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A 68-year-old man was transferred to our institution from an outside hospital because of ongoing daily fevers. His medical history was notable for stage IVB diffuse large B-cell lymphoma (DLBCL), diagnosed 2 months previously. The patient was admitted to the outside hospital 3 days after receiving the second cycle of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Vital signs were normal with the exception of a temperature of 39.4°C. Physical examination findings were remarkable for a 9×3-cm hematoma on the left upper extremity at the site of intravenous (IV) infiltration from a previous hospitalization and a healing stage II decubitus ulcer. Laboratory studies revealed the following (reference ranges shown parenthetically): hemoglobin, 7.4 g/dL (13.5-17.5 g/dL); leukocyte count, 0.4 × 109/L (3.5-10.5 × 109/L); platelet count, 12 × 109/L (150-450 × 109/L); alkaline phosphatase, 275 U/L (45-115 U/L); creatinine, 0.6 mg/dL (0.8-1.3 mg/dL); lactate dehydrogenous, 229 U/L (122-222 U/L); and normal levels of aspartate aminotransferase, alanine aminotransferase, and total bilirubin.
The patient's hematologic history was notable for DLBCL diagnosed 2 months previously. The International Prognostic Index score was 5/5 (high risk)1 because of the patient's age (>60 years), elevated lactate dehydrogenase level (which peaked shortly after initiation of the first cycle of R-CHOP at 6000 U/L), performance status of 2 or greater, Ann Arbor clinical stage IV, and more than one extranodal site of involvement. The patient had received 2 cycles of R-CHOP chemotherapy for treatment of lymphoma. The first cycle was complicated by neutropenia that persisted for 3 weeks. During this prolonged neutropenic period, the patient had an Escherichia coli bloodstream infection, Pneumocystis jirovecii pneumonia, and a stage II decubitus ulcer.
At the time of presentation, he had completed all antimicrobial treatment courses but continued to receive trimethoprim-sulfamethoxazole for P jirovecii pneumonia prophylaxis. Other medications included omeprazole and prochlorperazine as needed for nausea. The patient was employed as a travel agent and frequently traveled to Mexico, the last trip being 3 months before the current presentation. His family history was noncontributory.
Gram-negative bacilli were the most commonly identified pathogens in patients with neutropenic fever and hematologic malignancies until the 1980s. Pseudomonas species in particular are associated with one of the highest mortality rates from bacterial pathogens identified in these patients. Recent reexamination of the most common pathogens has shown that gram-positive organisms account for 62% to 76% of bloodstream infections in patients with neutropenic fever.2,3 The most common gram-positive organisms identified include Staphylococcus aureus, Staphylococcus epidermidis, Streptococci species, and viridans group streptococci. Factors leading to an increase in the number of gram-positive pathogens are speculated to include the use of long-term indwelling central venous catheters, use of empirical antibiotics targeted to cover gram-negative organisms, particularly Pseudomonas, and increased use of prophylactic antimicrobials targeting gram-negative organisms. The possible role of the newer chemotherapeutic agents has also been entertained. Anaerobic, atypical, and acid-fast bacteria are not the most commonly identified organisms.
At the outside hospital, blood and urine cultures were obtained. Chest radiography revealed no abnormalities. Cefepime and vancomycin were administered, and the patient underwent successful incision and drainage of the hematoma site.
Antifungal treatment is not warranted on the first day of presentation in a patient with a first episode of neutropenic fever, even if a central IV line is present. Patients are considered at high risk for a fungal infection if they have persistent or recurrent fever 4 to 7 days after initiation of antibiotics or if their expected duration of neutropenia is more than 7 days, even without an identified source of fungal infection.4 Therefore, waiting a month or until a fungal infection has been identified before initiating antifungal therapy is not appropriate.
Despite broad-spectrum antimicrobial therapy, the patient remained febrile, and 5 days later, he was transferred to our hospital for further evaluation. The infectious evaluation from the outside institution was reviewed. Blood cultures had not yielded any organisms. Pyuria was present, and urine culture grew Candida albicans. Cultures obtained from the hematoma also grew C albicans.
Bronchoscopy is used to obtain a microbiologic diagnosis in patients with identified pulmonary infiltrates, which is not the case in this patient. Because patients with neutropenia may not have an inflammatory response that is visible on chest radiography,5 those who have normal chest radiographic findings should undergo CT of the chest when they have persistent fever. Indeed, more than 50% of neutropenic patients with normal chest radiographic findings have evidence of pneumonia on CT.6 Chest CT can identify invasive pulmonary infection, such as invasive mold infections, in neutropenic patients with normal findings on chest radiography. Further, CT of the abdomen and pelvis can identify etiologies of persistent fever such as intra-abdominal abscesses, neutropenic colitis, cholecystitis, or appendicitis. Without symptoms of headache, meningismus, or other neurologic manifestations, pursuing an invasive procedure such as lumbar puncture would not be indicated. Because the cause of the patient's febrile neutropenia has not been identified, further testing is indicated to guide treatment. Echocardiography should be considered in neutropenic febrile patients when clinical suspicion for endocarditis exists but would not be the most appropriate next step in the evaluation of fever in this patient.
