Goodpasture Syndrome

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Diagnosis and reasoning

This young man has presented with respiratory distress, as evidenced by the presence of dyspnea, tachypnea, and a low oxygen saturation; the immediate priority should be his resuscitation and stabilization. Once this is done, the next step should be careful evaluation of his clinical findings and investigations to determine the causative etiology. His history is positive for cough and dyspnea, in association with chills and night sweats; the examination is mainly significant for a few crackles in the lower zones of both lung fields. However, the investigation results available are considerably more alarming - aside from a severe anemia, they also reveals the presence of acute kidney injury (AKI), glomerulonephritis (as evidenced by microscopic hematuria with erythrocyte casts), and bilateral lower zone pulmonary infiltrates. As is evident, the findings above involve both pulmonary and renal systems; thus, key differential diagnoses to consider include: - Vasculitides such as Wegener’s granulomatosis or Churg Strauss syndrome - Connective tissue diseases such as SLE or scleroderma - Pulmonary-renal syndromes such as Goodpasture’s syndrome or Microscopic polyangiitis - Atypical pneumonia due to Legionella, Chlamydia, Mycoplasma or Rickettsia. An atypical pneumonia is clinically less likely, as he has already been treated with an azalide for 2 weeks; however, a serological screen is still clinically prudent, if only because these are so common. This however turns out to be negative. An autoimmune screen is probably a good next step in his workup; this is negative for ANA and ANCA, but positive for Anti-glomerular basement membrane (Anti-GBM) antibodies. Along with the supportive clinical picture, this is sufficient to diagnose Goodpasture’s syndrome. Thus, the pulmonary infiltrates are very likely secondary to diffuse alveolar hemorrhage (DAH); this is confirmed by the bronchoalveolar lavage findings. Renal biopsies should be performed in all patients with Goodpasture’s syndrome to establish the degree of renal involvement; this shows features suggestive of a rapidly progressive glomerulonephritis (RPGN) with pauci-immune staining, which is characteristic of the disease. Plasmapheresis in combination with immunosuppression (i.e. with corticosteroids) is the treatment of choice in Goodpasture’s syndrome. He should also be transfused with packed red blood cells (PRBC) in view of the severe anemia and ongoing bleeding. Diuretics are not indicated in his current management.


Discussion

Goodpasture's syndrome (anti-GBM antibody disease) is a rare autoimmune disease characterized by diffuse alveolar hemorrhage and a rapidly progressive glomerulonephritis in association with detectable levels of anti-GBM antibodies in serum or tissue. The disease is rare, with an incidence of 1 case per 1 million population per year. The disease is mainly encountered in Caucasian population, and has a bimodal distribution, affecting young males in their second and third decades and patients of both genders in the fifth to sixth decades The anti-GBM antibodies are directed against the NC1 domain of the alpha-3 chain of type IV collagen. In the glomeruli, these bind to target antigens in the basement membrane, and activate proteases and complements, resulting in disruption of the filtering process and crescent formation. Note that the pulmonary capillaries are usually much less porous than those of the glomeruli; thus large molecules such as immunoglobulin cannot reach target antigen sites. However, when these are damaged due to some extrinsic reason (such as infections, smoking, or exposure to toxins) the alveolar Goodpasture antigen is exposed, resulting in alveolar disease. Goodpasture’s syndrome typically presents with a nonspecific flu like syndrome, breathlessness, cough and asthenia. Dyspnea, cough and hemoptysis are manifestations of alveolar hemorrhage and chest auscultation may reveal crackles. The glomerulonephritis results in non-nephrotic proteinuria and hematuria (which can be macroscopic) with red cell casts. Note that constitutional symptoms such as weight loss, fever, or malaise are usually not encountered in these individuals. Chest radiography typically shows bilateral alveolar infiltrates; bronchoalveolar lavage demonstrates uniformly bloody aliquots which confirm the presence of pulmonary hemorrhage. Most of these patients have detectable levels of anti-GBM antibodies in their serum; if a suggestive clinical picture is present, this is sufficient to establish the diagnosis. Where anti-GBM antibodies are negative, or the clinical picture is equivocal, a kidney or lung biopsy should be considered; this will demonstrate linear deposition of antibodies along the glomerular or alveolar membrane respectively. Note that renal biopsies are also important in establishing the degree of renal involvement; this typically shows focal segmental glomerular necrosis with crescent formation in the later stages. Plasmapheresis in combination with immunosuppression is the mainstay of the management in Goodpasture's syndrome; a combination of corticosteroids with cyclophosphamide is usually used. Alternative agents include azathioprine and mycophenolate mofetil. Depending on the severity of renal involvement and pulmonary hemorrhage, patients may require dialysis or respiratory support. The prognosis of Goodpasture's syndrome strongly depends on the likely ultimate renal outcome. Indicators of a poor prognosis include a serum creatinine over 5.7 mg/dL or renal biopsy findings showing crescents in over 80% of glomeruli at the time of diagnosis.


Take home messages

  1. Important causes of combined pulmonary and renal disease include atypical pneumonias, connective tissue diseases, vasculitides and pulmonary renal syndromes.
  2. Goodpasture's syndrome is a rare pulmonary-renal syndrome of autoimmune origin.
  3. The presence of anti-GBM antibodies in association with a suggestive clinical picture is sufficient to diagnose the disease.
  4. Renal biopsies are indicated in all patients, as this will quantify the renal involvement and predict the ultimate outcome.

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  1. Clin Chest Med. 2004 Sep;25(3):583-92, vii, Diffuse alveolar hemorrhage, Collard HR, Schwarz MI.
  2. Crit Care. 2007;11(3):213, Bench-to-bedside review: pulmonary-renal syndromes--an update for the intensivist, Papiris SA, Manali ED, Kalomenidis I, Kapotsis GE, Karakatsani A, Roussos C.
  3. N Engl J Med. 2003 Jun 19;348(25):2543-56, Alport's syndrome, Goodpasture's syndrome, and type IV collagen, Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG.
  4. Orphanet Encyclopedia 2002 Sep, Goodpasture’s Disease, rossert J.
  5. Respir Med. 2011 Oct;105(10):1413-21. doi: 10.1016/j.rmed.2011.05.012, Pulmonary-renal syndromes: an update for respiratory physicians, McCabe C, Jones Q, Nikolopoulou A, Wathen C, Luqmani R.