Goodpasture Syndrome: Causes, Symptoms, Diagnosis, Treatment

Goodpasture Syndrome is an autoimmune syndrome that includes alveolar  pulmonary hemorrhage and glomerulonephritis caused by circulating anti-GBM antibodies. Goodpasture syndrome most often develops in people with hereditary predisposition, who smoke cigarettes, but possible additional factors are the inhalation of hydrocarbon and viral infections of the respiratory tract. Symptoms of Goodpasture's syndrome include shortness of breath, cough, fatigue, hemoptysis and / or hematuria. Goodpasture's syndrome is suspected in patients with hemoptysis or hematuria and is confirmed by the presence of anti-GVM antibodies in the blood. Treatment Goodpacers syndrome includes plasmapheresis, glucocorticoids and immunosuppressants such as cyclophosphamide. The prognosis is favorable if the treatment is started before the development of respiratory or renal insufficiency.

The Goodpasture Syndrome was first described by Goodpasther in 1919. Goodpasture syndrome is a combination of glomerulonephritis and alveolar bleeding in the presence of anti-GVM antibodies. Goodpasture syndrome is most often manifested by a combination of diffuse alveolar bleeding and glomerulonephritis, but sometimes causes isolated glomerulonephritis (10-20%) or lung damage (10%). Men are sick more often than women.

[1], [2]

What Causes Goodpasture Syndrome?

The cause of the disease is not exactly established. The genetic predisposition to Goodpasture's syndrome is supposed, its marker is considered the presence of HLA-DRW2. There is a point of view about the possible role of the transferred virus infection (hepatitis A virus and other viral diseases), production hazards, drugs (especially D-penicillamine).

The basis of the pathogenesis of Goodpasture's syndrome is the formation of autoantibodies to the basal membranes of capillaries of the glomeruli of the kidneys and alveoli. These antibodies belong to the IgG class, they bind to the antibodies of the basal membranes in the presence of the complement C3 component, followed by the development of immune inflammation of the kidneys and lung alveoli.

Anti-GVM antibodies are directed against the non-collagen (NC-1) domain of the a3 chain of collagen type IV, which is at the highest concentration in the basal membranes of the renal and pulmonary capillaries. The impact of environmental factors such as smoking, viral ARI and inhalation of hydrocarbonate suspensions (more often) and, less often, pneumonia, activates the presentation of alveolar capillary antigens to circulating antibodies in people with hereditary predispositions (most often HLA-DRwl5, DR4 and DRB1 alleles ). Circulating anti-GVM antibodies bind to the basal membranes, fix complement and cause a cellular inflammatory response leading to the development of glomerulonephritis and / or pulmonary capillaritis.

Probably, there is a definite generality of auto-antigens of the basal membrane of capillaries of the glomeruli of the kidneys and alveoli. The autoantigen is formed under the influence of the damaging effect of the etiologic factor. An unknown etiologic factor damages and modifies the structure of the basal membranes of the kidneys and lungs. Excretion of the formed degradation products of the basal membranes of the glomeruli of the kidneys during their lesion slows down and decreases, which naturally creates the prerequisites for the development of autoimmune lesions of the kidneys and lungs. It is still completely unknown which component of the basal membrane becomes an auto-antigen. At present, it is assumed that this is an internal structural component of the basal membrane of the glomerulus of the kidney a3-chain of type 4 collagen.

The formed immune complexes are deposited along the basal membranes of the glomerular capillaries, which leads to the development of an immuno-inflammatory process in the renal glomerulus (glomerulonephritis) and alveoli (alveolitis). The main cells involved in the development of this immune inflammation are T-lymphocytes, monocytes, endotheliocytes, polymorphonuclear leukocytes, alveolar macrophages. Interaction between them is provided by molecular mediators, cytokines (growth factors - platelet, insulin-like, b-transforming, interleukin-1, tumor necrosis factor, etc.). A major role in the development of immune inflammation is played by the metabolites of arachidonic acid, free oxygen radicals, proteolytic enzymes, adhesion molecules.

