Nodular disease (sarcoidosis) is a granulomatous disease with multisystem and multiorgan involvement. It often invades the lungs, bilateral hilar lymph nodes, and clinically more than 90% have pulmonary changes, followed by skin and ocular lesions, superficial lymph nodes, liver, spleen, kidney, bone marrow, nervous system, heart, and almost every organ in the body can be involved. The disease is a self-limiting disease with mostly good prognosis and a tendency to spontaneous remission.
The incidence of nodular disease varies considerably around the world, being more frequent in colder regions and countries and less frequent in tropical areas. Sweden has the highest annual incidence of 64/100,000, with an actual autopsy prevalence of up to 267/100,000-641/100,000. The other Nordic regions have an annual incidence of 17.6/100,000 – 200,000/100,000. The annual incidence rate in the United States is 11/100,000-40/100,000, with a predominance of blacks. In Japan, 3106 cases were reported in 1990 since 1912, and the first case was reported in China in 1958, and more than 400 cases were reported nationwide by 1991.
Nodular disease is mostly seen in young and middle-aged people, but children and the elderly can also suffer from it. According to statistics, 55.4% of the total number of patients aged 20-40 years, 12.9% aged under 19 years and 8.3% aged over 60 years. The average age of onset of the disease in China is 38.5 years old, and 55.6% are aged 30-49. The incidence rate of men and women is about the same, slightly more women than men (female: male is 7:5), and black women are twice as many as men.
Etiology and pathogenesis.
Etiology and pathogenesis: The etiology is unknown. Infectious factors (e.g., bacteria, viruses, mycoplasma, fungal species, etc.) have been observed and no definitive conclusions have been obtained. Genetic factors have also been studied and could not be confirmed. In recent years, some authors have found a 50% positive rate of Mycobacterium tuberculosis DNA in patients with nodular disease by PCR technique, thus proposing that nodular disease is the result of invasion of tissue by Mycobacterium bovis, but many experiments have not confirmed this argument. Most people now believe that cellular and humoral immune dysfunction is an important pathogenesis of nodular disease. Macrophages (Am) and T4 cells are activated in the alveoli in response to stimulation by a (certain) nodoplasmogenic antigen. Activated Am releases interleukin-1 (IL-1), a powerful lymphokine that stimulates lymphocytes to release IL-2, which multiplies T4 cells and, in response to lymphokines, activates B lymphocytes. release of immunoglobulins, and hyperfunction of autoantibodies. Activated lymphocytes can release monocyte chemokines, leukocyte inhibitory factors and macrophage migration inhibitory factors. Monocyte chemokines cause a steady flow of monocytes from the peripheral blood to accumulate in the alveolar interstitium, with intra-alveolar concentrations about 25 times higher than in the blood during nodular disease. In the presence of many unknown antigens and mediators, T lymphocytes, monocytes and macrophages infiltrate the alveoli, forming the early stage of tuberculosis, the alveolitis stage. As the lesion progresses, the cellular component of alveolitis decreases, while the macrophage-derived epithelioid cells gradually increase, and under the action of their synthesis and secretion of granuloma-inciting factor (GIF), etc., a typical non-caseating nodular disease granuloma is gradually formed. In the later stage, fibronectin (Fn) released from macrophages attracts a large number of fibroblasts (Fb) and causes them to adhere to the extracellular matrix, which, together with the growth factor of fibroblasts (GFF) secreted by macrophages, leads to an increase in the number of fibroblasts; at the same time, the surrounding In addition, the growth factor of fibroblasts (GFF) secreted by macrophages increases the number of fibroblasts; at the same time, the surrounding inflammatory and immune cells are further reduced to the point of disappearance, leading to extensive fibrosis of the lung.
In conclusion, nodulopathy is the result of the interaction between unknown antigens and the cellular and humoral immune functions of the body. Due to individual differences (age, gender, race, genetic factors, hormones, HLA) and the modulation of the antibody immune response, depending on the state of imbalance between the promoting and antagonistic factors produced, the development and regression of granulomas are determined, showing different pathological states of nodulosis and a tendency to natural remission.
