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 first, including tuberculosis, malignancy (particularly lymphoma and myeloproliferative neoplasms), infectious endocarditis, and tickborne rickettsial diseases, followed by systemic inflammatory conditions and chronic infections.

Immediate Life-Threatening Considerations

Tickborne Rickettsial Diseases

• Initiate doxycycline 100 mg twice daily immediately if rickettsial disease is suspected based on geographic exposure, outdoor activities, or characteristic laboratory findings (thrombocytopenia, leukopenia, elevated transaminases), without waiting for serologic confirmation 1
• Most patients do not recall tick bites, so absence of documented exposure does not exclude diagnosis 1
• Early treatment within the first 3 days is critical to prevent mortality 1

Tuberculosis

• Consider tuberculous disease, particularly in endemic areas or with risk factors for exposure 2
• A "probable" diagnosis can be made with proof of TB elsewhere in the body combined with unexplained fever, night sweats, and weight loss 2
• Constitutional symptoms include fever, night sweats, and weight loss >10% in 6 months 2
• Obtain chest radiograph, sputum cultures, and consider pericardial or other site-specific evaluation based on clinical presentation 2

Infectious Endocarditis

• Obtain at least two sets of blood cultures (one peripheral, one from central line if present) before initiating antibiotics 1
• Brucellosis presents with acute or insidious onset of fever, night sweats, undue fatigue, anorexia, weight loss, headache, and arthralgia 2

Malignancy

Myeloproliferative Neoplasms

• Constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C) are diagnostic criteria for post-polycythemia vera and post-essential thrombocythemia myelofibrosis 2
• These symptoms indicate advanced disease and warrant immediate hematologic evaluation 2
• Obtain complete blood count with differential, peripheral blood smear, and bone marrow biopsy if cytopenias or splenomegaly present 2

Lymphoma and Other Hematologic Malignancies

• Night sweats combined with fever and weight loss constitute "B symptoms" that increase suspicion for lymphoma 3
• Serum immunoglobulin levels should be obtained if Waldenström's macroglobulinemia is suspected 3
• Consider CT imaging of chest, abdomen, and pelvis to evaluate for lymphadenopathy and organomegaly 1

Systemic Inflammatory and Autoimmune Conditions

Polymyalgia Rheumatica

• Typically presents in patients >60 years with proximal muscle pain, but constitutional symptoms including fatigue and weight loss can occur 4
• Measure inflammatory markers (ESR and CRP), which are typically elevated 4
• Obtain rheumatoid factor and anti-CCP antibodies to exclude rheumatoid arthritis 4

Autoinflammatory Syndromes

• Febrile attacks associated with rash, abdominal pain, or joint pain suggest familial Mediterranean fever, TRAPS, or hyper-IgD syndrome 2
• Consider genetic testing for pyrin, TNF receptor I, and MVK if recurrent febrile episodes with these features 2
• Rule out other causes of recurrent inflammation including malignancy and autoimmune disease before pursuing autoinflammatory diagnosis 2

Chronic Infections

Geographic and Travel-Related Infections

• Document travel within the past year to tropical/subtropical regions, as most tropical infections become symptomatic within 21 days of exposure 1
• Malaria must be ruled out in patients from endemic areas with three malaria tests performed over 72 hours 1
• Obtain hepatitis B and C screening if risk factors are present 3

HIV and Opportunistic Infections

• Consider HIV testing in all patients with unexplained constitutional symptoms 2
• Opportunistic infections may present with cyclic fever patterns in immunocompromised patients 1

Essential Initial Workup

Laboratory Assessment

• Complete blood count with differential to assess for leukopenia, thrombocytopenia, anemia, or leukocytosis 1
• Comprehensive metabolic panel with liver function tests to evaluate for elevated transaminases and renal dysfunction 1, 3
• Inflammatory markers: ESR and CRP 4
• Blood cultures (minimum two sets) before antibiotics 1
• Chest radiograph 1

Advanced Imaging When Initial Workup Non-Diagnostic

• CT chest/abdomen/pelvis for patients with recent surgery, unexplained fever, or concern for occult malignancy 1
• CT is particularly sensitive for posterior-inferior lung base pathology and small nodular/cavitary lesions 1
• Consider 18F-FDG PET/CT if other diagnostic tests fail and patient is stable for transport 1

Special Population Considerations

Immunocompromised Patients

• Maintain lower threshold for hospitalization and empiric antimicrobial therapy 1
• Consider opportunistic infections and atypical presentations of common infections 1

Young Women

• Night sweats warrant thorough evaluation including the workup outlined above 3
• Consider endocrine disorders and obtain comprehensive metabolic panel 3

Critical Pitfalls to Avoid

• Never delay doxycycline for suspected rickettsial disease while awaiting serologic confirmation 1
• Do not assume absence of tick bite excludes rickettsial disease 1
• Early serologic testing for rickettsial diseases is often negative; treatment decisions must be based on clinical findings 1
• Do not overlook constitutional symptoms as diagnostic criteria for myeloproliferative neoplasms 2
• Nonspecific autoantibodies can be present in autoinflammatory conditions and should not automatically redirect diagnosis toward autoimmune disease 2