What is the initial workup and treatment for a patient presenting with fever, night sweats, and weight loss?

Initial Workup for Fever, Night Sweats, and Weight Loss

Begin with a chest X-ray, complete blood count with differential, inflammatory markers (ESR/CRP), comprehensive metabolic panel including liver enzymes and LDH, HIV testing, and tuberculosis screening (TST or IGRA), as these constitute the essential first-line evaluation for this constellation of B symptoms. 1, 2, 3

Immediate Priority: Tuberculosis and HIV Assessment

The combination of fever, night sweats, and weight loss represents classic WHO-endorsed symptoms for tuberculosis screening, particularly in high-risk populations. 4

• Obtain chest radiograph immediately as first-line screening for pulmonary pathology, mediastinal adenopathy, and TB. 1, 2
• Perform tuberculosis screening with either tuberculin skin test (TST) or interferon-gamma release assay (IGRA), especially if the patient has risk factors including immigration from endemic areas, HIV risk factors, incarceration history, or known TB exposure. 4, 1, 2
• If TB screening is positive, rule out active TB with clinical history, physical examination, chest radiograph, and submit three sputum specimens for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing. 1
• HIV testing is essential given the strong association with night sweats, opportunistic infections, and the need to assess for HIV-related TB. 4, 1, 2

Critical TB Context

In HIV-positive patients eligible for antiretroviral therapy, the prevalence of pulmonary TB can be as high as 32%, with the WHO-endorsed symptom screen (any one symptom) being more sensitive than cough alone for detecting TB. 4

Essential Laboratory Studies

Complete the following baseline laboratory evaluation:

• Complete blood count with differential to evaluate for cytopenias, leukocytosis, or abnormal cells suggesting hematologic malignancy. 1, 2, 3
• Inflammatory markers (ESR and CRP) to assess for systemic inflammation. 1, 2, 3
• Comprehensive metabolic panel including liver enzymes, alkaline phosphatase, lactate dehydrogenase (LDH), and albumin. 1, 2, 3
• Thyroid-stimulating hormone (TSH) to rule out hyperthyroidism as a cause of night sweats and weight loss. 1

Physical Examination Priorities

Focus your examination on these high-yield findings:

• Thorough lymph node examination of all lymphoid regions (cervical, supraclavicular, axillary, inguinal) to identify painless adenopathy suggestive of lymphoma. 1, 2, 3
• Hepatosplenomegaly assessment through abdominal palpation. 2, 3
• Skin examination for rashes, lesions, Kaposi sarcoma, and molluscum contagiosum. 2
• Oropharyngeal examination for candidiasis and oral hairy leukoplakia. 2

Advanced Imaging: When and What to Order

If initial workup is unrevealing or suggests malignancy:

• Contrast-enhanced CT of chest and abdomen should be performed to evaluate for lymphadenopathy, organomegaly, or masses, particularly if lymphoma is suspected. 1, 3
• For patients with recent thoracic, abdominal, or pelvic surgery, perform CT in collaboration with the surgical service if fever etiology is not readily identified. 4
• PET/CT scan should be considered if lymphoma is strongly suspected based on clinical presentation, as it has high sensitivity for bone marrow involvement and can guide biopsy. 1, 3

Important Imaging Caveat

Bilateral hilar adenopathy without B symptoms is highly specific for sarcoidosis and may not require biopsy in the right clinical context. 2

Tissue Diagnosis When Indicated

If lymphadenopathy is present:

• Excisional or incisional lymph node biopsy is preferred over fine-needle aspiration, with fresh tissue sent for pathology, flow cytometry, and cytogenetics. 1, 3
• Fine-needle aspiration alone is insufficient except in unusual circumstances. 3

If blood counts are abnormal or lymphoma/leukemia is suspected:

• Bone marrow biopsy should be considered with fibrosis grading and molecular testing. 1, 3

Risk-Stratified Approach for Persistent Symptoms

Consider escalating workup if:

• Persistent symptoms despite negative initial workup. 2
• Development of additional B symptoms or worsening clinical status. 2
• Abnormal laboratory findings suggesting hematologic malignancy (cytopenias, elevated LDH, abnormal differential). 2
• High clinical suspicion for lymphoma based on examination findings (painless adenopathy, hepatosplenomegaly). 2, 3

Common Diagnostic Pitfalls

Avoid these errors:

• Do not dismiss tuberculosis in patients without classic risk factors, as TB can present atypically. 4
• Do not rely on fine-needle aspiration alone for lymph node evaluation when lymphoma is suspected. 3
• Do not overlook HIV testing even in patients without obvious risk factors, as HIV significantly increases TB risk and changes management. 4, 1
• Initial biopsy interpretation can be incorrect in primary liver lymphoma, which may be misdiagnosed as poorly differentiated carcinoma. 5

Specific Disease Considerations

If Lymphoma is Suspected

Document the presence of B symptoms (fever, drenching night sweats, unexplained weight loss >10% over 6 months) as these indicate more advanced disease and poorer prognosis. 1, 3 Look for painless regional or diffuse lymphadenopathy, hepatosplenomegaly, or extranodal involvement. 1, 3 Assess for oncologic emergencies including superior vena cava syndrome, respiratory compromise, or spinal cord compression. 1

If Tuberculosis is Confirmed

A three-drug regimen of rifampin, isoniazid, and pyrazinamide is recommended for the initial 2-month phase, with a fourth drug (streptomycin or ethambutol) added if INH resistance likelihood is not very low or if community INH resistance rates exceed 4%. 6 Treatment should continue with rifampin and isoniazid for at least 4 additional months, longer if the patient remains sputum/culture positive or is HIV-positive. 6