How are multisystem diseases diagnosed ?
Diagnosis relies on careful clinical assessment (history and examination) with investigations helping to exclude other pathology including malignancy and infection.
- It can often take time to confirm a diagnosis and this can be a worrying time for the family.
- The fever chart is helpful; certain patterns of fever suggest multisystem disease.
- Investigations include blood tests (such as full blood count, inflammatory markers, autoantibodies), urinalysis (to look for renal involvement), and imaging (such as radiographs, ultrasound and often MRI or CT). Some autoantibodies are more specific for rheumatic illnesses and, in particular, connective tissue diseases and vasculitis. This can be helpful as some autoantibodies can essentially confirm the diagnosis (e.g ds DNA antibodies in Juvenile Systemic Lupus Erythematosus [JSLE]). However, some autoantibodies (e.g ANA) are present in normal healthy children or after transient illness (such as viral infection).
- A persistently positive ANA can be associated with JSLE, drug-induced lupus, undifferentiated connective tissue disease, Sjögrens Syndrome, Juvenile Dermatomyositis, Scleroderma and Systemic Sclerosis. Other autoantibodies suggest specific diagnoses or risk of disease complications. Examples are given below:
- Anti-double Stranded DNA Antibodies (dSDNA); highly specific for JSLE and detected in lupus nephritis. Other extractable nuclear antigens (including anti RNP antibodies, anti-Sm antibodies, anti-Ro and anti-La antibodies) occur in JSLE.
- Antiphospholipid Antibodies may occur in primary antiphospholipid syndrome, JSLE and some vasculitides. They can also occur with viral infections and be drug induced. They can associate with arterial or venous thrombosis, recurrent abortions, or unexplained thrombocytopenia.
- Anti-neutrophil Cytoplasmic Antibodies (ANCAs) can be detected in chronic infection (including TB, viral hepatitis and HIV), malignancy, inflammatory bowel disease and can be drug-induced. Specific types can be observed in certain vasculitides e.g PR3-ANCA is commonly found in granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) and microscopic polyangiitis. MPO-ANCA is typically associated with microscopic polyangiitis or occasionally with Churg-Strauss syndrome.
- Anti-topoisomerase 1 (Scl 70) occurs in systemic sclerosis and is associated with lung fibrosis and renal disease.
- Anti-U1RNP associates with Mixed Connective Tissue Disease / overlap syndromes.
- Anti-centromere antibody is found in limited cutaneous systemic sclerosis and associates with an increased risk of pulmonary hypertension.
- Anti-Jo antibodies predict lung involvement in children with Juvenile Dermatomyositis.
Persistent Fever syndromes may be suggested with fever that is persistent or recurrent for longer than 5 days without an apparent cause.
- A family history of similar fever and other features may be apparent.
- Careful clinical examination is needed (looking for rashes especially when pyrexial), lymphadenopathy, mouth ulcer, evidence of heart murmurs or nail fold changes (endocarditis), joints and fundoscopy.
- 'First line' investigation (to exclude infection and autoimmune disease) usually includes: Blood cultures when pyrexial, Urine microscopy and culture, Autoantibodies, Chest radiograph, Cerebrospinal fluid analysis. Further investigation is dependent on the clinical context and includes Abdominal Ultrasound / MRI / CT / Angiography and Bone marrow (to help exclude malignancy and infections).
- Persistent fever (more than 7 days) and with quotidian pattern (i.e. high in the evenings) suggests systemic JIA to be more likely. Genetic tests are available for some of the periodic fever syndromes.