What are constitutional symptoms?

Constitutional Symptoms: Definition and Clinical Significance

Constitutional symptoms are a cluster of systemic manifestations that include fever, night sweats, unintentional weight loss, and profound fatigue/weakness, which serve as critical markers of underlying systemic disease and warrant systematic evaluation for malignancy, autoimmune disorders, or chronic infection. 1

Core Components

The four primary constitutional symptoms are:

• Fever – typically low-grade and persistent, often without an identifiable infectious source 1
• Night sweats – defined as drenching perspiration requiring change of clothing or bedding 1
• Unintentional weight loss – defined as >5% of body weight over 6 months, or >10% over 6 months in more severe presentations 1
• Fatigue or weakness – characterized as profound exhaustion not relieved by rest 1

Additional manifestations that may accompany these core symptoms include:

• Anorexia 2, 3
• Myalgias 4
• Lymphadenopathy 5

Clinical Significance and Disease Associations

Constitutional symptoms indicate systemic disease burden and correlate directly with prognosis across multiple disease states. 1

Hematologic Malignancies

• In lymphomas, these symptoms are formally designated as "B symptoms" and serve as important prognostic markers 1
• Constitutional symptoms with lymphadenopathy mandate evaluation for acute lymphoblastic leukemia, chronic lymphocytic leukemia, or lymphoma with bone marrow involvement 6
• In Waldenström macroglobulinemia, fever, night sweats, and fatigue are formal diagnostic criteria for disease progression 1

Solid Tumors

• In Ewing sarcoma and bone malignancies, constitutional symptoms may be present at diagnosis and correlate with elevated LDH and leukocytosis 1
• Malignant pleural effusion commonly presents with fever, chills, fatigue, weakness, and weight loss as prominent features 1
• Digestive tract malignancies account for 51.3% of all malignant tumors presenting with constitutional syndrome 3

Autoimmune Diseases

• Weight loss >2 kg, low-grade fever, fatigue, and night sweats are key clinical findings in active giant cell arteritis or Takayasu arteritis 1

Myeloproliferative Neoplasms

• Development of >10% weight loss in 6 months, night sweats, and unexplained fever >37.5°C represents diagnostic criteria for post-polycythemia vera or post-essential thrombocythemia myelofibrosis 1

Etiologic Spectrum

The causes of constitutional symptoms can be categorized into three major groups 2:

• Malignant neoplasms – account for 35% of cases, with digestive tract tumors being most common 3
• Psychiatric diseases – account for 24.3% of cases 3
• Non-neoplastic organic diseases – primarily digestive tract diseases including peptic disease 3

Diagnostic Approach

The presence of constitutional symptoms mandates systematic evaluation for underlying malignancy, autoimmune disease, or chronic infection. 1

Initial Laboratory Workup

• Complete blood count with differential 1
• Serum lactate dehydrogenase (LDH) 1, 7
• Inflammatory markers: ESR and CRP 1
• Comprehensive metabolic panel including liver function tests 6

Advanced Evaluation When Indicated

• Cross-sectional imaging: CT chest/abdomen/pelvis with contrast 1
• Bone marrow examination for patients with chronic constitutional symptoms, cytopenias, and lymphadenopathy 6
• Flow cytometry and immunophenotyping for lymphoproliferative disorder classification 6
• Cytogenetic studies for prognostic stratification 6

Additional Testing Based on Clinical Context

• Morning hormonal panel (TSH, free T4, cortisol, ACTH) when fatigue predominates 7
• EBV serology and quantitative PCR if chronic active EBV infection suspected 7
• Hepatitis B and C screening, HIV testing 6

Prognostic Implications

The presence and severity of constitutional symptoms correlate directly with disease burden, treatment urgency, and overall prognosis. 1

• In Ewing sarcoma, absence of constitutional symptoms at presentation indicates favorable prognosis 1
• In lymphoproliferative disorders, constitutional symptoms trigger risk stratification changes and treatment initiation 1
• In myeloproliferative neoplasms, development of constitutional symptoms defines disease transformation to more aggressive phases 1

Important Clinical Caveats

• Constitutional symptoms are strongly related to health-related quality of life across all domains (physical function, emotional well-being, and social function) 4
• In approximately 9% of cases, constitutional syndrome may be self-limited without identifiable underlying disease 3
• The basic pathophysiological process involves amino acid mobilization from muscle (proteolysis), which reduces muscle mass and can be life-threatening 8
• Treatment depends primarily on identifying and addressing the underlying etiology 2