System-Specific Syndromes

Skin infections: Skin lesions of various types are common in pts with cancer and may be the first sign of bacterial or fungal sepsis, particularly in neutropenic pts (those with <500 functional neutrophils/µL).
- - Cellulitis: most often caused by group A Streptococcus and Staphylococcus aureus. Unusual organisms (e.g., Escherichia coli, Pseudomonas, fungi) may be involved in neutropenic pts.
- - Macules or papules: due to bacteria (e.g., Pseudomonas aeruginosa causing ecthyma gangrenosum) or fungi (e.g., Candida)
- - Sweet's syndrome or febrile neutrophilic dermatosis: Most often seen in neutropenic pts (particularly those with acute myeloid leukemia), it presents as red or bluish-red papules or nodules that form sharply bordered plaques; high fever; and an elevated ESR. The skin lesions are most common on the face, neck, and arms.
- - Erythema multiforme with mucous membrane involvement: Often due to HSV infection, it is distinct from Stevens-Johnson syndrome, which is associated with drugs and has a more widespread distribution. Both conditions are common in pts with cancer.
- - Drug rashes: Rashes associated with drugs, particularly cytokines used in cancer therapy, complicate the differential diagnosis of rashes in pts with cancer.
Catheter-related infections: Exit-site infections, often with erythema around the insertion site, are most common.
- - Infections caused by coagulase-negative staphylococci can often be treated medically without catheter removal.
- - Infections caused by other organisms, including S. aureus, P. aeruginosa, Candida, Stenotrophomonas, and Bacillus, usually require catheter removal.
- - If a red streak develops over the SC part of a “tunneled” catheter, the device must be removed to prevent extensive cellulitis and tissue necrosis.
Upper GI infections: Breakdown of mucosal surfaces due to chemotherapy and infection is common.
- - Oral mucositis is associated with viridans streptococci and HSV.
- - Oral candidal infections (thrush) are common.
- - Esophagitis can be caused by Candida albicans and HSV.
Lower GI infections: Transmigration of bowel flora across the intestinal epithelium can lead to severe conditions.
- - Chronic disseminated candidiasis: results from seeding of organs (e.g., liver, spleen, kidneys) during neutropenia in pts with hematologic malignancy and generally presents symptomatically when neutropenia resolves. Pts have persistent fever unresponsive to antibiotics, abdominal pain, and increased alkaline phosphatase levels. Although biopsies may reveal granulomas, yeasts, or pseudohyphae, the diagnosis is often made on the basis of radiographic studies (CT, MRI). Treatment should be directed to the causative agent; C. albicans is usually responsible, but C. tropicalis or other Candida species are sometimes involved.
- - Typhlitis (necrotizing colitis): more common among children than among adults and among pts with acute myeloid leukemia or acute lymphocytic leukemia than among pts with other forms of cancer. Pts have fever, RLQ tenderness, and diarrhea that is often bloody. The diagnosis is confirmed by documentation of a thickened cecal wall via imaging. Treatment should include antibiotics directed against bowel flora and surgery (in the case of perforation).
CNS infections: The susceptibility of pts to specific infections depends on whether they have prolonged neutropenia, defects in cellular immunity (e.g., due to high-dose glucocorticoid therapy or cytotoxic chemotherapy), or defects in humoral immunity (e.g., pts with chronic lymphocytic leukemia, those who have previously undergone splenectomy or bone marrow transplantation [BMT]).
- - Meningitis: Consider Cryptococcus or Listeria, particularly for pts with defects in cellular immunity. Pts with defects in humoral immunity are also at risk for infection with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
- - Encephalitis: Pts with defects in cellular immunity are particularly prone to infection with VZV, JC virus (the cause of progressive multifocal leukoencephalopathy), CMV, Listeria, HSV, and human herpesvirus type 6.
- - Brain masses: most often present as headache with or without fever or neurologic abnormalities. Pts with prolonged neutropenia are at increased risk for a brain abscess due to Aspergillus, Nocardia, or Cryptococcus. Pts with defects in cellular immunity are at increased risk for infection with Toxoplasma and EBV (lymphoproliferative disease). A definitive diagnosis may require a biopsy.
Pulmonary infections: Pneumonia can be difficult to diagnose in immunocompromised pts, given that many of the conventional findings (e.g., purulent sputum, physical findings suggestive of chest consolidation) rely on the presence of neutrophils. Radiographic patterns of infiltration can help narrow the differential diagnosis.
- - Localized infiltrate: Consider bacterial pneumonia (including Legionella and mycobacteria), local hemorrhage or embolism, and tumor.
- - Nodular infiltrate: Consider fungal infection (e.g., Aspergillus, Mucor), Nocardia infection, and recurrent tumor. In pts with Aspergillus infection, hemoptysis may be an ominous sign. A biopsy performed with direct visualization may be required for definitive diagnosis.
- - Diffuse infiltrates: Consider infection with viruses (particularly CMV), Chlamydia, Pneumocystis, Toxoplasma, or mycobacteria. Viruses that cause URIs in immunocompetent hosts (e.g., influenza, respiratory syncytial) can cause fatal pneumonitis in immunocompromised pts. Noninfectious causes include radiation pneumonitis, CHF, diffuse alveolar hemorrhage (after BMT), and drug-induced lung injury (e.g., bleomycin, alkylating agents).
Renal and ureteral infections: These infections are usually associated with obstructing tumor masses.
- - Candida has a predilection for the kidneys, reaching this site via either hematogenous seeding or retrograde spread from the bladder. Persistent funguria should prompt a search for infection in the kidney (e.g., fungus ball).
- - BK virus and adenovirus can cause hemorrhagic cystitis.

Approach to the Patient: Febrile Neutropenia

Approach to Diagnosis and Treatment of Febrile Neutropenic Pts Figure 79-1 presents an algorithm for the diagnosis and treatment of pts with febrile neutropenia.

The initial regimen should be refined on the basis of culture data; surface cultures of skin and mucous membranes may be misleading.
Adding antibiotics to the initial regimen is not appropriate unless there is a clinical or microbiologic reason to do so. Administering additional antibiotics for fear of a gram-negative infection (e.g., “double coverage,” synergistic addition of aminoglycosides to β-lactam therapy) does not enhance efficacy (but does increase toxicity), even for infections involving P. aeruginosa.
For empirical antifungal treatment, amphotericin B deoxycholate is being supplanted by liposomal formulations of amphotericin B, newer azoles (e.g., voriconazole or posaconazole), and echinocandins (e.g., caspofungin). Echinocandins are useful against infections with azole-resistant Candida.
Clinical experience related to antiviral therapy is most extensive with acyclovir for HSV and VZV infections. Newer agents (e.g., cidofovir, foscarnet) with a broader spectrum of action have heightened the focus on treatment of viral infections.
- - Prophylactic antibiotics (e.g., fluoroquinolones) in pts expected to have prolonged neutropenia or antifungal agents (e.g., fluconazole) in pts with hematopoietic stem cell transplants (see below) may prevent infections. Pneumocystis prophylaxis is mandatory for pts with acute lymphocytic leukemia and for those receiving glucocorticoid-containing regimens.

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