Guess the Diagnosis: Case 2 - Episode 3

David Fajgenbaum, MD, MBA, MSc: Significant Tests in the Diagnostic Workup

What other tests are important in his diagnostic workup?

Dr. David Fajgenbaum, Perelman School of Medicine, University of Pennsylvania, says that based on the positive ANA, SLE was suspected, and the patient was treated with high-dose corticosteroids with insufficient response, which prompted further testing. The absence of specific antibodies for SLE (negative dsDNA, anti-Smith and antiphospholipid antibodies) and normal complement levels ruled out SLE. Inactive urinary sediment and the absence of proteinuria with negative ANCA and antistreptolysin O titer made a systemic vasculitis or acute glomerulonephritis unlikely. Testing for EBV infection and blood cultures were negative. The patient was further tested for HIV by serology and HHV-6 by quantitative PCR, both of which were negative. A vascular endothelial growth factor (VEGF) level was found to be elevated at 500 pg/ mL. Coombs test was positive and haptoglobin was normal. The patient was tested for the presence of platelet autoantibodies, which were present.

The severity of the inflammatory syndrome can be determined by clinical presentation, disease course, and laboratory parameters. Typically, there is anemia, elevated sedimentation rate, elevated C-reactive protein, low albumin, and hypergammaglobulinemia. IL-6 is often elevated and in many cases drives the inflammatory syndrome. However, IL-6 is not specific for MCD and many inflammatory disorders and infections can give rise to an elevated IL-6. There is some variation from laboratory to laboratory in sensitivity of the assay. Lastly, IL-6 is not the crucial cytokine in all cases, and in some cases of iMCD; IL-6 is not elevated. The IL-6 in this patient was only elevated at 6 pg/mL (normal range: <5 pg/mL).

Guess the Diagnosis: Case 2

Mark F. is a 25-year-old law school student from Florida with a 3-week history of severe fatigue, night sweats, and weight loss; he has also reported high fevers for the past week. He did not complain of joint pain.

  • He presents to the emergency department complaining of abdominal pain. His past medical history is notable for enlarged thyroid incidentally found 5 years before; family history relevant for an aunt with rheumatoid arthritis
  • Physical exam was notable for generalized lymphadenopathy (1-2 cm), hepatosplenomegaly, bilateral pleural effusions, ascites, and 4+ peripheral edema. Laboratory findings show anemia (7 gm/dL), elevated CRP (150 mg/L), ESR (120mm/hr), creatinine (3.0 mmol/L), Albumin of 2.1 g/dL and normal immunoglobulin levels (IgG: 1100 mg/dL, IgA: 300 mg/dL, IgM 200 mg/dL), low platelets (50,000/mL), positive ANA 1:160 with a speckled pattern. RhF was negative. Coagulation screen was not suggestive of DIC. LDH was normal

The patient was admitted for further assessment.

  • Regressed germinal centers, scattered hyperplastic follicles, preserved architecture with patent peripheral sinuses and florid interfollicular plasmacytosis with no light chain restriction
  • Rheumatologist diagnosed the patient with SLE and treated with high-dose steroids; this did not result in a major improvement in symptoms, laboratory parameters or lymphadenopathy

Mark&rsquo;s SLE diagnosis was reviewed and further testing was performed:

  • The patient was believed to be too sick to be taken to the OR to undergo a lymph node biopsy, so a bone marrow biopsy was performed. Bone marrow showed a hypercellular marrow with mild increase in polyclonal plasma cells and moderate reticulin fibrosis
  • Laboratory work: Negative dsDNA, anti-Smith and anti-phopsholipid antibodies with normal complement levels; ANCA and anti-streptolysis O titer are negative. No M protein on protein electrophoresis. 24-hour urine showed mild proteinuria. Monospot negative. TSH, T4, and T3 normal. Normal thyroglobulin and thryoid peroxidase antibodies. Urinary sediment is negative as are urine and blood cultures. IL-6 is 6 pg/mL
  • CT-PET: generalized lymphadenopathy with low-positive FDG uptake
  • Without a clear diagnosis, a lymph node biopsy was performed of the cervical chain: Regressed germinal centers, scattered hyperplastic follicles, preserved architecture with patent peripheral sinuses; florid interfollicular plasmacytosis, prominent vascularization with absence of light chain restriction. Negative LANA-1, IgG4, and EBER stains. Negative PCR for B-cell clonality