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Fever, Cough, Dyspnea

Slim, Jessica MD, MPH; Wiler, Jennifer L. MD, MBA

doi: 10.1097/01.EEM.0000461015.30707.da
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Dr. Slimis a third-year emergency medicine resident in the Denver Health Emergency Medicine Residency Program. Dr. Wileris an associate professor of emergency medicine and the vice chair of the department of emergency medicine at the University of Colorado School of Medicine. Read her past columns athttp://bit.ly/WilerConsult.

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A 38-year-old, previously healthy man presented with a several-week history of intermittent fever, cough, exertional dyspnea, and a heart rate in the 110s. His examination was remarkable for moderate diffuse crackles on auscultation. A chest x-ray was obtained. What is the differential diagnosis, and what is the next step in the patient's evaluation?

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Diagnosis: AIDS

The patient's chest x-ray shows multiple, well-circumscribed opacities that are most concerning for metastatic disease, including familial breast cancer, testicular cancer, renal cell carcinoma, and lymphoma. An infectious etiology, including septic emboli, is another possibility.

A CT of the chest, abdomen, and pelvis with IV contrast showed no evidence of a primary tumor, but was positive for pulmonary nodules concerning for metastases as well as findings concerning for liver and bone metastases and hepatosplenomegaly. The patient was found to have a new diagnosis of acquired immune deficiency syndrome (AIDS) with a CD4 count of 48 and a viral load greater than 4 million copies/mL, increasing the likelihood of AIDS-associated malignancies. Various opportunistic infections, such as disseminated mycobacterial and fungal infections, were also considered. The patient underwent biopsy of one of his lung nodules, which demonstrated diffuse large B-cell lymphoma (DLBCL), Stage 4BE.

Human immunodeficiency virus (HIV) is known to predispose a person to developing cancer. Three of these are known as AIDS-defining malignancies: Kaposi's sarcoma, non-Hodgkin lymphoma (NHL), and invasive cervical carcinoma. (Curr Opin Oncol 1994;6[5]:489.) The pathogenesis of NHL in HIV is poorly understood. It is thought that T cell immunodeficiency and chronic B cell stimulation, leading to a loss of control of transforming viruses, plays an important role. (Am J Clin Pathol 2005;124[5]:790.)

DLBCL is the most common type of NHL, making up about 30 percent of all lymphomas. It can develop from less aggressive forms of lymphoma or as a first occurrence of lymphoma. This malignancy is found most commonly in the middle-aged or elderly, with the average age of diagnosis being 64. (Blood 2006;107[1]:265.) Risk factors for DLBCL include immunosuppression or immunodeficiency, family history of lymphoma or other hematopoietic malignancy, past radiation or chemotherapy treatment, exposure to certain agricultural pesticides, or infectious agents including HIV, human papilloma virus, Epstein-Barr virus, hepatitis C, and hepatitis B. (Hematol Oncol Clin North Am 2008;22[5]:941.)

The first sign of DLBCL is typically an enlarged lymph node in the neck, groin, or abdomen. Patients may also experience systemic “B” symptoms such as fever, weight loss, and night sweats. DLBCL does not begin in the lymph nodes in about 40 percent of cases but presents as extranodal lymphoma. The most common site of extranodal involvement is the stomach or gastrointestinal tract, but the disease can occur in nearly any tissue. (Br J Haematol 2004;124[2]:151.) Systemic lymphoma in the HIV-positive population is characterized by more frequent B symptoms, extranodal lymphoma, involvement of unusual locations (body cavity, rectum, soft tissue), and advanced stage at diagnosis than lymphoma in the HIV-negative population. (Am J Med 2001;111[9]:704.)

The diagnosis of DLBCL is best made based by excisional tissue biopsy, most commonly a lymph node. Patients who do not present with overt lymphadenopathy may undergo pathologic evaluation of a different tissue (pulmonary nodule, pleural fluid, spleen) for diagnosis. The Ann Arbor staging system with Cotswold modification is used for staging NHL and Hodgkin's lymphoma in HIV-positive and HIV-negative patients. This staging system focuses on the number of tumor sites (nodal and extranodal) and location of the tumor sites relative to the diaphragm. When a stage is assigned, it also includes an A or B to denote the absence (A) or presence (B) of B symptoms. The letter E is added if the disease is extranodal or has spread from lymph nodes to adjacent tissue. Most patients (about 60%) are not diagnosed with DLBCL until the disease is advanced (stage III or IV). (CA Cancer J Clin 2009;55[6]:368.)

The most common chemotherapy regimen for advanced DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Etoposide may be added, resulting in a drug combination called R-EPOCH. This regimen is generally given every three weeks for six to eight cycles in the United States. Patients who do not have an expected response are treated for refractory disease. (Cancer Control 2012;19[3]:204.) The International Prognostic Index tool is used in patients with NHL to determine a score that correlates with progression-free survival and overall survival after standard therapy. It uses patient age, performance status, serum lactate dehydrogenase level, disease stage, and degree of extranodal involvement. (N Engl J Med 1993;329[14]:987.) DLBCL is aggressive and fast-growing, but approximately 60 percent of all patients can be cured with appropriate and timely treatment. (Cancer 2012;118[17]:4173.)

Seventeen months after diagnosis, this patient's CD4 count was 126, and his viral load was undetectable. His PET/CT continues to show no evidence of recurrence.

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