Goodpasture’s Syndrome

Epidemiology

History

  • Goodpasture’s Syndrome was First Described by Ernest Goodpasture in 1919
    • Initial Case Involved a Multisystem Disease Which Occurred in an 18 y/o Male (Following an Influenza Epidemic): however, questions exist as to whether the reported case actually reflected a true case of Goodpasture’s Syndrome
      • Diffuse Alveolar Hemorrhage
      • Glomerulonephritis
      • Pleuritis
      • Splenic Infarctions
      • Vasculitis of Small Intestine

Epidemiologic Features

  • Incidence: 1 case per million per year
  • Bimodal Age Peaks
    • Peak from Age 20-30: male predominance in this group
    • Peake from Age 60-70 y/o: female predominance in this age group
  • Race: more common in caucasians than in blacks

Risk Factors

  • Genetic Factors
    • Increased Frequency of HLA-DR15 (Previously Known as HLA-DR2), DRB103, and DRB104
    • Decreased Frequency of DRB101 and DRB107
    • Strong Association with the DRB11501 Allele: however, this allele is present in up to 33% of caucasian populations
    • Lesser Association with the DRB11502 Allele
  • Alemtuzumab (Campath, MabCampath, Campath-1H, Lemtrada) (see Alemtuzumab, [[Alemtuzumab]])
    • Physiology: lymphocyte-depletion therapy
  • Cocaine Exposure (see Cocaine, [[Cocaine]])
    • Epidemiology: xxx
  • Influenza A2 (and Other Respiratory, Particularly Viral) Infections (see Influenza Virus, [[Influenza Virus]])
    • Epidemiology: xxx
  • Metallic Dust Exposure
    • Epidemiology: increased risk in auto mechanics
  • Penicillamine (see Penicillamine, [[Penicillamine]]))
    • Epidemiology: case reports of drug-induced Goodpasture’s syndrome
  • Tobacco Exposure (see Tobacco, [[Tobacco]])
    • Epidemiology
      • Tobacco Smoke Exposure Increases the Risk of Diffuse Alveolar Hemorrhage (DAH): 100% of smokers with Goodpasture’s develop DAH, compared to only 20% of non-smokers with Goodpasture’s
      • Tobacco Increases the Risk of Recurrence of DAH in Cases with Prior Remission
    • Physiology: tobacco probably acts to increase alveolar-capillary membrane permeability
  • Volatile Hydrocarbon Exposure
    • Agents
      • Pesticides
      • Petroleum Products
      • Toluene
      • Turpentine

Physiology

  • Autoimmune Disorder with Formation of Antibodies Against the Renal Glomerular and Alveolar Basement Membrane
    • Type II (Antibody-Mediated) Immune Hypersensitivity Reaction (see Immune Hypersensitivity, [[Immune Hypersensitivity]])
    • In Most Patients, the Antibody is Directed Against the 28-kD Monomeric Subunit within the Noncollagenous Domain of the Alpha 3 Chain of Type IV Collagen

Pathology

  • Pathology with Diffuse Alveolar Hemorrhage: pulmonary capillaritis is usually not present (present in some cases though)
    • Absence of alveolar wall necrosis

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Anemia (see Anemia, [[Anemia]])

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • Increased DLCO: during active diffuse alveolar hemorrhage
    • Increase of 30% above baseline indicates acute bleed
    • May precede abnormal CXR or symptoms in some cases)

Bronchoscopy (see Bronchoalveolar Lavage, [[Bronchoalveolar Lavage]])

  • Bronchoalveolar Lavage (BAL): RBC’s/hemosiderin-laden macrophages

Chest X-Ray (see Chest X-Ray, [[Chest X-Ray]])

  • Findings
    • Normal CXR: occurs in 18% of cases
    • Diffuse or Patchy Focal Alveolar Infiltrates
      • Bilateral, Symmetric Perihilar, and Bibasilar-Predominant
      • Typically with Apical and Costophrenic Sparing
    • Interstitial Infiltrates: may appear with chronic or recurrent DAH
    • Absence of Pleural Effusions

Chest CT (see Chest Computed Tomography, [[Chest Computed Tomography]])

  • Findings
    • Diffuse or patchy focal alveolar infiltrates
    • Interstitial infiltrates: may appear with chronic or recurrent DAH
    • Ground-Glass infiltrates or Consolidation: HRCT is more sensitive than CXR

High-Resolution Chest CT (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]])

  • More Sensitive than CXR
  • Findings
    • Ground-Glass infiltrates or Consolidation:

Anti-Nuclear Antibody (ANA) (see Anti-Nuclear Antibody, [[Anti-Nuclear Antibody]])

