What is the differential diagnosis for a patient presenting with night sweats, nausea, and fatigue?

Differential Diagnosis for Night Sweats, Nausea, and Fatigue

Life-Threatening Conditions to Exclude First

The most critical diagnoses to rule out immediately are tuberculosis, lymphomas (particularly Hodgkin and non-Hodgkin), and HIV infection, as these present with this symptom triad and require urgent intervention. 1, 2, 3

Malignancies

• Hodgkin Lymphoma presents classically with B symptoms (fever, night sweats, weight loss >10% over 6 months) along with fatigue, and may include lymphadenopathy, splenomegaly, or hepatomegaly on examination 1, 2, 3
• Non-Hodgkin Lymphomas including diffuse large B-cell lymphoma and marginal zone lymphomas commonly manifest with this symptom constellation 2
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma where night sweats, fatigue, and weight loss are specific indications for initiating treatment 1
• Acute Lymphoblastic Leukemia presents with constitutional symptoms including night sweats, fatigue, and nausea, often with easy bruising or bleeding 1
• Waldenström's Macroglobulinemia frequently presents with B symptoms and warrants serum immunoglobulin level testing 2, 3

Infectious Diseases

• Tuberculosis is critical to exclude, particularly in high-risk populations (close TB contact, TB-endemic countries, prisons, homeless shelters, long-term care facilities, immunocompromised status), presenting with night sweats, weight loss, prolonged cough, hemoptysis, and fatigue 1, 3, 4
• HIV infection must be considered, especially when accompanied by fever and weight loss 3, 4
• Granulomatosis with Polyangiitis (GPA) presents with relatively minor upper respiratory symptoms associated with disproportionate unwellness, fatigue, weight loss, and night sweats heralding generalized disease 1

Common Non-Malignant Causes

Endocrine and Metabolic

• Hyperthyroidism is a frequent cause requiring thyroid-stimulating hormone testing 5, 4
• Hypoglycemia should be considered, particularly in patients on diabetes medications 4
• Menopause in appropriate age groups is a common benign cause 5

Gastrointestinal

• Gastroesophageal reflux disease (GERD) is an underrecognized but important cause of night sweats that responds excellently to anti-reflux treatment 5, 6, 4

Other Common Causes

• Mood disorders including anxiety and panic attacks are frequently associated with night sweats 5, 4
• Obstructive sleep apnea should be considered, particularly in obese patients 5, 4
• Obesity itself is associated with night sweats 5
• Medications including antihypertensives, antipyretics, and drugs of abuse (alcohol, heroin) may cause this symptom complex 4

Diagnostic Algorithm

Initial Evaluation

Obtain focused history on: duration and pattern of symptoms, weight loss quantification (>10% body weight over 6 months is significant), TB risk factors, HIV risk factors, medication review, alcohol use, and associated symptoms including lymphadenopathy, cough, hemoptysis, or bleeding 1, 2

Physical examination must include: thorough examination of all lymphoid regions, spleen, liver, and assessment for hepatosplenomegaly 1, 2

First-Line Laboratory and Imaging Studies

Order these tests systematically for all patients without obvious clinical diagnosis: 5, 4

• Complete blood count with differential 1, 2, 5
• Tuberculosis testing (PPD or interferon-gamma release assay) 1, 5, 4
• HIV testing 3, 5, 4
• Thyroid-stimulating hormone 5, 4
• Comprehensive metabolic panel (liver and kidney function) 2, 3
• Erythrocyte sedimentation rate or C-reactive protein 5, 4
• Chest radiography 1, 5, 4

Additional Testing Based on Initial Results

• If chest X-ray is abnormal or high TB suspicion with normal X-ray in immunocompromised patients: CT chest with contrast 1
• If lymphadenopathy present: Excisional lymph node biopsy (not fine-needle aspiration alone) for tissue diagnosis 2
• If Waldenström's suspected: Serum immunoglobulin levels 3
• If hepatitis risk factors present: Hepatitis B and C screening 3
• If initial workup negative: Consider CT chest/abdomen, bone marrow biopsy, or polysomnography selectively 5, 4

Critical Pitfalls to Avoid

• Do not dismiss night sweats as benign without systematic evaluation, as tuberculosis and lymphoma remain important diagnoses despite being less common in modern practice 4
• Chest radiography may be deceptively normal in immunocompromised patients (particularly AIDS patients with low CD4 counts), warranting CT imaging with high clinical suspicion 1
• Fine-needle aspiration alone is insufficient for lymphoma diagnosis; excisional biopsy is required 2
• ANCA testing for GPA has only 50% sensitivity in limited disease or after corticosteroid therapy, so negative ANCA does not exclude the diagnosis 1
• If specific clinical diagnosis is apparent initially, offer targeted treatment for 4-8 weeks before extensive workup 5
• If all testing is normal and no additional disorders suspected, reassurance and monitoring are appropriate, as night sweats alone do not indicate increased mortality risk 5