplenomegaly

Viral infection(rubella virus; herpes simplex virus; cytomegalovirus; VZV; enteroviruses;Epstein-Barr virus; hepatitis A, B, C, D, E)

Bacterial infection (septicemia, endocarditis,brucellosis, tuberculosis, syphilis, leptospirosis, relapsing fever)

Fungal infection (histoplasmosis, coccidioidomycosis)

Parasitic infection (visceral larvalmigrans, toxoplasmosis, Chagas disease)

Other causes of fever and hepatosplenomegaly

Neoplasia(leukemia, Hodgkin disease, non-Hodgkin lymphoma, neuroblastoma)

Langerhans histiocytosis

Collagen vascular disease (juvenilerheumatoid arthritis, systemic lupus erythematosus)

See Chap.30, Hepatomegaly and Chap. 62, Splenomegaly.

Fever without Localizing Signs

Most childrenwith fever and no apparent focus of infection have self-limitedviral infection that resolves without treatment and has no sequelae.

Small percentage of children with acuteonset of fever ≥39°C and no localizing signs, especiallyat 3–36 mos, may have urinary tract infection, bacteremia,or meningitis.

In infants <1 mo of age, commoncauses of septicemia and meningitis are group B Streptococcus andgram-negative enteric bacteria, commonly E. coli. Much less commonis infection with L. monocytogenes.

At 1–3 mos of age, most commoncauses of septicemia and meningitis are S. pneumoniae, group B Streptococcus,and N. meningitidis.

In children >3 mos of age,S. pneumoniae, N. meningitidis, and Salmonella species (usually occurringwith gastroenteritis) cause most bacterial infections that occurwithout a focus.

Diagnostic and management approachto child with fever without apparent focus of infection dependson age, exposure history, usual pathogens, and severity of illness.

See references at end of chapter forfurther information.

Lab Findings

Lab tests(cultures and radiographs most commonly) are used to confirm diagnostic impressionof infection.

WBC and differential may suggest bacterialor viral infection, but they are not diagnostic. WBC count >20,000/mm³ withpredominance of neutrophils (>70%) or <5,000/mm³ withlarge number of band forms (>5%–10%)suggests bacterial infection. Although similar WBC counts sometimeoccur with viral infections, in such cases there is usually predominanceof lymphocytes and few band forms.

Principal Causes of Fever of Unknown Origin

1. Infection
   1. Typesof infections
   2. Prolonged viral illness
   3. Urinary tract infection
   4. Lower respiratory tract infection
   5. Sinusitis
   6. Endocarditis
   7. Intraabdominal abscess
   8. Osteomyelitis
   9. Meningoencephalitis
   10. Bacterial meningitis
   11. Parameningeal abscess
   12. Dental infection
   13. Specific diseases
       1. Viral
          1. Epstein-Barrvirus
          2. Cytomegalovirus
          3. Herpes simplex virus
          4. Human immunodeficiency virus
       2. Bacterial
          1. Salmonellosis
          2. Yersiniosis
          3. Tuberculosis
          4. Brucellosis
          5. Cat scratch disease
          6. Streptococcosis
          7. Tularemia
          8. Leptospirosis
          9. Relapsing fever
          10. Psittacosis
          11. Lyme disease
          12. Syphilis
          13. Chronic meningococcemia
       3. Rickettsial
          1. Rocky mountain spotted fever
          2. Q fever
          3. Ehrlichiosis
       4. Fungal
          1. Histoplasmosis
          2. Coccidioidomycosis
       5. Parasitic
          1. Malaria
          2. Visceral larva migrans
          3. Giardiasis
          4. Toxoplasmosis
          5. Amebiasis (extraintestinal)
2. Connective tissue diseases
   1. Juvenilerheumatoid arthritis
   2. Systemic lupus erythematosis
   3. Polyarteritis nodosa
   4. Other vasculitis syndromes
3. Neoplasia
   1. Leukemia
   2. Hodgkin disease
   3. Solid tumors including neuroblastoma
4. Miscellaneous
   1. Drug fever
   2. Inflammatory bowel disease
   3. Sarcoidosis
   4. Langerhans histiocytosis
   5. Periodic fever
      1. PFAPAsyndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis)
      2. Cyclic neutropenia
      3. Familial periodic fevers
   6. Fever without acute phase response
      1. Familialdysautonomia
      2. Central thermoregulatory disorder
      3. Diabetes insipidus
   7. Factitious fever
5. Undiagnosed

