FEVER
| WORK-UP OF THE FEBRILE IMMUNOCOMPROMISED PATIENT —Kimberly A. Howerton, MD, Assistant Professor,
Department of Family Medicine, University of Tennessee Health Sciences Center, Jackson
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| Risk for febrile illness in immunocompromised patients: high risk—patients with hematologic malignancies
who have absolute neutrophil count (ANC) <500/µL; bone marrow transplant recipients; AIDS patients (who have already
had opportunistic infections); children with congenital immune deficits; intermediate risk—patients with solid tumors
or solid organ transplants; HIV-infected patients (who have not yet developed opportunistic infections); low risk—
patients with autoimmune diseases, eg, rheumatoid arthritis (RA); diabetics; patients with cirrhosis; history of long-term
corticosteroid use (eg, patients with chronic obstructive pulmonary disease; those on <40 mg/day at lower risk)
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| Febrile neutropenic patient: defined by single temperature >101.3°F or sustained temperature >100.4°F for >1 hr;
exceptions—elderly patients, patients with history of long-term steroid use (may be so immunocompromised, they cannot
mount fever; may instead present with hypothermia, hypotension, or rapid clinical deterioration); risk factors—
ANC <100/µL; rapid decline in ANC; neutropenia >7 days; hospitalization for comorbid conditions; peripheral or central
venous lines
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| Patient evaluation: history—duration of immunocompromised state (longer the duration, greater the risk for infection);
comorbid conditions (ask patients with RA when they last had infusion of infliximab [Remicade]); history of pulmonary
pathogens in previous hospital admissions; travel or occupational exposure (over lifetime); previous therapeutic
or prophylactic antibiotic use; physical examination (PE)—rapid assessment of vital signs, including oxygen (O2 ) saturation;
complete unclothed PE, including sinuses, fundi, skin (look for subtle erythema), mucous membranes, perirectum
and perineum (do not do rectal examination unless highly suspicious of that area; may seed new infection); locate
and inspect chronic indwelling catheters (tenderness and mild erythema at site may indicate infection of skin overlying
catheter; inability to infuse or withdraw through catheter may indicate abscess); after starting antibiotic therapy, must repeat
review of symptoms and PE daily (patient may localize infection until immunocompromised state improved); laboratory
studies—com-plete blood cell count; comprehensive panel; cultures (urine; blood from each intravenous port
and at least 1 peripheral site); lumbar puncture (LP) if central nervous system involvement suspected; sputum samples;
nasal washings or swabs; radiologic examinations—initial chest x-ray (CXR) mandatory for every patient; if symptoms
or any signs suggesting respiratory illness present, do chest computed tomography (CT); other possible studies (imaging
of sinuses, abdomen, pelvis); additional studies—stool studies if patient has diarrhea; Clostridium difficile
toxin; skin biopsy; because these patients often cannot produce sputum, invasive procedure, eg, bronchoscopy, may be
necessary
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| Common pathogens: bacterial—with use of prophylactic antibiotics and current therapies, common bacterial pathogens
have largely shifted from gram-negative to gram-positive organisms (eg, Staphylococcus aureus; anaerobic bacteria
not common source of fever but should be considered in cases of pelvic infection; consider reactivation of
tuberculosis (TB); fungal—extremely common; include yeast (eg, Candida) and Aspergillus; reactivation of endemic
fungi acquired during travel (eg, histoplasmosis; blastomycosis; coccidiodomycosis); risk for fungal infection increases
with rounds of chemotherapy and duration of neutropenia; viral—HSV types 1 and 2; varicella zoster; cytomegalovirus
(acquired from blood transfusion); Epstein-Barr virus; respiratory syncytial virus (RSV); influenza
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| Common infections: in neutropenic patients with hematopoietic malignancy—urinary tract infection (UTI); skin
and soft tissue; perineal and perirectal; in patients with solid tumors—pulmonary infections most common
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| Pulmonary infections: CXR clues to diagnosis—acute onset of consolidation (bacterial infection); subacute consolidation
(fungal, TB, nocardial infection); peribronchial or interstitial pattern indicates subacute viral infection, pneumonia
(Pneumocystis jirovecii—[formerly carinii] pneumonia [PCP]), or rejection of lung transplant; large nodular legions
(fungal or nocardial); CT clues to diagnosis—cavitary lesions (Mycobacteria, Aspergillus, Pseudomonas, Klebsiella
infections common); peripheral opacified secondary lobules (Aspergillus); peribronchial opacities (PCP, viral infection,
allograft rejection, fluid overload); additional clues—peripheral lesions on CXR (result of bacteremia); hypoxemia with
increased lactate dehydrogenase activity and minimal CXR findings (PCP); absence of hypoxemia, with consolidation