In the development of alveolitis in Goodpasture's syndrome, the activation of alveolar macrophages is of great importance. In the activated state, they release about 40 cytokines. Cytokines of group I (chemotaxins, leukotrienes, interleukin-8) increase the flow of polymorphonuclear leukocytes into the lungs. Cytokines of group II (growth factors - platelet, macrophage) promote the movement of fibroblasts into the lungs. Alveolar macrophages also produce active forms of oxygen, proteases that damage the lung tissue.

Pathomorphology of Goodpasture's syndrome

The main pathomorphological manifestations of Goodpasture's syndrome are:

• the primary lesion of the microcirculatory bed of the kidneys and lungs. In the lungs there is a picture of venules, arteriolites, capillaritis with marked destruction and proliferation; the defeat of capillaries is observed mainly in interalveolar septa, the alveolitis with hemorrhagic exudate develops in the alveoli. Renal damage is characterized by the development of extracapillary proliferative glomerulonephritis followed by the formation of hyalinosis and fibrosis, which leads to the development of renal failure;
• severe intra-alveolar hemorrhage;
• development of hemosiderosis of the lungs and pneumosclerosis of varying severity, as a result of the evolution of the alveolitis.

Symptoms of Goodpasture Syndrome

The disease most often begins with clinical manifestations of pulmonary pathology. Hemoptysis is the most prominent symptom; however, hemoptysis may be absent in the presence of hemorrhagic manifestations, and the patient can only detect infiltrative changes in chest radiography or infiltrate and respiratory distress syndrome and / or insufficiency. Often dyspnea develops (mainly with physical activity), coughing, malaise, disability, chest pain, fever and weight loss. Up to 40% of patients have macrohematuria, although pulmonary hemorrhage may precede renal manifestations for weeks and years.

Dyspnea may increase during hemoptysis. Worries are also weakness, disability.

Symptoms of Goodpasture's syndrome vary over a long period of time ranging from pure lungs to auscultation to crackling and dry wheezing. Some patients experience peripheral edema and pallor due to anemia.

On examination, attention is drawn to the pallor of the skin, cyanosis of the mucous membranes, pastness or pronounced edema of the face, reduction of muscle strength, loss of body weight. Body temperature is usually increased to febrile digits.

With percussion of the lungs, shortening of the percussion sound over the vast foci of pulmonary hemorrhage can be determined, but this is rare, there is usually no change in the percussion sound.

A characteristic auscultative sign of Goodpasture's syndrome is dry and wet wheezing, the number of them increases significantly during or after hemoptysis.

When examining the cardiovascular system, arterial hypertension is detected, it is possible to increase the border of relative dullness of the heart to the left, muffled heart tones, quiet systolic noise, with the development of severe renal failure appears pericardial friction noise. With progressive renal damage against a background of significant arterial hypertension, it is possible to develop acute left ventricular failure with a picture of cardiac asthma and pulmonary edema. Usually this situation develops in the terminal stage of the disease.

As a rule, kidney damage manifests later, after a certain time after the development of pulmonary symptoms. Characteristic clinical signs of renal pathology are hematuria (sometimes macrohematuria), rapidly progressing renal failure, oligoanuria, arterial hypertension.

In 10-15% of cases the Goodpasture syndrome begins with clinical signs of renal pathology - the glomerulonephritis clinic (oliguria, edema, arterial hypertension, pronounced pallor) appears, and then symptoms of pulmonary involvement are added. Many patients may have myalgia, arthralgia.

Regardless of the options, Goodpasture's syndrome in most cases is difficult, the disease progresses steadily, severe pulmonary and renal failure develops. The life expectancy of patients from the onset of the disease ranges from several months to 1-3 years. Most often, patients die from uremia or pulmonary hemorrhage.