Clinical Features and Diagnosis: Fever of Unknown Origin

Variousdefinitions of fever of unknown origin have been proposed. Reviewof the literature suggests that a useful definition is the presenceof fever for ≥2 wks with temperature >38.3°C orallyfor children >3 yrs of age and rectally for children <3yrs of age.

For this discussion, fever of unknownorigin refers to persistent fever for ≥2 wks without apparentcause after performing repeated physical exams and routine screeningtests and cultures.

Causes of such fever can be dividedinto four categories: infection, connective tissue diseases, neoplasia,and miscellaneous.

Most children with prolonged feverhave common disorder that is atypical in presentation and thus causesconfusion and delay in diagnosis.

Fever of unknown origin in most children <6yrs of age is caused by infection. In this age group, connectivetissue diseases and neoplasia are uncommon.

From 6 yrs of age through adolescence,infection and connective tissue disease are about equal in incidenceas cause of persistent fever. In a number of children with persistentfever, cause remains undiagnosed, and eventually fever abates.

Many causes of fever of unknown originare discussed here and in other chapters.

Infection

Types of Infections

Prolongedviral illness

Urinary tract infection

Lower respiratory tract infection

Sinusitis

Endocarditis

Intraabdominal abscess

Osteomyelitis

Meningoencephalitis

Bacterial meningitis

Parameningeal abscess

Dental infection

Specific Diseases

Viral

Epstein-Barrvirus

Cytomegalovirus

Herpes simplex virus

HIV

Bacterial

Salmonellosis

Yersiniosis

Tuberculosis

Brucellosis

Cat scratch disease

Streptococcosis

Tularemia

Leptospirosis

Relapsing fever

Psittacosis

Lyme disease

Syphilis

Chronic meningococcemia

Rickettsial

Rocky Mountain spotted fever

Q fever

Ehrlichiosis

Fungal

Histoplasmosis

Coccidioidomycosis

Parasitic

Malaria

Visceral larva migrans

Giardiasis

Toxoplasmosis

Amebiasis (extraintestinal)

Connective Tissue Diseases

Juvenilerheumatoid arthritis

Systemic lupus erythematosus

Polyarteritis nodosa

Other vasculitis syndromes

Neoplasia

Leukemia

Hodgkin disease

Solid tumors including neuroblastoma

Miscellaneous

Drug fever

Inflammatory bowel disease

Sarcoidosis

Langerhans histiocytosis

Periodic fever

PFAPA syndrome (periodic fever, aphthousstomatitis, pharyngitis, adenitis)

Cyclic neutropenia

Familial periodic fevers

Fever without acute phase response

Familial dysautonomia

Central thermoregulatory disorder

Diabetes insipidus

Factitious fever

Undiagnosed

Even after extensive investigation, sometimesthe cause of the fever remains undiagnosed.

Periodic Fever

PFAPA Syndrome

Constellationof periodic fever, aphthous stomatitis, pharyngitis, and adenitis(PFAPA) occurs at 4- to 6-wk intervals and may recur for years.

Episodes consist of fever, chills,headache, pharyngitis, tender cervical adenopathy, and ≥1 aphthousulcers, usually lasting 4–5 days.

These children are well between episodes.

Diagnosis is clinical.

Cyclic Neutropenia

Rare causeof periodic fever.

Typically occurs every 3–4wks and lasts for 3–6 days.