Pathology: granulomas of nodular disease are seen on histological sections as aggregates of dermatoblasts with multinucleated macrophages surrounded by lymphocytes without caseous lesions (Figure 2-11-1). Inclusions such as ovoid Schaumann bodies, birefringent crystals, and asteroid bodies are seen in the vesicular pulp of macrophages. The initial lesions of pulmonary tuberculosis have more extensive alveolitis with infiltration of monocytes, macrophages, and lymphocytes, involving the alveolar wall and interstitium. Both alveolitis and granulomas may dissipate on their own. However, in the chronic stage, the fibroblasts surrounding the granuloma collagenize and become glassy, becoming nonspecific fibrosis. The histomorphological manifestations of granulomas are not characteristic and may be seen in mycobacterial and fungal infections, or as a tissue reaction to foreign bodies or trauma, or in beryllium disease, stage III syphilis, lymphoma, and exogenous allergic alveolitis, and should be differentiated. However, the same histologic lesions seen in multiple organs, combined with clinical data, can diagnose the disease.
Clinical manifestations.
The clinical manifestations of nodular disease vary depending on the urgency of its onset and the number of organs involved. The early stage of intrathoracic nodular disease often has no obvious symptoms and signs. Sometimes there is cough, coughing up a small amount of sputum, and occasionally a small amount of hemoptysis; there may be weakness, fever, night sweats, loss of appetite, weight loss, etc.. When the lesion is extensive, chest tightness, shortness of breath, and even cyanosis may occur. The disease may be aggravated by co-infection, emphysema, bronchiectasis, and pulmonary heart disease. If other organs are also involved in the nodular disease, corresponding symptoms and signs may occur. For example, erythema nodosum is most common in the skin, mostly on the face, neck, shoulders or extremities. There are also lupus pernio, maculopapular rash and papules. Sometimes subcutaneous nodules are found. Invasion of the scalp may cause hair loss. Skin damage can occur in about 30% of patients. Ocular damage may occur in about 15% of cases, and may include iridocyclitis, acute uveitis, and keratoconjunctivitis. Ocular pain, blurred vision, and ciliary congestion may be present. Some patients have hepatomegaly and/or splenomegaly, and mildly increased bilirubin and elevated alkaline phosphatase may be seen, or there may be liver function impairment. The mediastinum and superficial lymph nodes are often invaded and enlarged. If the joints, bones and muscles are involved, there may be multiple arthritis and multiple small cystic bone defects (bone cysts) in short bones of the extremities, hands and feet are seen on x-ray. Muscle granuloma can cause local swelling and pain. The nervous system is involved in about 50% of cases, and its symptoms are variable. Clinical manifestations such as cerebral nerve palsy, neuromyopathy, intracerebral occupying lesions, and meningitis may be present. When myocardium is involved, arrhythmias and even heart failure may be present, and the heart is involved in about 5% of cases. Pericardial effusion may also be present. Nodular disease can interfere with calcium metabolism, leading to increased blood and urine calcium, resulting in kidney calcium deposits and kidney stones. Involvement of the pituitary gland can lead to urolithiasis, and involvement of the inferior optic thalamus can lead to hyperlactation and elevated serum lactogen. Involvement of the parotid gland, tonsils, larynx, thyroid, adrenal glands, pancreas, stomach, and reproductive system can cause related signs and symptoms, but are less common.
Nodular disease can involve one organ or invade multiple organs at the same time.
Laboratory tests.
