Evaluation And Management Of The Febrile Patient

The differential diagnosis of fever in the early engraft-ment period is broad. Essential considerations include the patient's prior infectious disease history in the preengraftment and pretransplant periods; timing of onset of fever; the presence or absence of localizing signs and symptoms; the presence or absence of GVHD or symptoms suggestive of GVHD; risk of CMV; and current medications. The differential diagnosis for common clinical syndromes is summarized in Table 99.5 and includes both infectious and nonin-fectious causes.

Fever at the time of engraftment raises several special considerations, including engraftment syndrome, which is often accompanied by a diffuse maculopapu-lar rash; acute GVHD; or flare of occult infection as leucocytes return and migrate to a site of inflammation.

Fever in the absence of localizing symptoms during the early postengraftment period has many causes. Bacteremia or fungemia from intravascular devices or from the bowel in patients with GVHD may present without localizing symptoms. Patients with pulmonary

Common causes of fever in the early engraftment period


Common sources, pathogens

Fever at engraftment

Engraftment syndrome Acute GVHD Occult focal infection

Fever without localizing findings

■ Bacteremia

Intravascular devices Staphylococci Gram-negative bacilli Gut GVHD

Gram-negative bacilli Enterococci

■ Fungemia

Intravascular devices Candida species Gut GVHD Candida species

■ Occult pneumonia




■ Viral infections

■ Drug fever

GVHD, bacterial infection CMV, HHV6

Penicillins, cephalosporins, trimethoprim-sulfamethoxazole, vancomycin, phenytoin

Fever and a pulmonary infiltrate

■ Fungal pneumonia

Aspergillosis, Fusariosis, Zygomycosis

Staphylococci, Gram-negative bacilli, Legionellosis CMV, community respiratory viruses

Aspiration, idiopathic interstitial pneumonia, diffuse alveolar hemorrhage

Fever and a pulmonary infiltrate

■ Fungal pneumonia

■ Bacterial pneumonia

■ Viral pneumonia

■ Noninfectious causes

Fever with diarrhea

■ Community viruses

Aspergillosis, Fusariosis, Zygomycosis

Staphylococci, Gram-negative bacilli, Legionellosis CMV, community respiratory viruses

Aspiration, idiopathic interstitial pneumonia, diffuse alveolar hemorrhage fungal infections such as aspergillosis, fusariosis, or zygomycosis may lack cough, dyspnea, and hemoptysis at the outset. Sinusitis from infection or GVHD may be asymptomatic except for fever. CMV infection may present only with fever and must be strongly considered in CMV seropositive allogeneic HSCT recipients and seronegative recipients with a CMV seropositive donor. HSCT recipients who are CMV D-/R- have a small risk of CMV in this period. The concern for reactivation CMV is heightened in at-risk and high-risk individuals who are being followed and monitored prospectively for viremia, rather than receiving prophylaxis from the time of engraftment. Fever without localizing signs or symptoms may also occur as an initial manifestation of adenovirus infection or reactivation of HHV6. Noninfectious causes of fever include early GVHD and new medications. Medications which are most likely to cause drug fever include trimetho-prim-sulfamethoxazole, penicillins, cephalosporins, vancomycin, and phenytoin.

The differential diagnosis of fever and a pulmonary infiltrate includes infectious and noninfectious causes. Infectious causes include bacterial pneumonia (including legionellosis), pulmonary fungal infections, and CRV infections during seasonal outbreaks. Noninfectious causes include diffuse alveolar hemorrhage (though fever may be absent), aspiration pneumonia, and idiopathic interstitial pneumonia.

In patients with fever and diarrhea, concerns include GVHD, CMV or adenovirus enterocolitis, C. difficile-associated diarrhea, and community-acquired viral gastroenteritis caused by rotavirus, Norwalk virus, or coxsackievirus during seasonal outbreaks. Diarrhea is infectious in origin in a minority of HSCT patients during this period.

The differential diagnosis of fever and rash depends upon the appearance of the rash. If maculopapular, concerns include engraftment syndrome, acute GVHD (especially if the rash involves the palms and soles), drug reaction, and reactivation of HHV6. A papulopus-tular rash consisting of only a few scattered lesions should suggest disseminated candidiasis. Nodular skin lesions may occur with disseminated aspergillosis or fusariosis, disseminated cryptococcosis, and nocardio-sis. The latter two infections are rare following HSCT, especially in the early postengraftment period, and are generally encountered beyond 100 days. A vesicular rash should suggest HSV or VZV, the latter being uncommon between days 30 and 100.

The diagnostic evaluation should be tailored based upon the presence or absence of localizing signs and symptoms to suggest a source of fever. Blood cultures for bacterial pathogens are indicated in most patients. In those with clinical clues as to the cause of fever, additional cultures and imaging studies may be pursued. In those without localizing findings, blood cultures should be obtained from each lumen of indwelling vascular devices and peripherally. Fungal blood cultures should be collected if unexplained fever persists. Patients at-risk for CMV infection should be tested using the pp65 antigenemia assay, polymerase chain reaction, or hybrid capture for CMV viremia. Computed tomo-graphic scans of the sinuses, chest, and abdomen should be considered in search of occult sinusitis, occult pulmonary infiltrates, and thickening of the bowel wall suggestive of GVHD or infectious enterocolitis. Biopsy for histopathologic examination and culture may establish a diagnosis in patients with rash; vesicular lesions should be unroofed and scraped for viral culture. In patients with fever and pulmonary infiltrates, bron-choscopy should be strongly considered.

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