When neutrophil count decreases, commonmanifestations include oral ulcers, stomatitis, gingivitis, andfurunculosis. Serious infections (e.g., pneumonia, abdominal abscesses,and septicemia) also may occur.

Measurement of sequential neutrophilcounts is diagnostic.

Familial Periodic Fevers

FamilialMediterranean fever is autosomal-recessive disorder of unknown cause, whichis characterized by recurrent episodes of fever that may be associatedwith pleuritis, peritonitis, or arthritis, particularly in childrenof Jewish, Arabic, or Armenian ancestry.

Similar disorder is known as Hibernianfever, which occurs in children of Celtic ancestry.

Another disorder consisting of recurrentfever, lymphadenopathy, leukocytosis, and increased serum immunoglobulinD has been described, especially in children of Dutch ancestry.

Fever without Acute Phase Response

Dysautonomiacan occasionally present with recurrent fever before appearanceof other manifestations. See Chap.65, Sucking and Swallowing Difficulty.

Thalamic dysfunction caused by seriousinjury to CNS may result in persistent fever.

Diabetes insipidus also may manifestas fever of unknown origin. See Chap.47, Polyuria and Polydipsia.

Diagnostic Approach: Fever of Unknown Origin

After completehistory and physical exam, patient should be carefully examinedevery day in the hospital for any new findings.

Presence of fever must be documentedin the hospital.

Any exposure to birds or other animals,drug use, recent travel, and family history of recent illness mustbe noted.

Initial tests should include CBC anddifferential; analysis of blood smear; sedimentation rate; chestradiography; UA; serum electrolytes, creatinine, calcium, phosphorus,amylase, and glucose; blood urea nitrogen; liver function tests;appropriate viral, bacterial, mycobacterial, and fungal cultures; antinuclearantibody; Epstein-Barr virus antibody titers; and PPD skin test.

Serologic testing may be useful todiagnose many disorders.

Radiologic modalities (abdominal U/S,scintigraphy, CT) may reveal occult abscess or malignancy.

Bone marrow, liver, lung, lymph node,and other tissue biopsies with appropriate cultures may be usefuldepending on clinical presentation and suspected diagnosis.

In cases of persistent fever, therapeutictrials of antibiotics or other treatment modalities are rarely indicatedunless child becomes very ill or is immunocompromised.

Inappropriate antibiotics can altertypical signs of infection and delay diagnosis and appropriate therapy.

References

1. Alpern ER, Henretig FM. Fever. In: FleisherGR, Ludwig S, eds. Textbook of pediatric emergency medicine, 4thed. Philadelphia: Lippincott Williams & Wilkins, 2000:257–266.
2. Behrman RE, et al., eds. Nelson textbook of pediatrics,16th ed. Philadelphia: WB Saunders, 2000.
3. DuBois EF. Fever and the regulation of body temperature.Springfield, IL: Charles C Thomas, 1948.
4. Elliot DL, et al. Pet-associated illness. N Engl JMed 1985;313:985–995.
5. Feigin RD, Cherry JD, eds. Textbook of pediatric infectiousdiseases, 4th ed. Philadelphia: WB Saunders, 1998.
6. Lange RD, Jones JB. Cyclic neutropenia—reviewof clinical manifestations and management. Am J Pediatr HematolOncol 1981;3:363–367.
7. Long SS, et al., eds. Principles and practice of pediatricinfectious diseases. New York: Churchill Livingstone, 1997.
8. Lorin MI. The febrile child. New York: John Wiley & Sons,1982.
9. Pickering LK, ed. 2000 Red book: report of the Committeeon Infectious Diseases, 25th ed. Elk Grove Village, IL: AmericanAcademy of Pediatrics, 2000.
10. Pizzo PA, Lovejoy FH Jr, Smith DH. Prolonged feverin children: review of 100 cases. Pediatrics 1975;55:468–473.
11. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.

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Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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