1. Detail the differential diagnoses for children with recurrent fever.

2. Discuss the importance of history and a fever diary in the diagnosis of recurrent fever in children.

3. Diagnose and manage familial fever syndromes in children.

4. Recognize the 4 clinical syndromes associated with Bartonella henselae infection.

5. Describe the treatment options for children with cervical lymphadenopathy caused by infection with nontuberculous mycobacteria.

Recurrent Fevers in Kids: When is it Not Just Another Virus?

Definition of recurrent fever: high fever without obvious source that occurs at regular or irregular intervals (often 4-6 wk) for ≥4 mo

Intercurrent acute infections: viral—children <2 yr of age have ≈10 viral infections per year; immune systems naive to many viruses, so vigorous immune response (including high fevers) common; bacterial—infections (eg, otitis media; osteomyelitis; urinary tract infections [UTIs]) common; infections poorly localized in children <2 yr of age, complicating diagnosis

Chronic infections: Epstein-Barr virus (EBV)—suspicion increased when fever accompanied by fatigue (but fatigue and hepatosplenomegaly not always present); fever typically chronic, not recurrent; parvovirus—may result in biphasic illness; not generally associated with repeated recurrences; HIV—birth history should always include maternal HIV status during pregnancy; tuberculosis (TB)—incidence increasing; important to ask about travel history and other potential exposures (eg, to high-risk individuals such as newly immigrated or recently incarcerated relative); borreliosis—vectors include lice and ticks; relatively rare cause of recurrent fevers in children

Rheumatologic disorders, autoimmune diseases, and malignancies: juvenile idiopathic arthritis (JIA)—ie, systemic-onset juvenile rheumatoid arthritis; associated with recurrent fever and (usually) evanescent rash; arthralgias or joint symptoms may occur; elevated sedimentation rate; inflammatory bowel disease (IBD)—recurrent fever may be accompanied by gastrointestinal symptoms (eg, abdominal pain, chronic diarrhea) or slow growth; oral ulcers and perirectal problems also suggestive; low hemoglobin, hematocrit, and albumin levels and elevated sedimentation rate increase index of suspicion; cyclic neutropenia—rare disorder; fevers occur at very regular intervals (eg, 21 or 28 days); lymphoma and leukemia—major source of parental concern

Familial fever syndromes: ethnicity important, but blended heritage common, so syndrome may occur in children without obvious ethnic associations

Familial Mediterranean fever (FMF): relatively uncommon; autosomal recessive inheritance; fevers occur every 4 to 6 wk, and last 1 to 3 days; other symptoms (eg, abdominal pain, pleuritic chest pain, arthralgias, arthritis) often accompany fever, but may not occur during first several episodes; ethnic association—most commonly seen among Sephardic Jews, Armenians, North Africans, and Turks; Ashkenazi Jews, Greeks, and Italians also at increased risk; gene—MEFV gene encodes pyrin (protein associated with fevers); mutation impairs function; diagnosis—genetic testing, based on clinical suspicion and patient ethnicity; diagnosis important, because patients with specific mutations may develop amyloidosis during adulthood

Tumor necrosis factor (TNF)-α–associated periodic fever syndrome (TRAPS): previously called familial Hibernian fever; autosomal dominant inheritance (family history usually positive); mutation in gene that encodes TNF receptor-1 (TNFR1); symptoms generally begin during first decade of life; ethnic association—Scottish; Irish; presentation—rash (appears vasculitic with mild dermatographia); fevers typically last ≥5 days (up to weeks); conjunctivitis or periorbital edema common; other symptoms include abdominal pain and myalgia

Hyper-IgD syndrome (HID): autosomal recessive inheritance; ethnic association—French; Dutch; gene—mutation in gene that encodes mevalonic kinase; presentation—children typically symptomatic during first year of life; episodes often stimulated by vaccination, viral infection, trauma, or stress; fevers last 3 to 7 days and often accompanied by chills, mild lymphadenopathy, abdominal pain, vomiting, and diarrhea; other symptoms include headache, arthralgias, aphthous ulcers, rash, and splenomegaly; diagnosis—clinical features; elevated IgD (and sometimes IgA) levels; genetic testing

Periodic fever with aphthous ulcers, pharyngitis, and adenopathy (PFAPA): most commonly occurs in children <5 yr of age and resolves within 2 to 3 yr; presentation—intervals between fevers range from 2 to 8 wk; high fevers (up to 105°F) last 3 to 5 days; children “fussy” and uncomfortable during fever but well between episodes; ibuprofen generally more effective than acetaminophen at reducing fever; other symptoms do not occur with every episode; these include aphthous ulcers (on lips or buccal mucosa; often small and easily missed), adenopathy (may be very tender), and pharyngitis (common); diagnosis—white blood cell (WBC) count and sedimentation rate elevated during fever but return to normal between episodes; diagnosis of exclusion

