Infectious Disease
Phuoc V. Le
Colin McCreight
Anne Griffin
Paritosh Prasad
Chadi El Saleeby
Fever of Unknown Origin
Definition
Fever >101°F ≥8 d w/o clear etiology after H&P and basic lab eval; definitions vary
Etiology
(Feigen et al. Textbook of Pediatric Infectious Disease, 4th ed. p 820)
Most often uncommon presentation of a common disease (Pediatrics 1975;55:468)
| Infectious | Malignancy | Autoimmune | Other |
|---|---|---|---|
|
|
|
|
| (Arch Pediatr 1999;6:330; Acta Paediatr 2006;95:463; Clin Infect Dis 1998;26:80) | |||
Diagnostic Studies
Hx (fever pattern, assoc sx’s, ethnicity, ingestion, travel, animal and insect exposure, meds, FHx); complete exam (including accessible LNs, HSM, scalp and skin, MSK and GU); review meds
Labs: CMP, U/A, ESR and CRP, CBC w/ diff and periph smear, PPD, HIV, Bld and U cx
Additional testing (based on H&P, sx’s); Stool cx’s and O and P, viral serologies, ANA, Immunoglobulin levels (if h/o recurrent infections)
Imaging: CXR, abd CT (if ↑ inflammatory markers or other concern for IBD)
Management
Generally avoid empiric Abx or corticosteroids until potential dx available
Empiric broad-spectrum antibiotics may decrease diagnostic yield
Complications
Mortality previously reported at <10%; less in more recent cohorts (Pediatrics 1975;55:468; Acta Paediatr 2006;95:463)
Infectious Meningitis
Etiology
Inflammation of meninges, covering brain and spinal cord 2/2 infection
Peak incidence in 6–12 mo (infants = perinatal exposure and relatively immunocompromised); though 2/2 vaccinations bulk of disease shifted to adulthood
Incidence: 2500 cases in U.S. annually; S. pneumo 7.5/1.0/0.2 per 100,000 in >2 yr/2–4 yr/5–17 yr. (Pediatrics 2006;118:e979; JAMA 2001;285:1729)
Microbiology
(N Engl J Med 1997;337:970)
| Neonate | 1–3 mo | 3 mo–3 yr | 3–12 yr | 12 yr–adult |
|---|---|---|---|---|
| GBS (early onset) E. coli/Gm-neg rods Listeria monocytogenes | GBS; late-onset = ↓ severe S. pneumoniae Listeria and Hib (rare) N. meningitidis, Salmonella | S. pneumoniae N. meningitidis H. influenzae
| S. pneumoniae N. meningitidis H. influenzae
| N. meningitidis S. pneumoniae |
Aseptic meningitis: Enterovirus (∼85%–95% of all viral meningitis), HSV, EBV, CMV, VZV, arbovirus (EEE, West Nile), influenza A/B, mycoplasma (Semin Neurol 2000;20:277)
Risk Factors
Functional/anatomic asplenia, sickle cell disease, nephrotic syndrome, IgG deficiency → ↑ risk encapsulated organism infections (S. pneumo, Hib, N. meningitidis)
Late complement deficiency (C5–C8) → N. meningitidis
Anatomic defects/CSF leak → S. pneumo, S. epi, S. aur, Strep spp., Corynebact.
VP shunt for hydrocephalus → Staph. epidermis (coagulase-negative staph)
Galactosemia → E. coli; HIV → C. neoformans; Endemic area → Lyme
Clinical Manifestations
Bacterial meningitis tends to present acutely (<24 hr)
Infant (nonspecific): fever, irritable, lethargy, ↓feeding, abn tone, bulging fontanel, szr’s, vomiting, Δ body temperature; e/o sepsis (hypotension, respiratory distress, jaundice)
Older children: fever, headache, vomiting, neck stiffness, photophobia
Skin: widespread petechiae/purpuric rash (esp associated with meningococcemia)
Diagnostic Studies
(Pediatr Infect Dis J 1996;15:298)
Hx: Neck stiffness or pain, progressive petechial/purpuric rash, seizure, vaccine Hx; recent infxns (sinusitis, otitis media); exposure pts w/ meningitis; travel; h/o head trauma/craniotomy; VP shunt; immunodeficiency; Hx recent Abx use.
