Lung sarcoidosis

Sarcoidosis (Behnier-Beck-Shauman's disease) is a systemic disease characterized by the development of productive inflammation with the formation of epithelioid-cell granulomas without necrosis with the outcome of resorption or fibrosis.

Sarcoidosis is characterized by the formation of noncaseating granulomas in one or more organs and tissues; the etiology is unknown. Most often the lungs and lymphatic system are affected, but sarcoidosis can affect any organ. Symptoms of sarcoidosis of the lungs vary from total absence (limited disease) to shortness of breath when exercising and, rarely, respiratory or other organ failure (a common disease). The diagnosis is usually first suspected with involvement in the lung process and is confirmed by chest radiography, biopsy and the exclusion of other causes of granulomatous inflammation. Glucocorticoids are the first line treatment. The prognosis is very good for a limited form of the disease, but it is unfavorable for a more common disease.

Sarcoidosis primarily affects people aged 20-40 years, but sometimes occurs in children and older adults. Across the world, prevalence is greatest in African Americans and northern Europeans, especially Scandinavians. The prevalence of sarcoidosis in the world is on average 20 per 100 000 population (in different countries, the figures range from 10 to 40). Manifestations of the disease vary widely, depending on race and ethnicity, with African Americans and Puerto Ricans more likely to have extrathoracic manifestations. For unknown reasons, sarcoidosis of the lungs is slightly more common in women.
 
The incidence increases in winter and early spring.

Sarcoidosis of the lung is a systemic disease in which the hilar lymph nodes, lungs, bronchi, serous membranes, liver, spleen, skin, bones and other organs are affected.

[1], [2], [3],

What causes sarcoidosis of the lungs?

Sarcoidosis is believed to develop as a result of an inflammatory reaction to the environmental factor in hereditarily predisposed people. Viral, bacterial and mycobacterial infections and inorganic (eg, aluminum, zirconium, talc) or organic substances (for example, pollen of pine, clay) are assumed to be involved in the role of triggers, but these assumptions have not yet been proven. Unknown antigens cause a cellular immune response characterized by the accumulation of T-lymphocytes and macrophages, the release of cytokines and chemokines, and the formation of granulomas. Sometimes a family history or an increase in morbidity in certain communities suggests a genetic predisposition, certain effects, or, less likely, transmission from person to person.

The result of the inflammatory process is the formation of noncaseating granulomas, a characteristic feature of sarcoidosis. Granulomas are clusters of mononuclear cells and macrophages that are differentiated into epithelioid and multinucleated giant cells surrounded by lymphocytes, plasmacyttes, mast cells, fibroblasts and collagen. Granulomas are usually found in the lung and lymph nodes, but can form in many other organs, including the liver, spleen, eye, nasal sinuses, skin, bones, joints, skeletal muscles, kidneys, reproductive organs, heart, salivary glands and nervous system. Granulomas in the lung are located along the lymphatic vessels, most often in the peribronchiolar, subpleural and perilobular regions.

Symptoms of sarcoidosis of the lungs

Symptoms of sarcoidosis of the lungs depend on the localization and extent of the lesion and change over time, ranging from spontaneous remission to chronic asymptomatic disease. Therefore, a regular examination is needed to identify new symptoms in various organs.

