What is the differential diagnosis for a patient presenting with fever, fatigue, and weight loss?

Differential Diagnosis for Fever, Fatigue, and Weight Loss

The differential diagnosis for a patient presenting with fever, fatigue, and weight loss must prioritize life-threatening conditions including tuberculosis, lymphoma (particularly Hodgkin lymphoma), HIV infection, and other hematologic malignancies, as these B symptoms (fever, night sweats, weight loss >10% over 6 months) significantly increase concern for serious pathology. 1, 2

Life-Threatening Conditions (Evaluate First)

Tuberculosis

• Most critical infectious diagnosis, particularly in high-risk populations 2
• Look for: chronic cough, hemoptysis, night sweats, exposure history, geographic risk factors 3, 2
• Initial workup: chest X-ray, three sputum specimens for acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing 4
• Perform tuberculin skin test (TST) or interferon-gamma release assay (IGRA) 4

Lymphoma (Hodgkin and Non-Hodgkin)

• Classic presentation with B symptoms: fever, drenching night sweats, weight loss >10% over 6 months 4, 2
• Examine for: painless lymphadenopathy (regional or diffuse), hepatosplenomegaly, extranodal involvement 4
• Screen for oncologic emergencies: superior vena cava syndrome, respiratory compromise, spinal cord compression 4
• Definitive diagnosis requires excisional lymph node biopsy with fresh tissue for pathology, flow cytometry, immunophenotyping, and cytogenetics 4
• Contrast-enhanced CT of neck, chest, and abdomen to evaluate lymphadenopathy and organomegaly 4
• PET/CT has high sensitivity for bone marrow involvement and guides biopsy 4

HIV Infection

• Must be considered, especially with associated fever and weight loss 3, 4
• HIV testing should be performed in all patients with unexplained constitutional symptoms 4

Other Hematologic Malignancies

• Acute myeloid leukemia (AML): associated with high mortality, particularly in patients >60 years, active disease, or pneumonia 3
• Myeloproliferative disorders: post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis 1, 4
• Look for: constitutional symptoms (>10% weight loss in 6 months), increasing splenomegaly, leukoerythroblastic peripheral blood picture 4
• Bone marrow biopsy with fibrosis grading and molecular testing if blood counts abnormal 4

Infectious Diseases

Tickborne Rickettsial Diseases

• Rocky Mountain Spotted Fever (RMSF), ehrlichioses, anaplasmosis 3
• Query regarding: tick exposure, outdoor activities, pet illness (dogs can serve as sentinels) 3
• Laboratory findings: thrombocytopenia, leukopenia, elevated liver enzymes 3
• Critical pitfall: Rash may be absent initially; do not wait for rash to initiate treatment if clinical suspicion high 3

Other Viral Syndromes

• Consider: Epstein-Barr virus, cytomegalovirus, adenovirus, enterovirus 3
• Particularly in patients with recent illness exposure or foodborne illness 3

Bacterial Infections

• Brucellosis: insidious onset of fever, night sweats, fatigue, anorexia, weight loss, headache, arthralgia 3
• Endocarditis: particularly if cardiac risk factors present 3

Malignancies Beyond Lymphoma

Waldenström's Macroglobulinemia

• Night sweats listed as clinical indication for initiating therapy 2
• Serum immunoglobulin levels should be assessed 2

Solid Tumors

• Weight loss and fatigue are common presenting symptoms across various malignancies 3, 4
• Chest X-ray as initial screening for pulmonary pathology 4

Autoimmune/Inflammatory Conditions

Autoinflammatory Syndromes

• Consider if recurrent fevers with systemic inflammation 3
• Evaluate for: rash, arthritis, bone lesions, granulomatous disease 3
• Important: Rule out other PIDDs, autoimmune disease, or malignancy first 3

Kawasaki Disease (in appropriate age group)

• Fever persisting ≥5 days with polymorphous exanthem, conjunctival injection, oral changes 3
• More common in children but can occur in young adults 3

Endocrine Disorders

Hyperthyroidism

• TSH testing mandatory to rule out 4
• Presents with weight loss, fatigue, heat intolerance 4

Other Endocrine Causes

• Hypothyroidism, hypogonadism, adrenal insufficiency, hypopituitarism 3
• Particularly in patients receiving immunotherapy 3

Chronic Non-Bacterial Osteitis (CNO)

• Consider if bone pain present with systemic symptoms 3
• Requires imaging (MRI preferred) showing bone marrow edema, sclerosis in typical sites 3

Essential Initial Workup

Laboratory Studies (Perform Immediately)

• Complete blood count with differential: evaluate for cytopenias, leukocytosis, abnormal cells 4
• ESR and CRP: assess for inflammation 4
• Comprehensive metabolic panel: liver enzymes, alkaline phosphatase, LDH, albumin 4
• TSH: rule out thyroid dysfunction 4
• HIV testing and TB screening (IGRA or TST) 4
• Urinalysis for protein, blood, glucose 3

Imaging Studies

• Chest X-ray: initial screening for pulmonary pathology 4
• Consider contrast-enhanced CT of neck, chest, abdomen if lymphadenopathy or organomegaly suspected 4

Additional Testing Based on Findings

• Bone marrow biopsy if blood counts abnormal or lymphoma/leukemia suspected 4
• Hepatitis B and C screening if risk factors present 2
• Blood, urine, stool cultures if sepsis suspected 3

Critical Clinical Pitfalls to Avoid

• Do not dismiss nonspecific symptoms: thrombocytopenia and leukopenia with worsening clinical condition should prompt immediate consideration of encephalitis, sepsis, or hematologic malignancy 3
• Do not wait for complete symptom constellation: lymphoma patients may not present with all B symptoms simultaneously 4
• Do not overlook geographic and exposure history: essential for tickborne diseases and endemic infections 3, 4
• Do not delay empiric treatment for RMSF if suspected: mortality increases significantly with delayed treatment 3
• Screen for treatable contributing factors: pain, emotional distress, sleep disturbances, nutritional imbalance, anemia, electrolyte disturbances 3, 4