Overview.
An unexplained systemic granulomatous disease with common symptoms including fever, muscle pain, dry eyes, rash, and arthralgia. The cause of the disease is unclear and may be related to genetic, environmental, and immunologic factors. Treatment includes general and pharmacologic therapies.
Definition
Nodular disease is a granulomatous disease of unknown origin involving multiple systems and characterized by non-caseating necrotizing epithelioid cell granulomas.
It primarily affects the lungs and lymphatic system, followed by the eyes and skin.
Incidence
Authoritative and recognized epidemiological data are lacking in our country.
Nodular disease has obvious regional and racial differences, with cold regions being more common than tropical regions, and blacks being more common than whites.
It is more common in young and middle-aged people (<40 years old), with a slightly higher prevalence in women than in men.
Causes
Causes
The cause of the disease is not clear, genetic factors, environmental factors, immune factors may be related to this disease.
Genetic factors
The clinical phenotype of nodular disease and the racial differences in the disease suggest the role of genetic factors.
The gene that has been shown to be most closely associated with susceptibility and phenotype of nodular disease is located in the major histocompatibility complex (MHC) region of chromosome 6.
Environmental factors
Infections such as Burkholderia sparsis, Propionibacterium acnes, tuberculosis, and other mycobacteria may be associated with the development of nodular disease.
Immunologic Factors
It is currently believed that human leukocyte antigens (HLA) are associated with the development of nodular disease, with HLA-DQB1 and HLA-DRB1 being closely associated with nodular disease.
Pathogenesis
The pathogenesis of Nodular Disease is not clear. It may be that genetically susceptible individuals are stimulated by specific environmental antigens, leading to cell aggregation, proliferation, differentiation and granuloma formation.
Symptoms
Nodular disease is a multi-systemic disease with clinical manifestations related to the organs involved. Acute cases are rare, and clinically insidious subacute or chronic onset is common. Some patients may be asymptomatic and occasionally found on physical examination.
Acute nodular disease
The main manifestations are arthritis and erythema nodosum, often accompanied by fever, muscle pain, general malaise and other symptoms.
Eighty-five percent of patients may resolve on their own within one year.
Subacute or chronic nodular disease
Systemic symptoms
Fever, malaise.
Weight loss.
Joint pain.
Enlarged lymph nodes.
Night sweats.
Lung involvement
More than 90% of nodular disease involves the lungs with insidious clinical manifestations.
Thirty to fifty percent of patients present with dry cough, chest tightness, dyspnea, and wheezing.
Retrosternal chest pain is relatively common, and most of it is insidious.
Lymph node involvement
Lymph node enlargement is palpable in 30% to 40% of patients.
Lymph nodes in the neck, axilla, medial epicondyle of the humerus, and groin are most commonly involved.
The swellings are nonfusing, mobile, and nontender.
Skin Involvement Symptoms
Erythema nodosum: Most commonly, scattered painful subcutaneous nodules occur on the face, back, and extensor surfaces of the extremities, with reddened skin on their surfaces, which may be accompanied by joint pain and fever.
Subcutaneous lesions: firm subcutaneous nodules of bean to corn size, adherent to the skin, mostly on the trunk.
Maculopapular eruptions: large lobulated nodular plaques with a flattened and slightly elevated surface, commonly found on the cheeks, nose, and arms.
Frostbite-like lupus: Symmetrical bluish-red or purplish-red plaques appear in areas prone to frostbite, such as the auricles, cheeks, tip of the nose and fingers (toes).
Other skin lesions: itchy skin rash, erythema multiforme, skin atrophy, hyperkeratosis, increased or decreased pigmentation.
Symptoms of eye involvement
Uveitis is the most common, mostly chronic granulomatous, but also acute or chronic non-granulomatous.
Most of them are characterized by eye pain, eye dryness, vision loss, photophobia, etc.
Symptoms of cardiac involvement
The main manifestations are fatigue, palpitations, heart failure or sudden death.
Nervous System Involvement
Nodular disease can invade any part of the nervous system, with peripheral and cerebral nerve damage being the most common.
It may be manifested as abnormal sensation, dizziness, headache, weakness of limbs and difficulty in swallowing.