  • Negative
    • Anti-dsDNA: negative

Rheumatoid Factor (RF) (see Rheumatoid Factor, [[Rheumatoid Factor]])

Negative

Anti-Neutrophil Cytoplasmic Antibody (ANCA) (see Anti-Neutrophil Cytoplasmic Antibody, [[Anti-Neutrophil Cytoplasmic Antibody]])

  • Positive in Up to 33% of Cases at Some Point During the Course of Goodpasture’s Syndrome (in Addition to Anti-GBM Antibody) (J Am Soc Nephrol, 1992) [MEDLINE]
    • In Most Cases, the ANCA Precedes the Anti-GBM (by Months-Years)
    • These are Usually Myeloperoxidase (MPO-ANCA): p-ANCA
    • In Patients with Anti-GBM and MPO-ANCA, Histologic Findings Differ from Patients with Anti-GBM Alone: renal survival in patients with Anti-GBM and MPO-ANCA is similar to patients with anti-GBM alone (but is worse compared to patients with MPO-ANCA only)

Serum Complement (see Serum Complement, [[Serum Complement]])

  • C3/C4/CH50: normal

Anti-Glomerular Basement Membrane Antibody (Anti-GBM) (see Anti-Glomerular Basement Membrane Antibody, [[Anti-Glomerular Basement Membrane Antibody]])

  • Technique: detection of anti-α3(IV) NC1 antibodies on solid-phase immunoassays
    • Radioimmunoassay (RIA) or Enzyme-Linked Immunosorbent Assays (ELISA)
      • Sensitivity: >95%
      • Specificity: >97%
    • Recombinant Antigen Fluorescence Immunoassay: has the best sensitivity/specificity
    • Western Blot on Collagenase-Solubilized Human GBM: confirmatory
  • Presence of Anti-GBM Antibodies in Normal Patients: normal/healthy patients may have circulating IgG2 and IgG4 subclass antibodies against glomerular basement membrane
    • However, with the Onset of Clinical Disease, IgG1 and IgG3 Subclass Antibodies Against Glomerular Basement Membrane Increase: levels may correlate with disease severity
    • Higher Levels of Anti-GBM Antibodies Against the EA and EB Epitopes Correlate with More Severe Renal Disease and Worse Prognosis

Serum Immunoglobulin A (IgA) Level (see Serum Immunoglobulin A, [[Serum Immunoglobulin A]])

  • Normal

Erythrocyte Sedimentation Rate (ESR) (see Erythrocyte Sedimentation Rate, [[Erythrocyte Sedimentation Rate]])

  • Usually Elevated

Urinalysis (see Urinalysis, [[Urinalysis]])

  • Usually abnormal with microscopic hematuria, red cell casts, and proteinuria
    • May be normal in some cases: but in these cases, renal biopsy is still abnormal
    • Gross hematuria is unusual

Clinical Manifestations

General Comments

  • 60-80% of Cases: pulmonary and renal disease appear simultaneously
  • 20-40% of Cases: renal disease occurs alone
  • <10% of Cases: pulmonary disease alone

Gastrointestinal Manifestations

Anorexia (see Anorexia, [[Anorexia]])

  • Epidemiology: may occur

Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])

  • Epidemiology: occurs in only 10% of cases

Nausea/Vomiting (see xxxx, [[xxxx]])

  • Epidemiology: may occur

Hematologic Manifestations

Anemia (see xxxx, [[xxxx]])

  • Physiology: due to recurrent DAH

Splenomegaly (see xxxx, [[xxxx]])

  • Epidemiology: occurs in only 10% of cases

Otolaryngologic Manifestations

Autoimmune Inner Ear Disease (AIED)

  • Epidemiology: occurs in some cases
  • Clinical: may mimic presentation of otitis media
    • Fullness in the Ear
    • Hearing Loss (see Hearing Loss, [[Hearing Loss]])
      • May Be Unilateral or Bilateral
      • May Be Sudden or Progress Over Weeks-Months
    • Roaring Sound in the Ear
    • Tinnitus (see Tinnitus, [[Tinnitus]])
    • Vertigo (see Vertigo, [[Vertigo]])

Pulmonary Manifestations

Acute Respiratory Distress Syndrome (ARDS) (see Acute Respiratory Distress Syndrome, [[Acute Respiratory Distress Syndrome]])

  • Epidemiology: may occur in some cases

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage, [[Diffuse Alveolar Hemorrhage]])