Neurologic exam; assess risk of ↑ ICP/herniation → follow neurologic exam during Rx
Meningeal signs: Nuchal rigidity; in >2 yo: Kernig (straighten flexed leg at knee → neck/back pain) and Brudzinski (passive neck elevation → hip flexion). Tripod sign: pt sitting w/ legs flexed and arms outstretched at the elbow
↑ ICP: Bulging fontanel in infants, ↑ head circum, papilledema in older, CN palsies
Labs: CBC w/ diff, blood culture × 2; chem. 10, LP (if suspect bacterial, do not delay)
LP most important dx test; low threshold in infants (↑ risk of untreated meningitis)
Contraindicated if e/o intracranial mass/↑ ICP/abscess (focal neuro deficit/papilledema) → herniation risk check CT/MRI
Safe to perform LP on infants with bulging fontanel if (-) focal neurologic signs
Herniation unlikely if (-) focal neurologic signs or comatose
LP: cell count, diff, gluc, prot, GS (↑ yield w/ cytocentrifug), cx/PCR/latex agglutination (latex agglut testing useful in partially rx’d meningitis)
| Bacterial Meningitis CSF | Viral Meningitis CSF |
|---|---|
| 1° neutrophils | 1° lymphocytes (may show neutrophils early) |
| ↑ protein | Mildly ↑ protein |
| ↓ glucose | NL glucose |
| ↑ opening pressure (20–75+ cm water) | NL or slightly ↑ opening pressure |
| Opalescent to purulent CSF appearance | Clear unless ↑ cell count |
Normal CSF findings
Neonate (<1 mo): WBC <15–20; 60% PMNs; protein <90; glucose 70–80
Infant (>1 mo): WBC <10; 0% PMNs; prot <40; gluc 50–60 (↑ BBB maturity)
CSF GS (+)90% S. pneumo and 80% N. mening; Bcx (+)90% Hib and 80% S. pneumo
Repeat LP in 24–36 hr if: possible resistant organism (e.g., PCN-resist S. pneumo); s/p dexamethasone; poor Rx response; GNR (after 2–3 d of Rx)
Management
(Cochrane Database Syst Rev 2007.CD004405; AAP Red Book 2006)
Empiric Abx after LP: 3rd gen. cephalosporin (ceftriaxone, cefotaxime) + vancomycin (+ ampicillin if <3 mo for Listeria coverage)→ Δ when cx/sensitivities available
Acyclovir prophylactically while HSV PCR on CSF pending if HSV suspected
Rx duration: 7 d N. mening; 10 d S. pneumo/H. influenzae; 14–21 d for others
Consider early dexamethasone w/ 1st Abx doses to ↓ risk hearing loss in H. influenzae
Most studies w/ no mortality difference w/ steroid Rx; limit to 2 d to dec side-effects
AAP rec’s steroids for Hib meningitis only; eval risk/benefit for S. pneumo in >6 wk old
Acyclovir (21 d) for HSV meningoencephalitis; supportive care for other viral etiologies
Complications:
(Pediatr Infect Dis J 1993;12:389)
Hypovolemia, HypoNa (2/2 SIADH), hypoglycemia, acidosis, septicemia, seizures, DIC, metastatic infection, cerebral edema, ↑ ICP/herniation, stroke
Mortality ∼100% in untreated meningitis vs. 0%–15% mortality for treated in pts >1 yr
Significant morbidity even w/ appt Rx (15%–30% nonneonates w/ permanent neuro sequelae)
Sensorineural hearing loss most common; 5%–10% w/ Hib
Seizures: Up to 30%; neonates > older; recurrent focal sz suggests focal lesion; Rx early w/ phenobarbital vs. phenytoin (less sedating than phenobarb)
Subdural effusions: up to 50% w/ Hib; noted on CT, no Rx unless ↑ ICP; consider aspiration/drainage if persistent fever
Cerebral edema: Steroids, mannitol, diuretics, hypervent; consider pressure monit
Prevention
(MMWR 2005;54:893; Eur J Clin Microbiol Infect Dis 2006;25:90)
Pneumococcal vaccine (PCV-7) → 33%–75% ↓ in invasive pneumococcal disease
MCV-4 conjugate vaccine (covers A, C, Y, W-135 strains (no B); ∼3–5 yr efficacy)
AAP recommends routine vaccination at 11–18 yr or at age 2–10 if increased risk
Hib vaccine → 75+% decrease in Hib meningitis rates
Close contact chemoprophy in N. meningitidis (rifampin, Cipro, CTX) and Hib (rifampin)
Periorbital (Preseptal) and Orbital Cellulitis
Definition
Infxn’s of eyelids, orbit, & surrounding structures. Separated by orbital septum
Periorbital cellulitis is a simple skin infxn and involves structures anterior to septum. Orbital cellulitis is posterior to septum; involves infxn of soft tissues w/i the orbit.