Systemic symptoms of sarcoidosis

System	Frequency of injury	Comments
Pleuropulmonary (lungs, pleura)	> 90%	Granulomas are formed in alveolar septa, bronchiolar and bronchial walls, causing diffuse pulmonary involvement; pulmonary arteries and veins are also involved Often asymptomatic. Spontaneously resolved in many patients, but can cause progressive pulmonary dysfunction, leading to limitations of physical activity, respiratory failure and death in a few patients Leads to the development of lymphocytic exudative effusions, usually bilateral
Lymphatic	90%	Involvement of the roots of the lungs or mediastinum in most patients is found by chance during chest X-ray. In others, mild peripheral or cervical lymphadenopathy
GI Hepatic Splenic Others	40-75%	Usually it is asymptomatic; manifested as moderate increases in functional hepatic tests, a decrease in the accumulation of the drug in CT with contrast Rarely leads to clinically significant cholestasis, cirrhosis It is unclear the difference between sarcoidosis and granulomatous hepatitis, when sarcoidosis damages only the liver Usually occurs asymptomatically, manifested by pain in the left upper quadrant of the abdomen, thrombocytopenia, an unexpected finding on the x-ray or CT Rare reports of gastric granulomas, rare intestinal involvement; mesenteric lymphadenopathy can cause abdominal pain
Body of sight	25%	Most often, uveitis with visual impairment, photophobia and lacrimation. Can cause blindness, but more often it is resolved spontaneously Conjunctivitis, iridocyclitis, chorioretinitis, dacryocystitis, infiltration of the lacrimal glands, leading to dry eyes, optic neuritis, glaucoma and cataracts also occur Involving the organ of vision more often in African Americans and Japanese For the early detection of ocular pathology, a survey is performed once or twice a year
Musculoskeletal	50-80%	Asymptomatic disease with increasing / no increase in enzymes in most patients; sometimes mute or acute myopathy with muscle weakness Ankle joint, knee, wrist, elbow joint - the most frequent localization of arthritis; can cause chronic arthritis with deformities of Jakkoud or dactylitis Léfgren's syndrome is a triad of symptoms, including acute polyarthritis, erythema nodosum and lymphadenopathy of the roots of the lungs. It has various features; more common in Scandinavian and Irish women, often sensitive to NSAIDs and often self-inflicted; low relapse rate Osteolytic or cystic lesions; osteopenia
Dermatological	25%	Nodular erythema: red solid tender nodules on the front surfaces of the legs; more often among Europeans, Puerto Ricans and Mexicans; usually takes 1-2 months; surrounding joints often with arthritis (Léfgren's syndrome); can be a good prognostic sign Nonspecific skin lesions; maculae and papules, subcutaneous nodules and hypopigmentation and hyperpigmentation also occur frequently Lumbar lupus: protruding spots on the nose, cheeks, lips and ears; more often in African Americans and Puerto Ricans; often associated with lung fibrosis; bad prognostic sign
Neurological	<10%	Neuropathy of the cranial nerves, especially the 7th (leads to paralysis of the facial nerve) and the 8th (hearing loss) of the pairs. Also, peripheral neuropathy and optic nerve neuropathy are common. Any pair of cranial nerves can be affected Involvement of the central nervous system, with nodal lesions or diffuse inflammation of the medullary membrane, is typical in the cerebellum and the region of the brainstem Hypothalamic diabetes insipidus, polyphagia and obesity, thermoregulatory disorders and changes in libido
Renal	10%	Asymptomatic hypercalciuria is most common; interstitial nephritis; chronic renal failure caused by nephrolithiasis and nephrocalcinosis requires renal transplantation (dialysis or transplantation) in some patients
Cordial	5%	Arrest blockades and arrhythmias are most frequent and can cause sudden death; also cardiac insufficiency is possible due to restrictive cardiomyopathy (primary) or pulmonary arterial hypertension (secondary) Transient dysfunction of papillary muscles and rarely pericarditis More often in Japanese, in whom cardiomyopathy is the most common cause of death from sarcoidosis
Reproductive	Rarely	There are data on the lesion of the endometrium, ovaries, epididymis and testicles. Does not affect fertility. The disease can subside during pregnancy and recur after delivery
Oral cavity	<5%	Asymptomatic swelling of parotid glands most often; parotitis with xerostomia is also possible; may be a component of keratoconjunctivitis dry Heerford's syndrome (also called uveoparotid fever): uveitis, bilateral parotid swelling, facial paralysis and chronic fever Lupus pernio oral cavity can mutilate the hard palate and affect the cheeks, tongue and gums
Nasal sinuses	<10%	Acute and chronic granulomatous inflammation of the mucous membrane of the sinuses produces symptoms that are indistinguishable from simple allergic and infectious sinusitis. A biopsy confirms the diagnosis. More common in patients with lupus erythematosus
Endocrine	Rarely	Infiltration of the hypothalamic zone and the stalk of the pituitary gland can cause panhypopituitarism; can cause infiltration of the thyroid gland without dysfunction; secondary hypoparathyroidism due to hypercalcemia
Mental	10%	Depression develops frequently. It is doubtful if this is the first manifestation of sarcoidosis, it is more often a reaction to a long course of the disease and frequent relapses
Hematological	<5-30%	Lymphopenia; anemia of a chronic disease; anemia due to granulomatous bone marrow infiltration, sometimes leading to pancytopenia; sequestration of the spleen leading to thrombocytopenia; leukopenia

