Overview.
Wegener’s granulomatosis (WG) is a necrotizing granulomatous vasculitis, an autoimmune disease. The lesions involve small arteries, veins, and capillaries, and occasionally large arteries. The pathology is characterized by inflammation of the vessel wall, which mainly invades the upper and lower respiratory tracts and the kidneys, usually starting with focal granulomatous inflammation of the nasal mucosa and lung tissue and progressing to diffuse necrotizing granulomatous inflammation of the blood vessels. Clinical manifestations often include nasal and sinusitis, pulmonary lesions, and progressive renal failure.
The etiology of the disease is unknown, and it occurs in 25 to 50 years of age, more often in men than in women, and it is a rare disease in pediatrics. The age of onset is from infancy to adolescence, with adolescence being the most common. Clinically, those with the typical triad of symptoms are called the systemic type, and those with only respiratory tract lesions and no renal damage are called the limited type.
Etiology
The etiology of Wegener’s granulomatosis in children may be related to autoimmunity and allergic reactions to unknown antigens. Since most patients have upper respiratory symptoms followed by glomerulonephritis, it has been suggested that slow-release proteins isolated after upper respiratory tract infections may be sensitizers, leading to an allergic reaction and the development of the disease.
Symptoms
The clinical manifestations are varied and can be cumulative and multisystem. The disease is characterized by a triad of upper respiratory tract, pulmonary infiltrates, and renal lesions. Children often present with nonspecific systemic symptoms such as fever, malaise, weight loss, muscle pain and arthralgia in the early stages of the disease. Many children also have some seasonal allergies. Upper respiratory tract symptoms appear later.
1. Upper respiratory tract symptoms
Most of the patients have upper respiratory tract lesions as the first symptom, with nasal symptoms being the most common. 90% of the children have persistent chronic rhinitis or paranasal sinusitis, with nasal congestion, sinus pain, pus flow and rhinorrhea, which may invade the nasal septum, and even extend to the palate, tongue, pharynx, larynx and other parts of the throat, and ulceration may occur. Inflammation spreads to severe cases of laryngeal and tracheal obstruction. Inflammation of the nose and nasopharynx can cause obstruction of the Eustachian tube, otitis media and hearing impairment. Some patients may have hoarseness and respiratory stridor due to subglottic stenosis.
2. Lower respiratory tract symptoms
Lung involvement is one of the basic features of WG. About 50% of patients have pulmonary manifestations at the onset of the disease, and a total of more than 80% of patients will develop pulmonary lesions throughout the course of the disease. Chest tightness, shortness of breath, cough, hemoptysis, and pleurisy are the most common symptoms. Massive alveolar hemorrhage is less common, but when it occurs, dyspnea and respiratory failure can occur. In about 1/3 of patients with intrapulmonary shadows on lung imaging, clinical symptoms may be lacking. On examination, there may be signs of turbidity to percussion, decreased breath sounds, and wet rales. Because of endobronchial involvement and scarring, more than 55% of patients may have obstructive ventilatory dysfunction on pulmonary function tests, and another 30% to 40% may have restrictive ventilatory dysfunction and diffusion dysfunction.
3. Renal damage
Most cases have renal lesions, which are characterized by proteinuria, leukocytosis and tubular urine, and in severe cases, hypertension and nephrotic syndrome, which can eventually lead to renal failure, one of the important causes of death in WG. Those without renal involvement are called limited WG, and should be alerted to the fact that some patients do not have renal lesions at the onset of the disease, but with the progression of the disease may gradually develop into glomerulonephritis.
4. Eye involvement
The highest proportion of eye involvement can be more than 50%, and about 15% of the patients have the first symptom. WG can involve any area of the eye, manifesting as proptosis, damage to the optic nerve and ocular muscles, conjunctivitis, corneal ulceration, superficial scleritis, iritis, and retinal vasculitis.
5. Skin manifestations
Half of the children have skin manifestations, mostly in the lower limbs, but the upper limbs, trunk and face can also be involved. Skin lesions include inflammation and necrotic nodules, fulminant purpura and gangrene, purpura lesions and nodules may progress to ulcers, which are formed secondary to necrotizing vasculitis of the skin vessels, and Raynaud’s phenomenon of the fingertips is occasionally seen.
6. Neurological manifestations
25%～50% of patients may have neurological damage, manifested by polyneuritis, motor sensory nerve disorder. Nasal or sinus granuloma may also invade the adjacent nerve tissues, causing ptosis, ophthalmoplegia, and uremia involving the posterior pituitary gland. A few are seizures or mental abnormalities. Peripheral neuropathy is the most common and polyneuritis simplex is the predominant type of lesion with a symmetrical peripheral neuropathy as the clinical picture. Electromyography and nerve conduction studies are useful in the diagnosis of peripheral neuropathy.