Pathophysiology
(Pediatr Infect Dis J 2002;12:1157)
Periorbital infxn 2/2 direct inoculation of bacteria (trauma, insect bite) or via bacteremia.
Etiology if 2/2 trauma usually skin flora (S. aureus, GAS), if bacteremia; S. pneumo
Orbital infxn generally sinusitis complication w/ infxn extension, rarely 2/2 trauma.
Periorbital cellulitis does not spread and become orbital cellulitis (Pediatr Infect Dis J 2002;12:1157).
Ethmoid sinus most common source; separated from orbit by thin lamina papyracea
Bacteria same as sinusitis (S. pneumo, nontyp H. influ, M. catar, GAS, S. aureus, anaerobes.)
Clinical Manifestations
(Pediatr Infect Dis J 2002;12:1157)
Essential to differentiate the 2 entities; can be challenging as symptoms overlap.
Periorbital cellulitis p/w erythema, induration, tenderness, and warmth of eyelid and periorbital tissue. No limitations or pain w/ eye mvmt. Systemic sx’s infrequently present.
Orbital cellulitis w/ same superficial inflamm, but w/ vision Δ’s, pain w/ and limitation of eye mvmt, chemosis (edema of bulbar conjunctiva) or proptosis. (Pediatr Rev 2004;25:312)
Eye pain can precede signif swelling; impaired ocular mvmt usually w/ upward gaze
Differential
(Pediatr Rev 2004;25:312)
Noninfectious causes of periorbital swelling:
Blunt trauma (black eye), p/w ecchymosis/swelling; ↑ first 48 hr then slowly resolves.
Tumor usually more gradual onset, w/ proptosis but usually no inflammation
Hemangioma of the lid; stereotypical vascular appearance
Ocular tumors (retinoblastoma, choroidal melanomas)
Orbital neoplasms (neuroblastoma, rhabdomyosarcoma)
Allergy w/ either hypersensitivity (more itchy than painful) or angioedema
Local edema 2/2 CHF or hypoproteinemia, usually w/o tenderness.
Infections that can be mistaken for preseptal cellulitis
Dacryoadenitis: Infxn of lacrimal gland w/ sudden and max at onset inflamm at outer upper eyelid (viral [EBV, mumps, CMV, coxsackie, echo, VZV] or bacterial).
Dacryocystitis: Bacterial infxn of lacrimal sac as complication of URI w/ inflamm most prominent at medial corner of the eye.
Hordeolum: Infxn of sebaceous glands at base of eyelashes; meibomian gland abscess.
Diagnostic Studies
No imaging needed with periorbital cellulitis.
CT of orbits/sinuses for orbital cellulitis, esp if persistence or worsening sx’s on appt Rx.
Treatment
(Pediatr Rev 2004;25:312)
For periorbital cellulitis, Rx PO if >1 yo and full vac w/o systemic sx’s to cover Gram+’s, (cephalexin, dicloxacillin, clinda). Good outpt f/u. Duration of Rx: 7–10 d.