(TB, early fungal infections)
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| Treatment: fever in immunocompromised patient is medical emergency; patient must be rapidly evaluated and treatment
started quickly (before he or she leaves emergency department [ED]); initiate broad-spectrum antibiotics as soon as possible
(timing critical)
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| Treatment recommendations based on 2002 Infectious Disease Society of America (IDSA) guidelines:
start with empiric antibiotic therapy; monotherapy and dual therapy equally effective (monotherapy with
cefepime, ceftazidime, imipenem, or meropenem; for dual therapy, use aminoglycoside plus antipseudomonal β-lactam
antibiotic or cephalosporin); vancomycin should not be routinely used (indicated only in cases of hypotension, skin or
catheter site infections, history of patient-specific methicillin-resistant S aureus colonization, or recent quinolone prophylaxis)
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| Duration of treatment: known source of fever—treat for normal duration for this infection; unknown source—if fever
resolves and ANC increases to >500/µL, switch to oral antibiotics after 2 days, and stop all antibiotics after 3 days; if
patient becomes afebrile but remains neutropenic, continue antibiotics for 1 wk after patient becomes afebrile; if patient
remains febrile >5 days, add empiric antifungal agent; if patient started on vancomycin remains febrile after 3 days and
cultures negative, stop drug; if after starting antifungal agent, patient becomes afebrile, stop everything after 4 to 5 days;
if ANC remains <500/µL, must continue treatment for 2 wk)
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| Antifungal treatments: include amphotericin (gold standard; not well tolerated; better options exist); caspofungin (associated
with slightly higher survival rate 7 days after starting therapy; much less likely to cause nephrotoxicity, infusion-
related events, or cessation due to lack of tolerance); itraconazole (contraindicated in patients with creatinine clearance
<30 mL/min; not well tolerated; many drug interactions); fluconazole not recommended
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| Caveats: catheter removal required in patients who have candidemia or bacteremia with S aureus or Pseudomonas, or
colonization with atypical mycobacteria; patients must be admitted
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| FEVER IN INFANTS: WHICH ALGORITHM IS BEST ?—Deborah A. Levine, MD, Assistant Professor of Pediatrics
and Emergency Medicine, New York University School of Medicine, New York
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| Case example: 7-wk-old boy (full term); brought in with history of fever at home but afebrile in ED (rectal temperature
101°F for 1 day); feeding well; nasal congestion; findings on PE—appearance nontoxic; heart rate 170 bpm, respiratory
rate normal; chest clear; capillary refill normal; fontanelle flat; mucous membranes moist; score of 6 on Yale Observation
Scale (YOS); laboratory data—RSV positive; white blood cell (WBC) count 14,000/µL with left shift; urinalysis negative;
no WBCs on lumbar puncture; CXR negative
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| Febrile infants <3 mo of age: at highest risk for serious bacterial infection (SBI); “essentially immunocompromised”;
missed SBIs have potential for devastating sequelae (eg, neurologic injury and death); these babies difficult to
assess clinically; SBIs—meningitis; bacteremia; UTI (most common SBI in this age group); bone or joint infection;
bacterial gastroenteritis
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| Yale Observation Scale: one of most widely used objective scores for assessing risk for SBI in children ≤2 yr of age;
score <10 indicates low risk for SBI, score >16 indicates high risk; reported to have moderate predictive value (sensitivity
77%, specificity 88%); however, in studies of infants <1 mo of age, objective scores have failed to predict SBI; Baker
et al found YOS not very effective when applied to febrile infants 1 to 2 mo of age (sensitivity only 33%, negative predictive
value [NPV] 91%); to identify infants at low risk for SBI, apply combination of clinical and laboratory criteria
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| Rochester criteria: goal—to identify infants at low risk for sepsis; children had to be previously healthy (full term; no
perinatal complications, underlying disease, or prior antibiotics) and have no focal infection on PE; criteria—WBC
count 5000 to 15,000 cells/mm3 ; absolute band count <1500/mm3 ; urinalysis (UA) ≤10 WBC per high-power field;
≤25 WBC per high-power field in stool
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| Boston criteria: goal—to identify low-risk infants who could be managed with outpatient therapy; applied to infants 1
to 3 mo old who were febrile and nontoxic; patients could not have focal infection on PE; all received complete sepsis
evaluation; criteria—objective observation score; WBC cutoff 20,000 cells/mm3 ; UA ≤10 WBC per high-power field
(or negative dipstick); ≤10 WBC/mm3 in cerebrospinal fluid (CSF); CXR negative (if done at discretion of physician);