After the patient was transferred to our facility, cefepime and vancomycin were continued, and high-dose IV fluconazole was added. Computed tomography of the chest, abdomen, and pelvis revealed innumerable new small hypodense lesions within the liver and spleen. In the context of the patient's history, the imaging findings were consistent with hepatosplenic candidiasis. The patient's neutropenia resolved, and his antimicrobial treatment was narrowed to fluconazole, with discontinuation of other agents.
Growth-stimulating factors are being used with increasing frequency. Current literature supports their use to reduce the incidence of neutropenic fever, to decrease the need for hospitalization for antibiotic therapy, and in some cases to maintain the dose intensity of chemotherapeutic agents.7 The use of growth-stimulating factors has not been associated with an increase in invasive fungal disease. However, invasive fungal disease has been associated with prolonged antibiotic use and the presence of an indwelling catheter. Other diseases resulting in impairment of cellular immunity, such as HIV infection, can be a separate risk factor for invasive fungal disease, largely due to an increased risk for invasive yeast disease. Appropriate screening should be instituted in cases in which other explanations for invasive fungal disease have not been identified. Invasive fungal disease has also been associated with prolonged neutropenia, usually regarded as more than 7 days in duration. Specifically, the duration and magnitude of neutropenia are the most important risk factors for development of invasive mold infection.
Three days after transfer to our hospital, the neutropenia resolved, but the patient continued to have daily fever, with maximum temperatures of 39.4°C. It was confirmed that the patient had recent negative test results for HIV (test was performed at the time of DLBCL diagnosis), given his dramatic and prolonged immunosuppression with R-CHOP.
The patient's findings were consistent with the diagnosis of hepatosplenic candidiasis, but the ongoing febrile episodes remained worrisome. It is not uncommon for disseminated candidiasis to cause persistent fevers for weeks despite appropriate treatment. Other considerations for ongoing fever in the setting of appropriate antifungal therapy included a concurrent infection not covered by fluconazole, a resistant strain of C albicans, or progression of chemotherapy-resistant lymphoma. Susceptibilities from cultures were pending. After discussion with interventional radiology staff and review of the patient's imaging studies, the patient underwent ultrasound-guided aspiration of one of the hypodense lesions in the liver.
With the current use of fluconazole as prophylaxis for certain hematologic diseases, a decrease in superficial candidal infections has been observed.8 A trend toward higher rates of colonization with fluconazole-resistant fungi has been noted, and this should be considered in patients receiving fluconazole prophylaxis.9 Fluconazole has no intrinsic activity against mucormycosis/Rhizopus, Aspergillus, and Fusarium species or against C krusei.
The cultures obtained from the liver biopsy were positive for C albicans, which was susceptible to fluconazole. At 2 weeks after the initial presentation, defervescence occurred, and the patient was discharged home on a regimen of oral fluconazole therapy with planned follow-up in 1 month with an infectious disease specialist and repeated imaging to assess the response to treatment.
Our patient represents an unusual case. The duration of his neutropenia immediately following systemic chemoimmunotherapy was longer than what is usually observed in patients treated with R-CHOP chemotherapy. Rituximab is associated with late-onset neutropenia, but this usually occurs months after treatment. Antifungal prophylaxis is not commonly used in patients treated with R-CHOP because this regimen usually does not result in prolonged neutropenia. Although persistent fever after initiation of appropriate antifungal therapy is commonly seen in patients with hepatosplenic candidiasis, it was not certain whether the fever and new hypodense lesions in our patient represented a systemic fungal infection or resistant lymphoma. An ultrasound-guided biopsy of a hepatic lesion was performed both to direct appropriate antimicrobial therapy and to determine whether R-CHOP should be continued once the patient recovered from his infection.
Hepatosplenic candidiasis is an infectious complication that can be seen in patients with the following risk factors: acute leukemia, the presence of intravascular catheters, administration of broad-spectrum antibiotics, and prolonged neutropenia. Before the use of prophylactic antifungal agents became established, hepatosplenic candidiasis was a common finding in patients with prolonged neutropenia. The typical presentation is that of high spiking fever in the setting of prolonged neutropenia, and right upper quadrant pain may also be present. Laboratory evaluation may reveal an elevated alkaline phosphatase level. Magnetic resonance imaging has been shown to be more specific than CT in diagnosing hepatosplenic candidiasis.10 Characteristic multiple lucencies in the liver, spleen, and sometimes the kidneys are seen on imaging. The lucencies represent microabscesses and may appear to worsen when the patient's neutrophil count recovers. The definitive diagnosis requires tissue biopsy that shows granulomas with yeast. Tissue culture results are commonly negative, especially in the setting of previous antifungal treatment, and negative findings do not rule out the diagnosis of hepatosplenic candidiasis. Patients frequently remain febrile shortly after initiation of appropriate therapy. Liposomal amphotericin B can be used, especially in unstable or severely ill patients, with transition to oral fluconazole therapy for the completion of the total course of treatment. If the patient's condition is stable at diagnosis, fluconazole can be initiated and continued for the duration of therapy. Antifungal therapy should continue until there is a resolution of the lesions on imaging and the patient improves clinically and should be reinstituted if further immunosuppression is expected.
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CORRECT ANSWERS: 1. b. 2. c. 3. b. 4. e. 5. a