For orbital cellulitis, Rx w/ IV Abx against potential pathogens.
Amp/sulbactam ≥200 mg/kg/d divided q6h. Add vancomycin if HA-MRSA suspected. Duration of Rx depends on clinical picture; usually 3 wk (w/ 1st 5–7 d parenterally).
Pts w/ large, well-defined abscess, ophthalmoplegia and/or visual impairment, or those w/o clinical improvement w/ 24–48 hr of IV Abx usually require surgical drainage of abscess and involved sinuses. (J Fam Pract 2007;56:662)
Acute Otitis Media
Definition
(Pediatrics 2004;113:1451)
AAP guidelines require Hx acute onset of signs/sx’s, presence middle ear effusion on exam, and signs/sx’s of middle ear inflammation for diagnosis.
Epidemiology
(Pediatr Rev 2004;25:187)
Accounts for ∼20% of pedi clinic visits and for most outpt Abx prescriptions.
50% of pediatric patients will have 1st episode of AOM before 6 mo, 90% by 2 yr.
Risk factors: atopic dz, low socioeconomic status, immune def, craniofacial abn (cleft palate), genetic syndr (Downs), day care, siblings, smoke exposure, pacifier use, bottle feeding, 1st AOM before 6 mo.
Pathophysiology
Middle ear connected to nasopharynx by Eustachian tubes, drain middle ear secretions and protect middle ear from nasopharyngeal secretions.
Eustachian tube obstruction and drainage impairment more common in children; more horizontal, less stiff and surrounded by lymphoid follicles (inflamed w/ URI)
W/ obstruction, nasopharyngeal secretions reflux into middle ear → infection
E. tube dysfunction → negative pressure → sterile middle ear effusion
Micro: S. pneumo (25%–50% cases, 50% resistant, 20% resolve spont), H. influ (25% cases, 40% w/ β-lactamase activity, 50% resolve spont), and M. cat (12.5% cases, 100% w/ β -lactamase, 80% resolve spont) (Pediatr Rev 2004;25:187)
Differential Diagnosis
Distinguished from simple otitis media w/ effusion (OME); fluid in middle ear space but no acute inflamm (otalgia or erythema of the TM).
Otitis externa (swimmer’s ear) bacterial infxn involving inflamm and skin breakdown of external ear canal. (Pediatr Rev 2007;28:77)
Peak btw 7–12 yo and most common agents are P. aeruginosa and S. aureus.
Exam w/ pain on pushing tragus or pulling pinna, edema in canal w/ secretions
Rx focuses on pain control and topical Abx (fluoroquinolones are Rx of choice)
Clinical Manifestations and Physical Exam
(Pediatrics 2004;113:1451)
Rapid onset signs and sx’s; otalgia, otorrhea, and/or fever; may be irritability in infant.
Prospective studies show sx’s present in 90% of children w/ AOM but in also in 72% of those w/o. (Pediatr Rev 2004;25:187)
Middle ear effusion (MEE) via otoscopy; w/ bulging tympanic membrane (TM), ↓ mobility TM, TM air fluid level, or otorrhea. Can be benign finding w/ URI.
Bulging TM has the highest predictive value for presence of MEE.
For MEE to indicate AOM, need middle ear inflamm (erythema of TM or otalgia).
Dx Studies
Generally none. Definitive dx via tympanocentesis (rarely). (Pediatr Rev 2004;25:187)
Treatment
(Pediatrics 2004;113:1451)
Pain; Rx w/ Tylenol/ibuprofen and/or topical agents in pts >5 yo (Auralgan).
Observe w/o Abx (Abx at 1st visit ↓ course 1 d in 5%–14% vs Abx adverse rxn in 5%–10%):
Applies in pts 6 mo–2 yo where dx uncertain and nonsevere, pts >2 yo where dx uncertain, and pts >2 yo where dx certain but nonsevere.
Antibiotics: In all pts <6 mo; pts 6 mo–2 yo w/ certain dx or w/ uncertain dx and severe illness; or failure to improve after 24–72 hr obs w/o Abx.