I. Blood tests
There may be leukopenia, anemia and increased sedimentation during the progressive stage of activity. Serum globulin is partially increased in about 1/2 of patients, with IgG increase being more common, followed by IgG and IgM increase being less common. Plasma albumin is decreased. Blood calcium is increased, serum uric acid is increased, and serum alkaline phosphatase is increased. Serum angiotensin-converting enzyme (SACE) activity is increased in the acute phase (normal value is 17.6-34u/ml), which is diagnostically informative, and serum interleukin-2 receptor (IL-2R) and soluble interleukin-2 receptor (sIL -2R) are elevated and are more important for the diagnosis of nodal disease. It can also a1-antitrypsin, lysozyme, ß2-microglobulin (ß2-MG), serum adenosine dehydrogenase (ADA), and fibronectin (Fn) are elevated, which has some reference significance in clinical practice.
B. Tuberculin test
About 2/3 of patients with nodular disease do not respond to the skin test of 100u tuberculin or have very weak response.
Third, nodular disease antigen (Kveim) test
Lymph nodes or spleen tissue of acute nodule patients are used to make 1:10 saline suspension as antigen. Take 0.1-0.2ml of the suspension for intradermal injection, and after 10 days, a purple-red papule appears at the injection site, spreading to 3-8mm after 4-6 weeks and forming granuloma, which is a positive reaction. The skin with positive reaction was excised for tissue diagnosis, and the positive rate was about 75%-85%. There are 2-5% false positive reactions. Because there is no standard antigen, so the application is restricted and gradually eliminated in recent years.
Biopsy
Take skin lesions, lymph nodes, anterior oblique muscle fat pad, muscle and other tissues for pathological examination can help diagnosis. Taking multiple tissue biopsies from different parts can improve the positive diagnosis rate.
V. Bronchoalveolar lavage fluid examination
Bronchoalveolar lavage fluid (BALF) examination in patients with tuberculosis shows a significant increase in lymphocytes and polymorphonuclear leukocytes, mainly T-lymphocytes, and a significant increase in CD4+ and CD4+/CD8+ ratios during the alveolitis stage. IgG and IgA were elevated in BALF, especially in IgG1 and IgG3. It has been reported that if the percentage of lymphocytes in the whole lung effector cells is greater than 28%, it indicates lesion activity.
VI. Trans-fiber bronchoscopic lung biopsy (TBLB)
The positive rate of TBLB for nodular disease can reach 63%-97%, with a very low positive rate in stage 0, more than 50% positive in stage I, and a higher positive rate in stages II and III.
VII. X-ray examination
Abnormal chest X-ray is often the primary finding of nodular disease, and more than 90% of patients have chest X-ray changes. At present, the staging of nodular disease by plain X-ray is still not unified. 1961, Scandding divided nodular disease into four stages (stages 1-4), and in recent years, it has been divided into five stages (stages 0, 1-4). The more commonly used is still the Siltzbach stage, and this classification is also used in China.
Stage 0 Negative lung x-ray with clear lungs.
Stage I Enlarged hilar and/or mediastinal lymph nodes on both sides, often accompanied by enlarged right paratracheal lymph nodes, accounting for about 51%.
Stage II Hilar lymph node enlargement with pulmonary infiltration. The pulmonary lesions are widely and symmetrically distributed on both sides in the form of 1-3 mm nodular, punctate or flocculent shadows. In a few cases, they may be distributed on one lung or certain lung segments. The lesions may gradually resorb over a year or develop into interstitial lung fibrosis in about 25% of cases.
Stage III Only pulmonary infiltration or fibrosis without hilar lymph node enlargement is seen in about 15% of cases.
The above stages do not indicate the sequential pattern of the development of nodular disease, and stage III does not necessarily develop from stage II.
VIII. Chest computed tomography (CT) scan
The correct diagnosis rate of nodular disease by plain X-ray chest film is only 50%, and even 9.6% of people with normal chest film have lung biopsy for nodular disease. Therefore, CT has been widely used for the diagnosis of nodular disease in recent years. It can more accurately estimate the type of nodular disease, the extent of interstitial lung lesions and lymph node enlargement. Especially, high-resolution thin layer CT is more accurate for the diagnosis of interstitial lung lesions, and its layer thickness is 1-2mm.