7. Arthropathy
Arthropathy is more common in WG. About 30% of the patients have arthropathy at the onset of the disease, and about 70% of the patients have joint involvement in the whole course of the disease. Most patients present with joint pain and myalgia, and one-third of patients may present with symmetric, asymmetric, or wandering arthritis (swelling and pain in one, a few, or many joints).
8. Other
Pericarditis and myocarditis may also involve the heart. Abdominal pain, diarrhea and bleeding may occur when the gastrointestinal tract is involved. Damage to the spleen (including necrosis, vasculitis, and granuloma formation) may be found at autopsy.
Examination
There may be anemia, increased white blood cell count and platelet count, accelerated blood sedimentation, increased C-reactive protein, and proteinuria, hematuria, and erythrocyte tubular pattern on routine urinalysis. In renal failure, blood urea nitrogen and creatinine are increased. Creatinine clearance, qualitative urine chemistry, and sedimentation tests for erythrocytes and tubular forms in the urine are used to diagnose and follow up patients with glomerulonephritis.
X-ray examination reveals multiple lesions in both lungs, nodules and nonspecific interstitial infiltrates in the middle and lower lung fields, some of which are cavities, isolated masses, etc., and some of which may range in size from a few centimeters in diameter to fine nodules, and in number from one to two to multiple. Similar to pneumonia, tuberculosis, lung cancer, etc., pleural effusion can be seen, and bronchial somatotopy shows tracheal or bronchial stenosis. X-ray of the upper respiratory tract shows thickening of the sinus mucosa and destruction of the nasal and sinus bones.
Upper respiratory tract, bronchial endothelium and kidney biopsy is an important basis for diagnosis, and the pathology shows that the walls of small pulmonary blood vessels are infiltrated with neutrophils and single nucleated cells, which can be seen as giant cells and polymorphic nucleated giant cell granulomas. It may destroy lung tissue and form cavities. Renal pathology is focal, segmental, crescentic necrotizing glomerulonephritis with no or little immunoglobulin and complement deposition by immunofluorescence.
Diagnosis
The current diagnostic criteria for WG use the 1990 American College of Rheumatology (ACR) classification criteria:
1. Nasal or oral inflammation
Painful or painless oral ulcers, purulent or bloody nasal discharge;
2. abnormal chest radiographs
Chest X-ray showing nodules, fixed infiltrating lesions or cavities;
3. Abnormal urine sediment
microscopic hematuria (>5 erythrocytes/high magnification view) or presence of erythrocyte tubular pattern;
4. Pathologic granulomatous inflammatory changes
Granulomatous inflammatory changes in the arterial wall or periarterial, or extravascular (arterial or microarterial) areas with neutrophil infiltration.
WG can be diagnosed when 2 or more of the above criteria are met, and the sensitivity and specificity of the diagnosis are 88.2% and 92.0%, respectively.
WG is often misdiagnosed clinically. In order to make early diagnosis, repeated biopsies should be performed on those with the following conditions: unexplained fever with respiratory symptoms; chronic rhinitis and paranasal sinusitis, with mucosal erosions or granulomatous hyperplasia; ulcers, necrosis, or granulomas of the eyes and oral mucosa; variable nodular shadows or cavities in the lungs; and purpura, nodules, necrosis, and ulcerations of the skin.
Differential diagnosis
1. Microscopic polyangiitis (MPA)
MPA is currently recognized as a separate systemic vasculitis. It is a kind of systemic necrotizing vasculitis that mainly involves small blood vessels, and can invade small arteries, microarteries, and small veins of capillaries in organs such as kidneys, skin, and lungs. It often manifests as necrotizing glomerulonephritis and pulmonary capillaritis. Proteinuria, microscopic hematuria, and erythrocyte tubular pattern are seen when the kidneys are involved.ANCA positivity is an important diagnostic basis for MPA, 60% to 80% are positive for myeloperoxidase (MPO)-ANCA, and perinuclear-type ANCA (p-ANCA) is positive by fluorescence detection.Chest X-ray may reveal characteristic lung infiltration shadows or small vesicular infiltration shadows at early stages, and interstitial pulmonary fibrosis in the middle and late stages. Fibrosis.
2. Granulomatous vasculitis with allergy (GSS)
There is severe asthma; small and medium-sized arteries, phlebitis and necrotic granulomas in the lungs and extrapulmonary organs; peripheral blood eosinophils are elevated. both WG and GSS can involve the upper respiratory tract, but the former often has upper respiratory ulcers, and the chest radiographs show destructive lesions in the lungs, such as nodules and cavities, whereas they are rare in GSS. there are very few eosinophils infiltrating the foci of WG, and the eosinophils in the peripheral blood are not obvious, and there are no asthma attacks. There is also no asthma attack.