  • Epidemiology
    • Symptoms are Usually Present for Only Days-Weeks Before Presentation
  • Diagnosis
    • Open Lung Biopsy (see Open Lung Biopsy, [[Open Lung Biopsy]])
      • Hemosiderin-Laden Macrophages within the Alveolar Spaces
      • Neutrophilic Capillaritis: may also be seen
      • Hyaline Membranes: may also be seen
      • Diffuse Alveolar Damage: may also be seen
      • Absence of Medium/Large-Vessel Vasculitis
      • Tissue Antibody Staining/Immunofluorescence (IF): useful
      • Electron Microscopy (EM): useful
  • Clinical
    • Hemoptysis (see Hemoptysis, [[Hemoptysis]]): may be absent on initial presentation in some cases, even after significant bleed
    • Cough (see Cough, [[Cough]])
    • Dyspnea (see Dyspnea, [[Dyspnea]])
    • Chest Pain (see Chest Pain, [[Chest Pain]]): occurs in <50% of cases
    • Crackles or Rhonchi

Renal Manifestations

Rapidly Progressive Glomerulonephritis (see xxxx, [[xxxx]]) with/without Acute Kidney Injury (AKI)/Chronic Kidney Disease (CKD) (see Acute Kidney Injury, [[Acute Kidney Injury]] and Chronic Kidney Disease, [[Chronic Kidney Disease]])

  • Epidemiology
    • Data from Australia and New Zealand (ANZDATA) Registry (Kidney Intl, 2013) [MEDLINE]
      • Goodpasture’s Syndrome was Found to Be an Uncommon Etiology of End-Stage Renal Disease
  • Diagnosis
    • Renal Biopsy (see Renal Biopsy, [[Renal Biopsy]]): provides definitive diagnosis (renal biopsy has a significantly higher yield than lung biopsy
      • Light Microscopy: proliferative or necrotizing glomerulonephritis with crescents
      • Tissue Antibody Staining/Immunofluorescence (IF): linear pattern of IgG (predominantly IgG1 subclass) + complement along the glomerular basement membrane
        • In Wegener’s and SLE, positive immunofluorescence may also be seen, but these are typically granular, not linear, staining
      • Electron Microscopy (EM): electron dense deposits with fragmented basement membrane
  • Clinical

Hypertension (see Hypertension, [[Hypertension]])

  • Epidemiology: uncommon

Other Manifestations

  • Absence of Rheumatologic or Dermatologic Involvement: except in cases with positive p-ANCA too (these cases may have systemic symptoms, like myalgias and rash)
  • Chills: may occur
  • Fatigue (see Fatigue, [[Fatigue]])
  • Fever (see Fever, [[Fever]])
  • Malaise

Treatment

Plasmapheresis (see Plasmapheresis, [[Plasmapheresis]])

  • Indications
  • Clinical Efficacy
    • Retrospective Review of Goodpasture’s Syndrome Therapy at Tertiary Referral Center in the UK (Ann Intern Med, 2001) [MEDLINE]
      • Plasmapheresis and Immunosuppression are Effective Treatments for Patients with Goodpasture’s Syndrome and Renal Failure: although patients requiring immediate hemodialysis were less likely to recover renal fuction

Corticosteroids and Cyclophosphamide (Cytoxan) (see Corticosteroids, [[Corticosteroids]] and Cyclophosphamide, [[Cyclophosphamide]]))

  • Standard Regimen
    • Immunosuppression is Required to Inhibit Antibody Production and Rebound Antibody Hypersynthesis (Which May Occur Following Discontinuation of Plasma Exchange)
  • Administration
    • Prednisone (see Prednisone, [[Prednisone]]): 1-1.5 mg/kg PO qday
      • If prompt remission, continue for approximately 6 mo
    • Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]]): 2 mg/kg PO qday, adjusted to maintain WBC of 5k
      • If prompt remission, continue for approximately 2-3 mo
  • Administration for Patients with Life-Threatening DAH
    • Pulse Methylprednisolone (Solumedrol) (see Methylprednisolone, [[Methylprednisolone]]): 1 g/day x 3 days may be used for life-threatening DAH
    • Cyclophosphamide (Cytoxan) (see Cyclophosphamide, [[Cyclophosphamide]]): 1 g/m2 IV (repeat in 3-4 wks, contingent on bone marrow recovery)

Other Therapies

  • Anti-B Cell Monoclonal Antibodies: have been used in patients with crescentic glomerulonephritis, but have an unclear role
  • Azathioprine (Imuran) (see Azathioprine, [[Azathioprine]])
    • May Be Substituted for Cyclophosphamide in Patients who Require Longer Immunosuppression
  • Mycophenolate Mofetil (Cellcept) (see Mycophenolate Mofetil, [[Mycophenolate Mofetil]])
    • xxxx
  • Rituximab (Rituxan) (see Rituximab, [[Rituximab]])
    • Depletes CD20-positive B-Cells Over 6–9 mo
    • May Be Used as Either an Initial Immunosuppressant (Instead of Cyclophosphamide) or in Cases of Cyclophosphamide Failure/Intolerance
    • Note: rituximab is removed by plasmapheresis