Choice of Abx:
At dx or clinical failure following obs w/o Abx: Amoxicillin at 80–90 mg/kg/d.
Amox/clav (90 mg/kg/d amox) in severe dz (temp >39°C and mod/sev otalgia)
At clinical failure after 48–72 hr of initial Abx Rx: amox/clav (90 mg/kg/d amox)
Ceftriaxone ×3 d, in severe disease (temp >39°C and mod/sev otalgia)
Complications
(Pediatr Rev 2004;25:187)
TM perforation is most common complication, seen in 5% of patients
Antibiotic drops are suggested if perforation is present, but no clear data for this
Persistent drainage or prolonged perforation is an indication for ENT referral
MEE (otitis media w/ effusion) persists following AOM normally, if it persists it can increase the risk for language delay due to partial hearing loss.
If effusion persists >3 mo, if child has >4 episodes of AOM in 6 mo or >5 in 12 mo, then formal hearing evaluation is recommended.
Consensus for tympanostomy tubes for children w/ persistent effusion bilaterally, >3 mo, >4 episodes AOM in 6 mo or >5 in 12 mo; no data supports this.
Mastoiditis rare but is most common serious complication of AOM; p/w fever, mastoid tenderness, displacement of the ear anteriorly.
Other much less common complications include bacteremia, meningitis, and abscess.
Lymphadenitis
Definition
Enlarged, inflamed, lymph node(s); also see Oncology section for more details
Clinical Manifestations
(Pediatr Rev 2000;21:399)
Hx: Duration, laterality, location, exposures (TB, kittens, uncooked meat), dental probs, vaccination Hx, B symptoms (F/C/S, weight loss), recent illness, travel
Etiology
(N Engl J Med 1963;268:1329)
| Infectious Cervical Lymphadenitis in Children | |
|---|---|
| Position and Time Course | Etiologies |
| Unilateral – acute | S. aureus or Group A strep (up to 80%), strep pyogenes, GBS (infants), tularemia, anaerobes |
| Unilateral – subacute/chronic | Mycobacteria (TB vs. atypical), Bartonella henselae (CSD), toxoplasmosis |
| Bilateral – acute | Viral URI, Group A strep, enterovirus, adenovirus, influenza, EBV, CMV, Mycoplasma pneumoniae. |
| Bilateral – subacute/chronic | EBV, CMV, HIV, toxoplasmosis |
Noninfectious causes: Neoplasms, Kawasaki, PFAPA Periodic Fever, Apthous stomatitis, Pharyngitis, Adenitis, CTD’s, Kikuchi dz, branchial cleft cyst, cystic hygroma
Diagnostic Studies
Unilateral (acute) → if mod sx’s, FNA for Cx. If severe → US/CT, I&D, Bcx
Bilateral (acute) → usually no w/u necessary as likely viral
Unilateral/bilateral (subacute/chronic) → consider CBC/diff, ESR, PPD, serologies for EBV/CMV/Bartonella/Tularemia, HIV, excisional biopsy
Management
Unilateral (acute) → Abx cover for Staph, GAS, +/- oral flora; if mild sx’s → cephalexin, clinda, amox/clav, TMP-SMX (if CA-MRSA prevalence high). If mod/severe sx’s, consider IV cefazolin, nafcillin, ampicillin/sulbactam, clindamycin, or vancomycin.
Lyme Disease
(Clinical Infectious Diseases 2006;43:1089)
Epidemiology
Most common vector born dz in U.S., ↑ trend; peak incidence in summer
Endemic areas include Northeast and Great Lakes regions, usually in rural, wooded areas (for local prevalences: American Lyme disease foundation: http://www.aldf.com/usmap.shtml)
Most prevalent in children 2–15 yo (Pediatrics 1998;102:905)
Micro
Spirochete Borrelia burgdorferi spread by tick (Ixodes scapularis) on deer and mice.
Coinfection w/ Babesia, and other rickettsial species not uncommon (up to 10%), may contribute to prolonged sx’s despite Rx for Lyme.