Symptoms of kidney involvement
Glomerular, tubular, or arteriolar involvement is rare in tuberculosis, but overproduction of 1,25-dihydroxyvitamin D3 is common and can lead to increased intestinal calcium absorption, increased bone calcium absorption, and increased urinary calcium with or without hypercalcemia.
This may be manifested as inattention, lethargy, anorexia, and polyuria.
Symptoms of digestive system involvement
Mainly involves the liver, spleen, pancreas and gastrointestinal tract.
It may manifest as abdominal pain, diarrhea, abdominal distension, etc.
Parotid Gland Involvement Symptoms
It can involve parotid gland, lacrimal gland and submaxillary gland.
It mostly manifests as unilateral or bilateral enlargement of the parotid gland.
Complications
The following complications can occur if nodular disease involves the eyes and kidneys:
Cataract: manifested by cloudy and blurred vision, loss of vision, etc.
Glaucoma: blurred vision, headache, eye swelling, visual field defects, etc.
Kidney failure: presenting with multi-system symptoms such as little or no urine, generalized edema, nausea and vomiting.
Consultation
Department of Medicine
Respiratory Medicine
It is recommended to consult the doctor promptly if the X-ray chest film appears abnormal during physical examination, or if shortness of breath, dry cough, chest tightness, etc. appear.
Rheumatology
If you have joint pain or erythematous nodules with tenderness, it is recommended that you consult a doctor promptly.
Preparation for medical treatment
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for medical treatment
Chest X-rays or chest CT are often needed, so avoid wearing clothing made of metal, and inform your doctor if you are pregnant or planning to become pregnant.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Is there a cough? Is there phlegm?
Is there chest tightness, shortness of breath or chest pain?
Is there a fever? What is the highest degree?
Are there painless, movable swellings in the armpits, neck, etc.?
Are there painful subcutaneous nodules on the face, back, etc.?
Is there any loss of vision, dry eyes, or eye pain?
How long have the symptoms been present?
Medical History Checklist
Particular attention needs to be paid to the time of onset of symptoms, specific presentations, etc.
Does anyone in the family have nodular disease?
Checklist
Test results for the last 6 months, which can be brought to the doctor’s office
Laboratory tests: blood test, C-reactive protein, erythrocyte sedimentation rate (ESR), tuberculin test
Imaging tests: Chest X-ray, Chest CT scan
Others: Bronchoscopy
Medication list
Medication used in the last 3 months, if there is a box or package, you can bring it with you to the doctor’s office
Glucocorticoid: prednisone, methylprednisolone
Immunosuppressants: methotrexate, azathioprine
Diagnosis
Disease diagnosis
Medical history
History of viral infection, autoimmune disease, or systemic disease.
Relatives who have had patients with this disease.
Clinical manifestations
Symptoms such as dry cough, chest tightness, shortness of breath, chest pain, and wheezing with or without fever, malaise, arthralgia, and rash.
Laboratory Tests
Routine blood tests
To find out the changes of blood cells (red blood cells, white blood cells, platelets) and hemoglobin.
Most patients may have anemia and a decrease in white blood cells and platelets in the blood.
Fasting is not required before the test.
Erythrocyte Sedimentation Rate and C-Reactive Protein
are the main indicators of disease activity.
Increased erythrocyte sedimentation rate and elevated C-reactive protein are often seen.
Serum calcium and immunoglobulin
Some patients may have elevated serum calcium and elevated IgG.
Tuberculin test
An important means of determining whether the organism is infected by Mycobacterium tuberculosis.
Tuberculin is injected intradermally, and the area of redness and sclerotic reaction of the skin around the skin test site is measured and recorded 48 to 72 hours after the skin test.
Patients often test negative or weakly positive.
Elderly people are slower to respond to the tuberculin test than younger people, and it may take up to 72 hours before a reaction is detected.
Liver and kidney function
It is important to know the status of liver and kidney function to determine how impaired it is.
Creatinine and urea nitrogen may be elevated in impaired kidney function.
When liver function is impaired, aminotransferases are elevated, as is bilirubin.
Fasting is required before blood tests.
Imaging
Chest X-ray
More than 90% of patients present with abnormal chest radiographs, which are a sensitive tool for suggesting the diagnosis. Bilateral hilar lymph node enlargement with or without right paratracheal lymph node enlargement is the most common sign.
Clinically, nodal disease is usually staged as follows based on the posterior anterior chest radiograph:
Stage 0: no abnormal X-ray manifestations.