Diagnostic clues: age of onset—PFAPA, HID, and cyclic neutropenia generally occur at young age; FMF, TRAPS, and JIA have later onset; response to prednisone—dramatic response in children with PFAPA or TRAPS; fever and symptoms resolve with 2 mg/kg prednisone (crush tablets into, eg, chocolate syrup); multiple doses effective in children with JIA; no effect in children with FMF, HID, or cyclic neutropenia; pharyngitis and adenopathy—most commonly present in children with PFAPA or cyclic neutropenia, but may occur with other fever syndromes; duration of fever—although some variation, fevers of 3 to 5 days common with most syndromes; periodicity—PFAPA and cyclic neutropenia most predictable

History: most helpful part of evaluation; pattern and course of fever most important; temperature should be measured each day during fever but not when child well; also important to note presence of associated symptoms and health of child between episodes; family history—similar episodes (including extended family); ethnic background; children with chronic infections; death from infection or unknown cause at young age; history of low WBC count or rheumatologic or autoimmune disorders; maternal HIV status during pregnancy; child’s response to varicella infection (clue to strength of immune system); environment—daycare exposure (increased exposure to viruses); travel; exposure to animals; history of insect bites; water and food sources; other unusual circumstances

Physical examination: gestalt—children who appear chronically ill more likely to have JIA or IBD; those who appear otherwise well more likely to have familial fever syndrome, PFAPA, or intercurrent viral infections; examination—examine head, ears, eyes, nose, and throat; assess nodal status; listen to lungs and heart (eg, check for murmur); check abdomen for tenderness, hepatosplenomegaly, and masses; palpate muscles, tendons, and bones (especially pelvis), checking for tenderness (suggesting, eg, osteomyelitis); perform neurologic examination, assessing reflexes and strength and checking ocular fundi; note acute or chronic rashes

Prioritizing differential diagnosis: find out what parents most worried about; if patient does not have “fever diary,” rule out malignancy, then ask family to keep track of fevers and symptoms for ≥3 mo; complete blood cell count (CBC) with blood smear and sedimentation rate (in addition to gestalt) often sufficient to rule out malignancy; if child ill, repeat tests when well; same tests, in addition to duration of fever and intervening intervals, helpful for ruling out chronic infection; most children with chronic infection have elevated sedimentation rates; familial recurrent fever syndromes—CBC with differential, sedimentation rate, and C-reactive protein (CRP) level when child well; IgD and IgA levels (if not elevated, child does not have HID); genetic testing; PFAPA—diagnosis of exclusion; consider trial dose of prednisone only if malignancy or serious infection ruled out; cyclic neutropenia—check WBC count when child well (may be elevated when ill); CBC with differential (finger-poke sufficient) recommended 3 times/week until next episode; IBD—abdominal computed tomography (CT); screening test difficult to interpret

Treatment: PFAPA—single dose of prednisone at first fever or suppressive therapy with cimetidine (3 times daily); tonsillectomy often curative; FMF—colchicine for patients with certain genetic mutations; TRAPS—prednisone; cyclic neutropenia—granulocyte-colony stimulating factor

Questions and answers: WBC count in children with cyclic neutropenia—red flag when <500 cells/µL; WBC count may increase when child ill; sedimentation rate vs CRP level—CRP levels increase and decrease faster than sedimentation rate; aphthous ulcers—children with PFAPA have few, small (≈0.5 mm) lesions; biopsy may help diagnosis; prednisone at home—provide trial dose to be given with next fever; instruct parents to give dose only if episode “absolutely typical” (otherwise, advise them to see primary care provider); refer to primary care provider for additional prescriptions

Interesting Pediatric Infections: Case Studies

Case 1: boy, 10 yr of age, with daily fevers (up to 105°F) and fatigue for 2 wk; no other associated symptoms; history—no ill family members; no travel history; child plays soccer and has no unusual hobbies; dog and cat present in household

Physical examination: child appears ill and fatigued; temperature 103°F; no significant lymphadenopathy; head, eyes, ears, nose, and throat examination reveals no abnormal findings; normal heart and lung sounds; mild abdominal tenderness (slightly worse on right side) but no hepatosplenomegaly; full range of motion and no extremity pain; no rash; no diarrhea or blood in stool; no flank tenderness; normal neurologic examination (ie, appropriately oriented; symmetric deep tendon reflexes; normal fundi); no heart murmur; normal, bilateral descended testes; circumcised; no meatal erythema