Infection usually requires tick attachment >36 hr
Clinical Manifestations
| System | Stage 1 (early localized – wk) | Stage 2 (early disseminated – mo) | Stage 3 (late chronic – yr) |
|---|---|---|---|
| Cardiac | N/A | AV block; myoperi-carditis, pancarditis | N/A |
| Constitutional | Flulike sx’s | Malaise; fatigue | Fatigue |
| Lymphatic | Regional LAD | Regional or generalized LAD | N/A |
| MSK | Myalgia | Migratory arthralgias, myalgias, oligoarthritis | Prolonged/recurrent arthritis, synovitis |
| Neurologic | Headache | Meningitis, Bell’s palsy, cranial neuritis, mononeuritis multiplex, transverse myelitis | Encephalopathy, polyneuropathy, leukoencephalitis |
| Cutaneous | Erythema Migrans (∼80%), macular lesions with central clearing, 6–40 cm | Multiple annular lesions | Lymphocytoma; acrodermatitis chronica atrophicans, panniculitis |
| (N Engl J Med 2001;345:115; Lancet 2003;362:1639; Ann Intern Med 2002;136:421) | |||
Diagnostic Studies
Clinical dx during early stages (erythema migrans), Ab against B. burgdorferi not detectable w/i first few weeks after infection.
In early disseminated or late dz, dx based on clinical findings and serologic tests.
2-step approach: 1st, screening test for serum Ab’s (IFA or EIA).
If +, then standardized Western blot (False +’s 2/2 EBV, other spirochete, HIV, SLE).
Early dz, IgG and IgM; late dz, IgG (lots of IgM false +).
+ IgM test needs 2 of 3 bands (Ab’s). A + IgG test requires 5 of 10 bands.
Note: Rx’d individuals early in course of infection might not develop Ab’s.
PCR and culture not recommended.
Treatment
Prophylaxis: RCT (>12 yo) w/ efficacy doxycycline 200 mg × 1 w/i 72 hr of tick bite (must have seen and removed tick) to prevent Lyme dz (N Engl J Med 2001;345:79)
Recommended treatment of Lyme disease in children (Lyme Disease. Red Book 2006:428)
| Disease Category | Drug(s) and Doses1 |
|---|---|
| Early Localized Disease1 | |
| >8 yo | Doxycycline 100 mg PO BID × 14–21 d2 |
| All ages | Amoxicillin 50 mg/kg/d PO divided t.i.d. (max 1.5 g/d) for 14–21 d -OR- Cefuroxime 30 mg/kg/d PO divided b.i.d. (max 1 g/d) for 14–21 d |
| Early disseminated and late disease | |
| Multiple erythema migrans | Same oral regimen as for early localized dz but for 21 d |
| Isolated facial palsy | Same oral regimen as for early localized dz but for 21–28 d3,4 |
| Arthritis | Same oral regimen as for early localized dz but for 28 d3,4 |
| Persistent or recurrent arthritis5 | Ceftriaxone 75–100 mg/kg IV or IM qd (max 2 g/d) for 14–28 d -OR- Penicillin, 300,000 U/kg/d IV, divided q4h (max 20 million U/d) for 14–28 d -OR- Same oral regimen as for early disease |
| Carditis | Ceftriaxone or penicillin: see persistent or recurrent arthritis |
| Meningitis/encephalitis | Ceftriaxone6 or penicillin: see persistent or recurrent arthritis for 14–28 d |
| 1For pts who are allergic to PCN, cefuroxime, and erythromycin are alternative drugs. 2Tetracyclines contraindicated in pregnancy. 3Corticosteroids should not be given. 4Rx has no effect on the resolution of facial nerve palsy; its purpose is to prevent late disease. 5Arthritis not considered persistent or recurrent unless objective evidence of synovitis exists at least 2 mo after Rx initiated. Some experts administer 2nd course of oral agent before using IV antimicrobial agent. 6Ceftriaxone should be administered IV for treatment of meningitis or encephalitis. | |
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