Stage I: bilateral hilar lymph node enlargement without pulmonary infiltrative shadows.
Stage II: bilateral hilar lymph node enlargement with reticular, nodular or lamellar infiltrating shadows in the lungs.
Stage III: reticular, nodular or lamellar infiltrating shadows in the lungs without bilateral hilar lymph node enlargement.
Stage IV: pulmonary fibrosis, honeycomb lung, pulmonary pustules, emphysema.
Chest CT
Typical presentation is a distribution of tiny nodules along the bronchovascular bundles, which may fuse to form a ball. Other abnormalities include ground-glass lesions, cords and bands, honeycomb lungs, stretched bronchiectasis, and twisting or distortion of blood vessels or bronchi.
The lesions tend to invade the upper lobes of the lungs, and the lung bases are relatively normal. Enlarged lymph nodes in the pretracheal, paratracheal, para-aortic, and subglottic regions are seen.
67Ga核素显像
The uptake of 67Ga by granulomatous activated macrophages is markedly increased, and granulomatous lesions can be visualized by 67Ga, which helps to understand the activity and degree of involvement of nodal disease lesions and provides a basis for biopsy sites.
Specialized tests
Lung function test
Lung function test can understand the degree of lung damage, early lung function can be normal, late stage can show restrictive ventilation dysfunction and diffusion impairment.
Bronchoscopy
Bronchoscopy may show widening of the tracheal eminence due to enlargement of the subglottic lymph nodes, and mucosal nodules due to involvement of the tracheal and bronchial mucosa.
Bronchoscopy also allows cytologic examination of the bronchoalveolar lavage fluid and transbronchoscopic lung biopsy, which confirms the presence of non-caseating necrotizing epithelioid granulomas and contributes to the diagnosis of the disease.
Fundoscopy
To make a definitive diagnosis of uveitis or other pathology of the fundus.
Differential diagnosis
The clinical manifestations of tuberculosis are complex and varied, and the doctor will differentiate the disease from other diseases according to the different clinical manifestations.
Tuberculosis of hilar lymph nodes
Similarities: fever, cough, night sweats, fatigue and weakness.
Differences: Tuberculosis of hilar lymph nodes often occurs in adolescents and can be differentiated by imaging and tuberculin test.
Lymphoma
Similarities: enlarged lymph nodes, fever, night sweats, dry cough.
Differences: Lymphoma is a group of malignant tumors originated from lymph nodes or other lymphatic tissues, which need to be differentiated according to clinical manifestations, laboratory tests, imaging tests and tissue biopsy.
Pulmonary hilar metastatic tumor
Similarities: cough, chest pain, shortness of breath, etc.
Differences: Lymph node enlargement may occur when the tumor in other parts of the body or the tumor in the lung metastasizes through the lymphatic vessels, and it mostly occurs in the unilateral lung, with poor physical condition of the patient and rapid development of the disease. It can be differentiated by imaging examination, laboratory examination and tissue biopsy.
Lung cancer
Similarity: cough, chest pain, shortness of breath, fever, etc.
Differences: Lung cancer, especially central lung cancer, is often accompanied by hilar lymph node metastasis, resulting in enlarged hilar lymph nodes on the same side of the lung. It needs to be differentiated by bronchoscopy, bronchoalveolar lavage fluid examination and tissue biopsy.
Treatment
Aims and principles of treatment
Purpose of treatment
To control the activity of nodal disease and protect the function of important organs.
Principles of treatment
Treatment of nodular disease requires a comprehensive decision based on the severity and extent of the disease involved.
If there are no symptoms or the symptoms are mild, the disease may be observed without treatment.
If significant intrapulmonary or extrapulmonary symptoms occur, especially involving the heart and nervous system, drug treatment is required.
Treatment
General treatment
Those with severe symptoms in the acute phase need bed rest and close monitoring of respiration, heart rate, blood pressure and oxygen saturation.
When breathing is labored, try to take a semi-recumbent position or sitting position, lying on the bed table to improve breathing.
Diet should be light, avoid spicy and stimulating foods, and eat small and frequent meals.
Medication
Glucocorticoids
The drug of choice for the treatment of nodular disease, usually need to be taken orally for a long time.
Prednisone and methylprednisolone can be used.