503 infants in patient cohort met low-risk criteria (most 1-2 mo of age); 5.4% had missed SBIs (NPV 94.5%); all treated
with intramuscular ceftriaxone and sent home
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| Philadelphia criteria: goal—to identify infants who could be sent home without antibiotic therapy; criteria applied to
febrile infants 1 to 2 mo of age (patients had to have no focal bacterial infection on PE; Infant Observation Score ≤10; no
immunodeficiency); all patients had complete sepsis evaluation; criteria—objective observation score; WBC count
<15,000 cells/mm3 ; band-to-neutrophil ratio <0.2; UA <10 WBC/high-power field; <8 WBC/mm3 in CSF; CXR negative
(if done based on respiratory symptoms); patient cohort had 747 infants, 28 of whom had bacteremia and meningitis; 287
met low-risk criteria (1 missed SBI with bacteremia; sensitivity 98%; NPV 99%); using retrospective database, criteria
applied to cohort of febrile infants 0 to 1 mo of age (109 babies identified as low risk; 5 had SBIs that would have been
missed by criteria; NPV 95.4%)
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| Pittsburgh criteria: applied to retrospective cohort of febrile infants 0 to 2 mo of age who were previously healthy; criteria
used enhanced UA (uncentrifuged urine; hemocytometer cell count and Gram stain) to identify children at risk for
UTI
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| Clinical decision rule: based on statistically derived computer model; authors used retrospective database of febrile infants
0 to 2 mo of age (no information from clinical examination); found positive UA, age <13 days, temperature
≥39.6°C, and WBC count >20,000 or ≤41,000/mm3 placed child at high risk for SBI; authors reported sensitivity of 82%
and NPV of 98%, but did miss 1.7% of SBIs
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| Risk for SBI in bronchiolitis: study looked at prospective cohort of febrile infants ≤24 mo of age, with small subgroup
≤2 mo of age (36 patients with bronchiolitis, 50 controls); no positive blood or urine cultures found in bronchiolitis
group (not statistically significant due to small numbers)
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| Risk for SBI and RSV: in multicenter prospective study of febrile infants ≤60 days of age, rate of SBI lower in babies
who tested RSV positive (7%) vs infants who were RSV negative (12.5%); rate of UTI also lower (5.4% in RSV-positive
vs 10.1% in RSV-negative infants); no difference in rates of bacteremia or meningitis; no difference in rate of SBI in infants
0-28 days of age
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| Is LP necessary? unclear (no data); not part of Rochester criteria (applied to large number of patients in multiple studies;
no cases of missed meningitis and no adverse outcomes without CSF evaluation; authors believe most pleocytosis
nonbacterial); LP included in Boston and Philadelphia protocols (author of Philadelphia protocol has reported identifying
case of Haemophilus influenza type B meningitis based solely on CSF pleocytosis)
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| Is CXR necessary? early 1990s study of febrile infants 0 to 2 mo of age concluded highly unlikely to get positive
CXR if patient does not have respiratory signs and symptoms; study by speaker et al looked for predictors of pneumonia
in cohort of 1200 febrile infants; 40% of patients had CXR (and of these, 6% had lobar pneumonia); logistic
regression analysis showed rales, high respiratory rate, and high band count predictors for pneumonia (however,
some cases still missed and some of those children had upper respiratory infections)
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| Is empiric therapy indicated? Rochester criteria and Philadelphia protocol both state children at low risk can be sent
home without therapy (both groups have had some cases of missed SBIs; all these children have reportedly done well
with delayed therapy; however, numbers of patients small, so unclear what effect delayed therapy might actually have on
outcome); Boston criteria advocates treatment even if child can be sent home (LP included in criteria; group has had one
delayed diagnosis of osteomyelitis; child ultimately did well)
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| Is hospitalization necessary? unclear; known that iatrogenic complications can occur; study by Baker et al comparing
children who were hospitalized without treatment vs those who were sent home without therapy found higher rate of
complications in inpatient group
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| Practice guidelines: for infants 0 to 1 mo of age—complete sepsis evaluation; hospitalize; observe or treat (decision
to give empiric antibiotics based on whether child meets published low-risk criteria); for infants 1 to 3 mo of age—
option 1 (full sepsis evaluation; LP; treat; discharge with close follow-up); option 2 (blood and urine cultures; if child
meets low-risk criteria based on results, child can be safely discharged without antibiotics; LP optional)
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Suggested Reading