Diagnosis of Goodpasture Syndrome

The diagnosis of Goodpasture's syndrome requires the detection of serum anti-GVM antibodies by indirect immunofluorescence or, if possible, direct enzyme-linked immunosorbent assay (ELISA) with recombinant human NC-1 a3. Other serological tests, such as the antinuclear antibody test (ANA), are used to detect SLE, antistreptolysin-O-titer for the detection of post-streptococcal glomerulonephritis, which can be the cause of many cases of pulmonary-kidney syndrome. ANCA are positive (in peripheral patterns) in 25% of cases of Goodpasture's syndrome. In the presence of glomerulonephritis (hematuria, proteinuria, erythrocyte sludge in the analysis of urine and / or renal failure), a kidney biopsy can be administered. Rapidly progressive focal segmental necrotizing glomerulonephritis with a progressive course is detected with biopsy at Goodpasture's syndrome and all other causes of pulmonary-kidney syndrome. Immunofluorescence staining of renal or pulmonary tissue classically reveals linear deposition of IgG along glomerular or alveolar capillaries. This also occurs in diabetic kidney and fibrillar glomerulonephritis, a rare disease that causes pulmonary-kidney syndrome, but the fixation of GBM antibodies in these diseases is non-specific.

Studies of lung function and bronchoalveolar lavage are not diagnostic in Goodpasture's syndrome, but can be used to confirm the presence of diffuse alveolar hemorrhage in patients with glomerulonephritis and pulmonary infiltrates, but without hemoptysis. The lavage fluid, which remains hemorrhagic after repeated washing, allows to confirm a diffuse hemorrhagic syndrome, especially with the concomitant decrease in hematocrit.

[3],

Laboratory Diagnosis of Goodpasture Syndrome

1. General blood test. Characteristic iron deficiency hypochromic anemia, hypochromia, anisocytosis, poikilocytosis of erythrocytes. There is also leukocytosis, a shift of the leukocyte formula to the left, a significant increase in ESR.
2. General analysis of urine. In the urine, a protein is detected (the degree of proteinuria can be significant), cylinders (granular, hyaline, erythrocyte), erythrocytes (may be macrohematuria). As the progression of chronic renal failure decreases, the relative density of urine, in the sample Zimnitsky develops isohypostenuria.
3. Blood chemistry. There is an increase in the urea, creatinine, haptoglobin, seromucoid, a2 and gamma globulin levels in the blood , a decrease in the iron content .
4. Immunological research. There can be a decrease in the number of T-lymphocytes-suppressors, circulating immune complexes are revealed . Antibodies to the basal membrane of the capillaries of the glomeruli and alveoli are detected by indirect immunofluorescence or by radioimmunoassay.
5. Sputum analysis. There are a lot of red blood cells in the sputum, hemosiderin, siderophages are found.

Instrumental Diagnosis of Goodpasture Syndrome

1. X-ray examination of the lungs. Characteristic radiographic signs are pulmonary infiltrates in the basal area with spreading to the lower and middle sections of the lungs, as well as progressive, symmetrical bilateral cloud-like infiltrates.
2. Examination of the function of external respiration. Spirography reveals a restrictive type of respiratory failure (a decrease in GEL), as the disease progresses, an obstructive type of respiratory failure (reduction of FEV1, Tiffno index) is added.
3. ECG. There are signs of pronounced myocardial dystrophy of anemic and hypoxic genesis (a decrease in the amplitude of the T wave and ST interval in many leads, more often in the left thoracic). With severe arterial hypertension, there are signs of myocardial hypertrophy of the left ventricle.
4. Investigation of the gas composition of blood. Arterial hypoxemia is revealed.
5. Investigation of lung and kidney biopsy specimens. A biopsy of the lung tissue (open biopsy) and kidneys is done for the final verification of the diagnosis, if it is impossible to accurately diagnose the disease with non-invasive methods. Histological and immunological examination of biopsy specimens is performed. Typical for Goodpasture's syndrome are the following symptoms:
   • presence of morphological signs of glomerulonephritis (most often extracapillary), hemorrhagic alveolitis, hemosiderosis and interstitial fibrosis;
   • detection by the immunofluorescence method of linear deposition of IgG and C3-complement components on basal membranes of pulmonary alveoli and renal glomeruli.