Pneumocystis Jirovecii Prophylaxis (see Pneumocystis Jirovecii, [[Pneumocystis Jirovecii]])

  • Required: due to immunosuppression

Renal Transplantation (see Renal Transplant, [[Renal Transplant]])

  • Indications
    • xxxx

Parameters to Monitor

  • Anti-GBM Titer: although decreasing titers do not correlate with rate of clinical improvement)

Prognosis

  • 5-Year Survival with Aggressive Regimen Above: >80%
    • <30% require hemodialysis
  • Spontaneous Remission: occurs in some cases without clinical renal disease
  • 6-Month Survival in Setting of Severe Renal Failure (with Oliguria/Anuria): 50%
  • Renal Bx
    • Bx with <30% crescents: suggests an expected therapeutic response with good prognosis
    • Bx with >70% crescents: suggests need for probable dialysis
  • Relapse Rate: higher in Goodpasture’s cases who also have p-ANCA positivity

References

  • D-penicillamine induced Goodpasture’s syndrome in Wilson’s disease. Ann Intern Med 1975; 82: 673-676 [MEDLINE]
  • Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol 1991; 36:107-113 [MEDLINE]
  • Antineutrophil-cytoplasmic antibodies and antiglomerular basement membrane antibodies in Goodpasture’s syndrome and in Wegener’s granulomatosis. J Am Soc Nephrol 1992;2:1227–34 [MEDLINE]
  • Goodpasture’s syndrome: molecular and clinical advances. Medicine 1994; 73:171-185 [MEDLINE]
  • Goodpasture’s syndrome. Kidney Int 1996; 50:1753-1766 [MEDLINE]
  • Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033–42 [MEDLINE]
  • Alveolar hemorrhage in anti-basement membrane antibody disease: a series of 28 cases. Medicine (Baltimore). 2007 May;86(3):181-93 [MEDLINE]
  • Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med. 2010 Jul 22;363(4):343-54. doi: 10.1056/NEJMoa0910500 [MEDLINE]
  • Plasma exchange for Goodpasture syndrome. Transfus Apher Sci 2010;42:115–6 [MEDLINE]
  • Anti-glomerular basement membrane disease: outcomes of different therapeutic regimens in a large single-center Chinese cohort study. Medicine (Baltimore). 2011 Sep;90(5):303-11. doi: 10.1097/MD.0b013e31822f6f68 [MEDLINE]
  • Anti-glomerular basement membrane antibody disease is an uncommon cause of end-stage renal disease. Kidney Int. 2013 Mar;83(3):503-10. doi: 10.1038/ki.2012.375. Epub 2012 Dec 19 [MEDLINE]
  • Anti-glomerular basement membrane disease treated with mycophenolate mofetil, corticosteroids, and plasmapheresis. Clin Nephrol 2013;80:67–71 [MEDLINE]
  • Comparison of double filtration plasmapheresis with immunoadsorption therapy in patients with anti-glomerular basement membrane nephritis. BMC Nephrol 2014;15:128 [MEDLINE]
  • Goodpasture syndrome and posterior reversible encephalopathy syndrome. J Neurol Sci. 2015 Jul 15;354(1-2):135-7. doi: 10.1016/j.jns.2015.05.002. Epub 2015 May 8 [MEDLINE]
  • Rituximab in anti-GBM disease: A retrospective study of 8 patients. Autoimmun. 2015 Jun;60:74-9. doi: 10.1016/j.jaut.2015.04.003. Epub 2015 May 4 [MEDLINE]
  • Severe adult respiratory distress syndrome from Goodpasture syndrome. Survival using extracorporeal membrane oxygenation. Am J Respir Crit Care Med. 2015 Jan 15;191(2):228-9. doi: 10.1164/rccm.201409-1625IM [MEDLINE]
  • Goodpasture’s syndrome: a clinical update. Autoimmun Rev. 2015 Mar;14(3):246-53. doi: 10.1016/j.autrev.2014.11.006. Epub 2014 Nov 15 [MEDLINE]
  • Atypical anti-glomerular basement membrane disease. Clin Kidney J. 2016 Apr;9(2):211-21. doi: 10.1093/ckj/sfv140. Epub 2015 Dec 30 [MEDLINE]