3. Lymphangiomatoid granulomatosis
Lymphomatoid granulomatosis is a polymorphic cellular infiltrative vasculitis and angiocentric necrotizing granulomatosis, with small lymphocytes, plasma cells, histiocytes, and atypical lymphocytes infiltrating the lungs, skin, nervous system, and renal mesangium, but not the upper respiratory tract.
4. Pulmonary hemorrhage-renalitis syndrome
It is a syndrome characterized by pulmonary hemorrhage and acute glomerulonephritis. Anti-glomerular basement membrane antibody is positive, resulting in diffuse alveolar hemorrhage and glomerulonephritis syndrome, which is characterized by fever, cough, hemoptysis, and nephritis, but there are usually no other signs of vasculitis. The disease mostly lacks upper respiratory tract lesions, and renal pathology shows immune complex deposits in the basement membrane.
5. Recurrent polychondritis
Recurrent polychondritis is mainly characterized by cartilage involvement, and the clinical manifestations may also include nasal collapse, hearing impairment, and tracheal stenosis, but the disease usually involves the auricle without sinus involvement, and the laboratory tests are negative for ANCA and positive for anti-type II collagen antibody in the active stage.
Complications
Hemoptysis, renal insufficiency, organic brain syndrome with psychiatric symptoms, hemianopsia, convulsions and hemiparesis, arthralgias and splenomegaly may occur as complications.
Treatment
Treatment can be divided into 3 phases, i.e. induction of remission, maintenance of remission, and control of relapse. Evidence-based medicine shows that the combination of glucocorticoids plus cyclophosphamide (CTX) has significant efficacy and should be the treatment of choice, especially in patients with renal involvement and severe respiratory disease.
1. Glucocorticoid
Prednisone 1.0~1.5mg/kg.d for 4~6 weeks during active phase, and then reduce the dosage after remission and maintain it in small doses. For serious diseases such as central nervous system vasculitis, respiratory tract lesions with hypoxemia such as alveolar hemorrhage, progressive renal failure, shock therapy can be used: methylprednisolone 1.0g/d × 3 days, the fourth day to oral prednisone 1.0 ~ 1.5mg/kg.d, and then tapered according to the condition.
2. Immunosuppressant
(1) Cyclophosphamide Different methods should be chosen according to the condition. Usually, oral cyclophosphamide 1~3mg/kg.d can be given, or 200mg of cyclophosphamide can be used once every other day. For patients with stable condition, 1mg/kg.d can be used for maintenance. For severe cases, cyclophosphamide can be given as intravenous shock therapy at 0.5~1.0g/m2 body surface area once every 3~4 weeks, and oral cyclophosphamide 100mg per day can also be given.Cyclophosphamide is the basic drug for the treatment of this disease, which can be used for one or several years, and the patients can have long-term remission after withdrawal of the drug. Observe for adverse effects, such as myelosuppression and secondary infections, while on the drug. Evidence-based medicine shows that cyclophosphamide can significantly improve the survival of patients with WG, but cannot completely control the progression of kidney and other organ damage.
(2) Others Azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, etc.
3. Gammaglobulin
Intravenous gammaglobulin interacts with complement and cytokine networks to provide anti-unique antibodies to act on T and B cells. High-dose gammaglobulin also has broad-spectrum antiviral and bacterial effects and neutralizes circulating antibodies. It is usually combined with hormones and other immunosuppressive agents.
4. Anti-infection treatment
Antibiotics are used if there is secondary infection.
5. Biological agents
Tumor necrosis factor (TNF)-a receptor blockers can also be tried in patients who have no effect on prednisone and CTX treatment.
6. Plasma exchange
Plasma exchange therapy can be used as a temporary treatment for active or critical cases. However, it should be combined with hormones and other immunosuppressants.
7. Dialysis
Dialysis is required in acute stage patients with renal failure, and 50% to 90% of patients can recover adequate function.
8. Surgical treatment
Surgical treatment can be considered for patients with subglottic stenosis and bronchial stenosis.
Prognosis
The prognosis of this disease is serious. Those with only upper respiratory symptoms can survive for a long time, but often leave destructive scars. Early diagnosis and rational treatment of the disease have significantly improved the prognosis, with 80% of patients surviving for more than five years; 90% of untreated patients die of renal and respiratory failure within two years. Glucocorticoids and cytotoxic drugs improve the prognosis of Wegener’s granulomatosis, but also cause severe toxicity and immunosuppressive side effects. Combined use of cyclophosphamide significantly reduces its mortality and improves its survival. However, cytotoxic drugs are ineffective in patients with progressive renal insufficiency.
Prevention
The development of this disease may be related to drug allergy, microviral infections, etc. It is especially important to prevent and control respiratory diseases, especially in children, and to treat the symptoms of rhinitis at an early stage.