 
Apparently, most cases are asymptomatic and therefore remain undiagnosed. Pulmonary disease occurs in more than 90% of adult patients with sarcoidosis.

Stages of sarcoidosis of the lungs

Stage	Definition	Frequency of spontaneous remissions
0	Normal chest radiography	Usual remission; there is no correlation with the forecast
1	Bilateral lymphadenopathy of the roots, paratracheal and mediastinal lymph nodes without parenchymal infiltrates	60-80%
2	Bilateral lymphadenopathy of the roots / mediastinum with interstitial infiltrates (usually upper pulmonary fields)	50-65%
3	Diffuse interstitial infiltrates without adenopathy of the roots	<30%
4	Diffuse fibrosis, often associated with fibrous-bearing formations, traction of the bronchi, traction cysts	0%

Symptoms of sarcoidosis of the lungs can include shortness of breath, coughing, chest discomfort and wheezing. Fatigue, malaise, weakness, anorexia, weight loss and a slight increase in body temperature also occur frequently; sarcoidosis is a frequent cause of fever of unknown origin. Often the only sign is lymphadenopathy, lymph nodes are enlarged, but painless. Systemic manifestations cause various symptoms of sarcoidosis, which vary depending on race, gender and age. Negro people are more likely to be affected by the eyes, liver, bone marrow, peripheral lymph nodes and skin (but not erythema nodosum). In women, nodosum erythema often occurs and the nervous system or eyes are involved. In men and older patients, hypercalcemia is more common. In children younger than 4 years, the most frequent manifestations are arthritis, rashes and uveitis. In this age group, sarcoidosis can be confused with juvenile rheumatoid arthritis.

Classification of pulmonary sarcoidosis

The most common and accessible classification of lung sarcoidosis is the classification of K. Wurm.

Unfortunately, in the Wurn classification, not all clinical aspects of sarcoidosis are reflected. In particular, there is no indication of the possibility of combining pulmonary and extrapulmonary manifestations of sarcoidosis, the activity of the pathological process is not reflected. In this respect, the classification of AG Khomenko deserves much attention.

[4], [5], [6], [7], [8], [9], [10]

Classification of respiratory sarcoidosis (K. Wurm, 1958)

• I Isolated enlargement of the intrathoracic lymph nodes (mediastinal lymphadenopathy)
• II Combined lesion of intrathoracic lymph nodes and lungs
  • II-A Strengthening of the pulmonary pattern, its mesh deformation (excessive, loopy pattern in the basal and lower parts of the lungs)
  • II-B Common bilateral small focal shadow in the lungs (miliary type)
  • II-B Conventional bilateral mid-range shadows (3-5 mm in diameter) in the lungs
  • II-D Common bilateral, large-focal shadows (9 mm in diameter and larger) in the lungs
• III The combination of mediastinal lymphadenopathy with pronounced disseminated fibrosis and large drainage formations:
  • III-A in the lower parts of the lungs
  • III-B in the upper and middle parts of the lungs

[11], [12], [13], [14], [15]

Diagnosis of pulmonary sarcoidosis

Sarcoidosis of the lung is most often suspected when chest radiography accidentally reveals lymphadenopathy of the roots of the lung. These changes are the most frequent radiologic signs of the disease, they are also prognostic signs of spontaneous remission in patients with lung involvement. Therefore, chest X-rays should be the first test if it has not yet been performed in patients with suspected sarcoidosis.