Bachur RG, Harper MB: Predictive model for serious bacterial infections among infants younger than 3 months of
age. Pediatrics 108:311, 2001; Baker MD: Evaluation and management of infants with fever. Pediatr Clin North Am
46:1061, 1999; Baker MD et al: Outpatient management without antibiotics of fever in selected infants. N Engl J Med
329:1437, 1993; Baker MD, Bell LM: Unpredictability of serious bacterial illness in febrile infants from birth to 1
month of age. Arch Pediatr Adolesc Med 153:508, 1999; Bergman DA et al: Does clinical presentation explain practice
variability in the treatment of febrile infants? Pediatrics 117:787, 2006; Bodey GP, Rolston KV: Management of
fever in neutropenic patients. J Infect Chemother 7:1, 2001; Byington CL et al: Serious bacterial infections in febrile
infants 1 to 90 days old with and without viral infections. Pediatrics 113:1662, 2004; Herr SM et al: Enhanced urinalysis
improves identification of febrile infants ages 60 days and younger at low risk for serious bacterial illness. Pediatrics
108:866, 2001; Hsiao AL, Baker MD: Fever in the new millennium: a review of recent studies of markers of serious
bacterial infection in febrile children. Curr Opin Pediatr 17:56, 2005; Jaskiewicz JA et al: Febrile infants at low risk
for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative
Study Group. Pediatrics 94:390, 1994; Klastersky J: Management of fever in neutropenic patients with different
risks of complications. Clin Infect Dis 39 Suppl 1:S32, 2004; Kuppermann N: Respiratory syncytial virus
infection and the risk of serious bacterial infections. Arch Pediatr Adolesc Med 156:1055, 2002; Kuppermann N et
al: Risks for bacteremia and urinary tract infections in young febrile children with bronchiolitis. Arch Pediatr Adolesc
Med 151:1207, 1997; Lee I, Barton TD: Viral respiratory tract infections in transplant patients: epidemiology, recognition
and management. Drugs 67:1411, 2007; Levine DA et al: Multicenter RSV-SBI Study Group of the Pediatric
Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk of serious bacterial
infection in young febrile infants with respiratory syncytial virus infections. Pediatrics 113:1728, 2004; Ohyashiki K:
Monotherapy versus dual therapy based on risk categorization of febrile neutropenic patients. Clin Infect Dis 39 Suppl
1:S56, 2004; Pantell RH et al: Management and outcomes of care of fever in early infancy. JAMA 291:1203, 2004;
Rolston KV: Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients
with cancer and neutropenia. Clin Infect Dis 40 Suppl 4:S246, 2005; Rolston KV: The Infectious Diseases Society of
America 2002 guidelines for the use of antimicrobial agents in patients with cancer and neutropenia: salient features and
comments. Clin Infect Dis 39 Suppl 1:S44, 2004; Sipsas NV et al: Perspectives for the management of febrile neutropenic
patients with cancer in the 21st century. Cancer 103:1103, 2005; Titus MO, Wright SW: Prevalence of serious
bacterial infections in febrile infants with respiratory syncytial virus infection. Pediatrics 112:282, 2003; Venkatesan P
et al: Evaluation and management of fungal infections in immunocompromised patients. Dermatol Ther 18:44, 2005;
Viscoli C et al: Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin
Infect Dis 40 Suppl 4:S240, 2005.
Educational Objectives
| The goal of this program is to improve the evaluation and treatment of the febrile immunocompromised patient and
the management of the young infant with fever. After hearing and assimilating this program, the clinician will be better
able to:
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 | 1. Stratify the risk for febrile illness in immunocompromised patients.
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| 2. Obtain a thorough patient history and perform a complete physical examination when evaluating the immunocompromised
patient who presents with fever.
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| 3. Explain and follow the recommended treatment guidelines for managing fever in immunocompromised patients.
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| 4. Discuss various protocols and criteria that have been developed to identify infants at low risk for serious bacterial
infection.
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| 5. Cite the practice guidelines for managing infants ≤90 days of age with fever.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee members
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Levine has received grant support from Roche
Pharmaceuticals, MedImmune Inc, and Sanofi-Aventis. Dr. Howerton and the planning committee reported nothing to disclose.
Acknowledgements
Dr. Howerton spoke at the Symposium on Critical Care and Emergency Medicine, held March 29-31, 2007, in Hot Springs,
AR and sponsored by the University of Arkansas for Medical Sciences College of Medicine and the University of Tennessee Health
Sciences Center College of Medicine. Dr. Levine was recorded at Contemporary Concepts in Clinical Emergency Medicine,
held June 6-8, 2007, in New York, NY, and sponsored by the New York University School of Medicine, Department of Emergency
Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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