Tests and imaging: CBC—relatively unremarkable; slightly low hematocrit; normal counts of platelets and WBCs; normal differential; smear showed slightly microcytic RBCs but no evidence of hemolysis or parasites; sedimentation rate—49 mm/hr; liver function tests—slightly elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT); other tests—no abnormal findings on urinalysis or blood culture; imaging—chest radiograph clear; abdominal CT revealed multiple hypodense lesions (≤1 cm in diameter; well-circumscribed; no capsule) on liver and spleen; diagnostic test—serology for Bartonella henselae (positive)

Cat scratch disease: infectious agent difficult to culture; infection spread by bite, lick, or scratch from infected cat (typically <1 yr of age) or flea bite; history of exposure sometimes difficult to elicit

Clinical syndromes: oculoglandular syndrome—initial lesion (usually maculopapular) at site of scratch; severe conjunctivitis and ipsilateral lymphadenopathy; generally self-limited, but faster resolution with antibiotic treatment; isolated lymphadenopathy—most common manifestation; single node (in distribution of scratch) affected; systemic symptoms rare; generally self-limited, but faster resolution with antibiotic treatment; encephalitis— nondescript encephalopathy may be accompanied by seizures, meningitis, or coma; cerebrospinal fluid (CSF) may not show evidence of infection; antibiotic therapy required (choose antibiotic that penetrates CSF); systemic infection—high fever common; inflammatory markers often elevated; lytic lesions of liver and spleen relatively common; bony lesions also may occur; exaggerated response to B henselae infection may indicate mild immunodeficiency; lesions commonly mistaken for malignancy; patients respond dramatically to antibiotic therapy

Diagnosis: IgG and IgM levels elevated; past exposure may result in elevated IgG levels (consider diagnosis in child with high IgG, even in absence of elevated IgM); polymerase chain reaction (PCR) may be performed if lesion biopsied; Warthin-Starry silver stain of limited value

Treatment: macrolides (eg, azithromycin, clarithromycin) preferred; trimethoprim-sulfamethoxazole used previously

Case 2: girl, 2 yr of age, with 6-wk history of cervical lymphadenopathy (swollen, discolored, and mildly tender) unresponsive to amoxicillin clavulanate (Augmentin); no history of high fever or symptoms of upper respiratory infection

Additional information: no exposure to cat; no ill family members; unilateral lymphadenopathy feels “like two nodes matted together” (not fluctuant); no respiratory symptoms; recent dental appointment raised no concerns; no dental procedures performed; no rash; no exposure to TB or to high-risk individuals, but child attends daycare; no conjunctivitis; no hepatosplenomegaly; ear, nose, throat examination unremarkable; no evidence of hypoperfusion; no exposure to rodents

Tests and imaging: CBC unremarkable; no abnormal findings on chest x-ray

Differential diagnosis: nontuberculous mycobacteria; B henselae; uncommon diagnoses include histoplasmosis, TB, and Actinomyces infection; rare diagnoses include Nocardia or Aspergillus infection, and sporotrichosis

Other useful tests: sedimentation rate (optional); tuberculin skin test (purified protein derivative [PPD]; recommended); serology (eg, B henselae, toxoplasmosis, EBV)

Nontuberculous mycobacterial infection: common diagnosis in infectious disease clinic; children <4 yr of age (most common among girls ≈2 yr of age; reason for gender bias unknown); infectious organisms—present in water and soil; include Mycobacterium avium complex and other Mycobacterium species (eg, M scrofulaceum, M chelonei )

Diagnosis: PPD often positive (but negative test does not exclude diagnosis); PPD considered positive in children <4 yr of age when wheal ≥10 mm; definitive diagnosis—fine-needle aspiration (FNA) or excisional biopsy (histopathology, PCR)

Treatment: complete excisional biopsy often curative; debulking majority of node may be sufficient; incision and drainage may cause chronic draining nodes (avoid); antibiotic therapy often required if complete excision not possible; antibiotics—standard therapy, 3 to 6 mo clarithromycin plus rifampin (highly effective); azithromycin used, but less experience

Etiology: infectious organisms introduced to mouth and enter systemic circulation through break in skin (eg, cutting molars); affected lymph nodes almost always cervical; rarely, infection causes lesions in lungs, tracheobronchial tree, and bones