IX. 67 gallium (67Ga) lung scan examination
Granuloma-active macrophage uptake of 67Ga is significantly increased. Granulomatous lesions of nodular disease and hilar lymph nodes in the lung can be revealed by 67Ga, which can assist in the diagnosis but is not specific.
Diagnosis and Differentiation.
Diagnosis: The diagnosis of nodular disease is determined by clinical signs and symptoms and tissue biopsy, with the exception of other granulomatous diseases. The diagnostic criteria can be summarized as follows: (1) symmetrical enlargement of bilateral hilar and mediastinal lymph nodes with or without intrapulmonary lattices, nodular or lamellar shadows on chest imaging; (2) non-caseating necrotizing granuloma confirmed by histological biopsy with negative antacid staining; (3) increased SACE or SL activity; (4) high sIL-2R in serum or BALF; (5) positive old tuberculin (OT) or PPD test or weakly positive; (6) lymphocytes >10% in BALF and CD4+/CD8+ ratio ≥3; (7) hypercalcemia and hypercalcemia; (8) positive Kveim test; (9) excluding tuberculosis or other granulomatous diseases. Among the above nine conditions, ①, ② and ③ are the main conditions, and the others are secondary conditions.
Differential diagnosis.
It should be differentiated from the following diseases.
I. Pulmonary hilar lymph node tuberculosis
Patients are younger, mostly under 20 years of age, and often have low-grade toxicity symptoms. Tuberculin tests are mostly positive, and hilar lymph node enlargement is usually unilateral and sometimes calcified. Primary lung lesions may be seen.
Second, lymphoma
Common systemic symptoms include fever, emaciation, anemia, etc. Pleural involvement, pleural effusion, asymmetric enlargement of intrathoracic lymph nodes, usually unilateral or bilateral, often involving the upper mediastinum, inferior bulge and mediastinal lymph nodes. Mediastinal compression may result in superior vena cava obstruction syndrome. Combined with other examinations and biopsy, it can be differentiated.
Metastatic tumor in the lung hilum
Lung cancer and extra-pulmonary carcinoma metastasizing to hilar lymph nodes have corresponding symptoms and signs, and further examination of the suspected primary foci can help differentiate them.
IV. Other granulomatous diseases
Such as exogenous alveolitis, beryllium disease, silicosis, granulomas caused by infectious and chemical factors, should be distinguished from nodular disease, combined with clinical data and relevant examinations for comprehensive analysis and judgment.
Treatment.
Because most patients can remit on their own, patients with stable and asymptomatic disease do not need treatment. Patients with obvious symptoms of stage II and III nodular disease and extra-thoracic nodular disease such as ocular nodular disease, nodular disease invasion of the nervous system, skin and myocardial involvement, persistent increase in blood calcium and urine calcium, and significant increase in SACE level can be treated with hormone therapy. Prednisone is commonly used at 30-60mg per day, once orally (or in divided doses), with a gradual reduction to 15-30mg/d after 4 weeks, and a maintenance dose of 5-10mg/d for one year or longer. Long-term use of glucocorticosteroids should be closely observed for side effects of hormones, followed by the treatment of chloroquine, methotrexate, azathioprine, etc.
Any drugs that can cause an increase in blood calcium and urine calcium, such as vitamin D, are listed as contraindications.
Prognosis prevention.
It is related to the condition of nodular disease. In acute cases, the prognosis is better with treatment or self-remission, whereas in chronic progressive cases, invasion of multiple organs, causing functional impairment, extensive pulmonary fibrosis, or acute infection, the prognosis is worse. The cause of death is often due to pulmonary heart disease or myocardial or cerebral invasion. On average, 34% of cases have been reported to recover completely, 30% to improve, 20% to remain unchanged, and 8% each to deteriorate and die during the 5-year follow-up.
Common sense of prevention.
Patients should first increase their confidence and patience in treatment. Most of the disease can be treated or remit naturally, but its recovery process often takes several years. It is important to protect the eyes, skin, and joints to prevent aggravation of the damage in that area; prevention of respiratory infections can reduce the damage to the lungs.