What is the differential diagnosis for generalized malaise?

Differential Diagnosis for Generalized Malaise

The differential diagnosis for generalized malaise is extensive and requires systematic evaluation prioritizing life-threatening conditions first, followed by infectious, inflammatory, metabolic, and psychiatric etiologies, with depression being the most common diagnosis when organic causes are excluded. 1

Immediate Life-Threatening Conditions to Exclude First

• Severe malaria should be considered in any patient with fever and travel history to endemic areas, as it can present initially with non-specific flu-like symptoms including malaise, headache, and vomiting before progressing to life-threatening complications. 2
• Guillain-Barré syndrome presents with malaise, fatigue, and poorly localized pain that can precede the onset of weakness, particularly in young children who may present with irritability and refusal to bear weight. 2, 3
• Cardiovascular sequelae of COVID-19 should be considered when malaise persists beyond 4 weeks after mild acute infection, particularly when accompanied by exercise intolerance, palpitations, or dyspnea. 2

Post-Infectious and Chronic Fatigue Syndromes

• Post-acute sequelae of SARS-CoV-2 infection (PASC) affects 10-30% of individuals following COVID-19, with one-third reporting persistent symptoms including tiredness, shortness of breath, and chest pain lasting 12 weeks or longer. 2
• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is defined by substantial impairment in function lasting more than 6 months with profound fatigue not alleviated by rest, post-exertional malaise, and unrefreshing sleep, plus either orthostatic intolerance or cognitive impairment. 2, 4, 5
• Postural orthostatic tachycardia syndrome (POTS) presents with malaise, fatigue, weakness, lightheadedness, and exercise intolerance, with heart rate increasing >30 beats per minute after 5-10 minutes of standing. 2

Infectious Etiologies

• Tuberculosis presents with chronic malaise, fever, night sweats, weight loss, and extreme fatigue lasting weeks to months, particularly in patients with travel to endemic regions or close TB contact. 6
• Histoplasmosis causes constitutional symptoms including malaise and fatigue in patients with exposure to Ohio/Mississippi River valleys or bird/bat droppings. 6
• Brucellosis is characterized by undulating fever with profound sweats, malaise, and arthralgias in patients with livestock exposure or unpasteurized dairy consumption. 6
• Visceral leishmaniasis presents with chronic malaise, fever, weight loss, and splenomegaly in patients with sandfly exposure in endemic areas. 6
• Viral infections including Epstein-Barr virus, cytomegalovirus, and human herpesvirus can trigger prolonged malaise and have been reported to precede ME/CFS. 2

Inflammatory and Autoimmune Conditions

• Rheumatoid arthritis causes overwhelming malaise and fatigue through inflammatory cytokines, hypothalamic-pituitary-adrenal axis dysfunction, dysautonomia, and monoamine disturbances. 7
• Immune-related adverse events from checkpoint inhibitors can present with malaise as part of polymyalgia-like syndrome, inflammatory arthritis, or myositis, typically with elevated inflammatory markers. 2
• Sarcoidosis may present with malaise and fatigue, either asymptomatically discovered or as part of Löfgren's syndrome, with higher incidence in northern Europeans and African Americans. 6

Metabolic and Endocrine Disorders

• Hypothyroidism, diabetes mellitus, vitamin B12 deficiency, and electrolyte disturbances should be screened with TSH, HbA1c, vitamin B12, and comprehensive metabolic panel. 3
• Acute kidney injury can present with malaise, nausea, fluid retention, and change in mental status, occurring in 9.9-29% of patients on immune checkpoint inhibitors. 2

Hematologic and Oncologic Causes

• Lymphoma presents with malaise accompanied by B symptoms (fever, night sweats, weight loss) plus painless lymphadenopathy and bulky mediastinal adenopathy on imaging. 6
• Anemia (hemoglobin <100 g/L) causes malaise and fatigue, particularly in the context of malaria or chronic disease. 2

Psychiatric Etiologies

• Depression is the most frequent etiology in patients with unexplained general malaise syndrome and should be the first consideration when organic causes are excluded. 1
• Generalized anxiety disorder causes malaise with worries about real-life concerns that are less irrational than obsessive-compulsive disorder but can be debilitating. 2

Diagnostic Approach Algorithm

Initial Assessment

• Obtain detailed history focusing on: duration of symptoms, travel and geographic exposure, infectious contacts, medication history (especially statins, immunosuppressants, checkpoint inhibitors), occupational exposures, and psychiatric symptoms. 2, 6
• Perform targeted physical examination assessing: vital signs, orthostatic changes, lymphadenopathy, splenomegaly, muscle strength, reflexes, cranial nerve function, and signs of autonomic dysfunction. 2

First-Tier Laboratory Testing

• Complete blood count, comprehensive metabolic panel, liver enzymes, creatine kinase, thyroid-stimulating hormone, vitamin B12, erythrocyte sedimentation rate, and C-reactive protein. 2, 3
• Thick and thin blood films if any travel to malaria-endemic areas, processed urgently with three negative films 12 hours apart to exclude malaria. 2
• HIV testing in patients with persistent or recurrent symptoms, particularly if accompanied by thrush or unexplained weight loss. 8

Second-Tier Testing Based on Clinical Suspicion

• Mycobacterial testing (sputum/tissue AFB smear and culture) and fungal testing (urine/serum Histoplasma antigen) if chronic symptoms with fever, night sweats, or weight loss. 6
• Cerebrospinal fluid analysis and electrodiagnostic studies if progressive weakness or neurologic symptoms suggesting Guillain-Barré syndrome. 2, 3
• Cardiopulmonary exercise testing if post-exertional malaise is prominent and ME/CFS is suspected. 9
• Serum ACE level and chest imaging if sarcoidosis is suspected based on bilateral hilar adenopathy. 6

Critical Pitfalls to Avoid

• Do not dismiss malaise as purely psychological without excluding organic causes, as depression diagnosis requires exclusion of medical conditions that could explain symptoms. 1
• Do not wait for complete diagnostic certainty before treating life-threatening conditions like severe malaria or Guillain-Barré syndrome, as delays can be fatal. 2
• Do not overlook immunocompromised status, as these patients have atypical presentations with higher dissemination risk for infections and may have multiple concurrent conditions. 6, 8
• Do not attribute persistent post-viral malaise to deconditioning alone without considering PASC, ME/CFS, or POTS, particularly if symptoms worsen with exertion. 2, 4
• Recognize that malaise may be the only presenting symptom of serious conditions before more specific signs develop, requiring close monitoring and low threshold for further investigation. 2, 1