Because lung involvement is so frequent, normal chest radiography generally excludes a diagnosis. In cases where the disease is still suspected, despite normal chest radiography, it is necessary to make a high-resolution CT chest, which is more sensitive to detecting lymphadenopathy of the roots of the lungs and mediastinum. CT results in later stages (II-IV) include thickening of bronchovascular joints and bronchial walls; knotty change of interlobular partitions; infiltration by the type of frosted glass; parenchymal nodules, cysts or cavities, and / or traction of the bronchi.

When sarcoidosis is suggested based on the results of visualization studies, the diagnosis is confirmed by the detection of noncaseating granulomas on a biopsy and the elimination of alternative causes of granulomatous disease. For diagnosis, it is necessary to select the right site for biopsy, exclude other causes of granulomatous disease and determine the severity and prevalence of the disease in order to assess the need for therapy.

Biopsy sites can be determined by physical examination and palpation: peripheral lymph nodes,
skin lesions and conjunctiva are readily available for biopsy. However, in patients with intrathoracic lymphadenopathy, bronchoscopic transbronchial biopsy is preferred, since sensitivity reaches 90% when performed by an experienced specialist. Videotoracoscopy can provide access to lung tissue when a bronchoscopic transbronchial biopsy is uninformative. Sometimes mediastinoscopy is performed if the lymphadenopathy of the roots or mediastinum exists in the absence of a pulmonary infiltrate, especially if lymphoma requires a differential diagnosis. However, even in patients with lymphadenopathy only in the mediastinum, according to X-ray or CT, transbronchial biopsies are often diagnostic. Open lung biopsy is another way to get tissue, but requires general anesthesia and is currently rarely done. Clinical and radiographic findings may be accurate enough for diagnosis in stage I or II, when biopsy is not possible.

Elimination of other diagnoses is mandatory, especially when the symptoms of lung sarcoidosis and radiographic signs are minimal, since granulomatous inflammation can be caused by many other diseases. The tissue of the biopsy should be sown on mushrooms and mycobacteria. An anamnesis of occupational hazards (silicates, beryllium) and environmental factors (crushed hay, poultry and other antigen triggers of pneumonitis of hypersensitivity) should be analyzed; tests for infectious antigens (tuberculosis, coccidioidomycosis, histoplasmosis) have been carried out. As soon as possible, cutaneous tuberculin samples should be delivered with anergy control.

The severity of the disease is assessed by lung function and pulsoximetry data. The results of lung function tests are often normal in the early stages, but demonstrate the restriction and reduced diffusion capacity of carbon monoxide (DL ^) in advanced stages of the disease. Also, there is sometimes an obstruction of the air flow, which can indicate the involvement of the bronchial mucosa. Pulse oximetry is often normal when measured at rest, but can show desaturation during exercise with more extensive lung involvement. Analysis of the gas composition of arterial blood at rest and during exercise is more sensitive than pulse oximetry.

Recommended screening tests for the detection of extrapulmonary disease include ECG, ophthalmological examination with a slit lamp and routine renal and hepatic tests. Echocardiography, brain imaging, lumbar puncture, bone imaging or NMR and electromyography may be useful when symptoms suggest involvement of the heart, nervous system, or rheumatic disease. CT of the abdominal cavity with radiopaque is usually not recommended, but it can reveal signs of involvement of the liver or spleen in the form of an increase in the size of organs and lesions of increased intensity.

Laboratory tests play an additional role in establishing the diagnosis and clarifying the prevalence of organ damage. Blood formula, electrolytes (including calcium ), blood urea nitrogen, creatinine and functional hepatic tests usually provide useful information in terms of revealing extrathoracic lesions. The blood formula can reveal anemia, eosinophilia or leukopenia. Serum calcium can be increased because of the production of vitamin D analogues by activated macrophages. Blood urea nitrogen, creatinine and functional liver tests can be increased in renal and hepatic sarcoidosis. The total protein can be increased because of hypergammaglobulinemia. Increased ESR is nonspecific. The study of calcium in daily urine is recommended to exclude hypercalciuria, even in patients with normal serum levels. Elevated serum angiotensin-converting enzyme (ACE) concentrations also suggest sarcoidosis, but are not specific; concentrations may be reduced in patients taking ACE inhibitors, or increased in a variety of other conditions (eg, hyperthyroidism, Gaucher's disease, silicosis, mycobacterial infection, hypersensitivity pneumonitis). A study of the level of ACE can be useful in controlling the activity of the disease and responding to therapy in patients with confirmed sarcoidosis. Increasing the level of ACE in the cerebrospinal fluid can help diagnose sarcoidosis of the central nervous system.