Diagnostic criteria for Goodpasture Syndrome

When making the diagnosis of Goodpasture's syndrome, it is advisable to use the following criteria.

1. The combination of pulmonary pathology and renal pathology, i.e. Hemoptysis (often pulmonary hemorrhage), dyspnea and symptoms of glomerulonephritis.
2. A steadily progressing course of the disease with the development of respiratory and renal failure.
3. Development of iron deficiency anemia.
4. Identification of multiple bilateral cloud-like infiltrates in the X-ray examination of the lungs against the background of a network deformation of the pulmonary pattern.
5. Detection in the blood of high titres of circulating antibodies to the basal membrane of renal glomeruli and alveoli.
6. Detection of linear deposits of the IgG and C3 complement components on the basal membranes of the glomerular capillaries and alveoli.
7. Absence of other systemic (except pulmonary and renal) manifestations.

[4], [5], [6], [7]

Differential diagnosis of Goodpasture's syndrome

Goodpasture's syndrome has to be differentiated with a number of diseases manifested by hemoptysis or pulmonary hemorrhage. It is necessary to exclude oncological diseases of the bronchi and lungs, tuberculosis, lung abscesses, bronchiectasis, heart and vascular diseases (leading to stagnation and hypertension in the small circle), systemic vasculitis, hemorrhagic diathesis.

[8], [9], [10]

The program of inspection in Goodpasture's syndrome

1. Common blood tests, urine tests.
2. Biochemical blood test: determination of the content of total protein and protein fractions, creatinine and urea, transaminases, seromucoid, haptoglobin, fibrin, iron.
3. Sputum analysis: cytological examination, definition of siderophages.
4. Immunological studies: determination of the content of B- and T-lymphocytes, subpopulations of T-lymphocytes, immunoglobulins, circulating immune complexes, antibodies to the basal membranes of the glomeruli of the kidneys and alveoli.
5. X-ray examination of the lungs.
6. ECG.
7. Spirography.
8. Investigation of lung and kidney biopsy specimens.

Treatment of Goodpasture Syndrome

Treatment Goodpascher's syndrome includes daily or daily plasmapheresis for 2-3 weeks (plasma replacement 4 l) to remove aHTH-GBM antibodies in combination with intravenous glucocorticoids (usually methylprednisolone 1 g for at least 20 minutes every other day 3 times with prednisolone 1 mg / kg body weight daily) and cyclophosphamide (2 mg / kg once daily) for 6-12 months to prevent the formation of new antibodies. Therapy can be reduced when the improvement of pulmonary and renal function ceases. Long-term mortality is associated with the degree of impaired renal function at the onset of the disease; patients requiring dialysis at the beginning, as well as those who had more than 50% of nephrons with crescents on biopsy, have a survival time of less than 2 years and often require dialysis if kidney transplantation is not performed. Hemoptysis can be a good prognostic sign, because it leads to an earlier detection of the disease; A minority of patients who are ANCA-positive respond better to the treatment of Goodpasture's syndrome. Relapse occurs in a small percentage of cases and is associated with the continuation of smoking and respiratory tract infection. In patients with terminal stage of renal failure who underwent renal transplantation, the disease can recur in the transplant.

What is Goodpasture's syndrome?

Goodpasture's syndrome often progresses rapidly and can be fatal if rapid diagnosis and treatment of Goodpasture's syndrome are not performed; the prognosis is favorable when the treatment begins before the development of respiratory or renal failure.

Immediate survival at the time of pulmonary hemorrhage and respiratory failure is associated with ensuring airway patency; Endotracheal sounding and artificial ventilation are recommended for patients with a borderline level of arterial blood gases and respiratory failure threatening.