If the clinical symptoms are relieved and stabilized, the drug can be gradually reduced or stopped according to the doctor’s opinion.
Long-term use of glucocorticosteroids should be aware of the adverse effects such as infection, osteoporosis and hypokalemia.
Immunosuppressant
For glucocorticoid treatment is ineffective, poorly tolerated and some of the patients with severe disease onset, other immunosuppressants can be considered. Currently, the most commonly used immunosuppressants are azathioprine and methotrexate.
Precautions for the use of azathioprine: patients’ blood and liver function should be closely monitored, especially in the first month of use, and regular review is recommended according to the doctor’s instructions.
Methotrexate medication precautions: due to the potential risk of lung damage, methotrexate is generally not used in patients with interstitial pneumonia. Adverse reactions such as bone marrow suppression, liver damage and gastrointestinal symptoms should also be noted during administration.
Special Reminder
During drug treatment, you should adhere to the strict instructions of the doctor, do not change the dose of the drug without authorization or stop the drug suddenly, to ensure that the treatment plan is implemented.
Prognosis
Cure
Some patients with nodular disease can remit on their own, and its natural remission rate is 55% to 90% in stage I, 40% to 70% in stage II, and 10% to 20% in stage III.
The prognosis of patients with chronic progressive, multiple organ function damage and extensive pulmonary fibrosis is poorer, with an overall mortality rate of 1% to 5%. The cause of death is often due to respiratory insufficiency or cardiac or central nervous system involvement.
Hazards
Symptoms such as cough, fatigue, night sweats, fever, and skin rashes often occur, which can seriously affect normal work and life.
With the development of the disease, it will also lead to the damage of multiple organs and systems, further affecting the health, and bringing a greater psychological and economic burden to themselves and their families.
If glucocorticoids are taken for a long period of time, serious adverse reactions such as infection, osteoporosis, hypokalemia, hypertension, hyperglycemia, hyperlipidemia, etc. may occur, further affecting health and quality of life.
Daily
Daily Management
Dietary management
Reasonable diet, it is advisable to choose light and easy-to-digest food.
Eat more fresh vegetables and fruits.
If there is no cardiac or renal insufficiency, drink more water in moderation to replenish the consumed water and dilute the sputum, which is conducive to sputum discharge.
Avoid eating spicy and stimulating foods, such as wine, strong tea, coffee, raw garlic, ginger, chili peppers, curry and so on.
Give patients enough time to eat, such as coughing, shortness of breath or feel swallowing effort, can be appropriate rest before continuing to eat.
If there are signs of malnutrition such as significant reduction in food intake, weight loss, mental weakness, loss of skin elasticity, etc., timely consultation should be made.
Life management
Appropriate activities and respiratory training can be carried out under doctor’s guidance to help restore lung function.
Activities with high oxygen consumption should be avoided, and you can start with low-intensity activities such as walking according to your condition.
In the more severe cases, to reduce physical exertion and oxygen consumption, bed rest is required and self-care activities and unnecessary operations should be minimized.
When breathing is labored, try adopting a semi-recumbent or sitting position, lying on the bed table to improve breathing.
Clothing is recommended to choose cotton fabrics and avoid chemical fibers to protect the skin.
Pay attention to a neat and clean environment and open windows regularly every day for ventilation.
Avoid going to places where people gather.
Observe the weather changes and increase clothing appropriately in cold weather.
Strictly quit smoking and avoid exposure to “second-hand smoke”.
Psychological support
Face the disease with a positive and optimistic attitude and build up confidence in overcoming the disease.
Talk to your family, partner and friends about your feelings.
Follow-up
Pay attention to changes in your condition and go to the hospital if your symptoms worsen or recur.
It is recommended that patients be followed up every 3 to 6 months for at least 3 years or until their condition stabilizes, so that doctors can understand and compare the changes in their condition and adjust their medication.
Prevention
The cause of nodular disease is not known and there is no effective preventive measure, but the risk of the disease can be reduced by the following measures:
If any of your relatives have nodular disease, you should have regular medical checkups and seek prompt medical attention if you feel unwell.
Actively treating autoimmune diseases or other systemic diseases.
Eat a balanced diet with a variety of food types.
Avoid closed, airless public places and crowded places during the epidemic season.
Ensure a good mood and adequate sleep, and have a regular work schedule.