Other additional studies include bronchoalveolar lavage and gallium scanning. The results of the bronchoalveolar lavage study vary significantly, but lymphocytosis (lymphocytes> 10%) and / or CD4 + / CD8 + ratio in the lavage fluid of more than 3.5 are diagnostic in the relevant clinical context. However, the absence of these changes does not exclude sarcoidosis.

Scanning with gallium of the whole organism can give useful information in the absence of tissue confirmation. Symmetric increased absorption in mediastinal and basal lymph nodes (lambda sign) and in lacrimal, parotid and salivary glands (panda sign) is especially characteristic for sarcoidosis. Negative outcome in patients receiving prednisolone is not informative.

[16], [17], [18],

Treatment of pulmonary sarcoidosis

Because sarcoidosis of the lungs is often spontaneously resolved, asymptomatic patients and patients with mild symptoms do not require treatment, although they should be inspected regularly for possible worsening. These patients may include periodic X-ray studies, lung function tests (including diffusion capacity), and extracorporeal lesion markers (eg, standard kidney and liver function tests). Regardless of the stage of the disease, treatment is required for patients with worsening symptoms, limited activity, a noticeable pathological or worsening lung function, anxiety changes on the x-ray (cavitation, fibrosis, grouped formations, symptoms of pulmonary arterial hypertension), heart, nervous system or eye disease, renal or hepatic insufficiency or disfiguring lesions of the skin and joints.

Treatment of sarcoidosis of the lungs is carried out by glucocorticoids. Standard protocol - prednisolone in a dose of 0.3 to1 mg / kg orally 1 time per day, depending on the symptoms and severity of changes. Alternative regimens are also used (for example, prednisolone 40-60 mg orally 1 time per day in a day). Rarely does the dose exceed 40 mg per day; however, higher doses may be required to treat complications in patients with eye, heart, or neurological lesions. The response to treatment is usually observed within 2-4 weeks, thus, the symptoms of lung sarcoidosis, the results of chest radiography and pulmonary function tests can be re-evaluated at 4 and 12 weeks. Chronic, mute cases can respond more slowly. Dosages are reduced to a maintenance dose (for example, prednisolone <10 mg every other day, if possible) after the response to treatment, treatment lasts a minimum of 12 months, if recovery occurs. The optimal duration of treatment is unknown. Premature dosing can lead to a relapse. The use of the drug is gradually stopped if the reaction is absent or doubtful. Glucocorticoids can ultimately be abolished in most patients, but since a relapse occurs in 50% of cases, follow-up examinations should be performed, usually every 3-6 months. Treatment of sarcoidosis of the lung with glucocorticoids should be resumed in case of relapse of symptoms and manifestations, including dyspnea, arthralgia, fever, hepatic insufficiency, cardiac arrhythmia, symptoms of the central nervous system, hypercalcemia, eye damage, lack of control by local drugs and disfiguring skin lesions.

Data on the use of inhaled glucocorticoids in pulmonary sarcoidosis are ambiguous, but some studies suggest that this route of administration may reduce cough in patients with endobronchial lesions. Local glucocorticoids may be useful in some cases of dermatological and ocular lesions.

Approximately 10% of patients requiring therapy are resistant to tolerable doses of glucocorticoids and require the appointment of a six-month trial of methotrexate, starting with weekly oral intake of 2.5 mg followed by an increase to 10-15 mg per week, at which blood leukocyte count is maintained at > 3000 / μl. First, methotrexate and glucocorticoids are assigned simultaneously; After 8 weeks, the dose of the glucocorticoid can be reduced and, in many cases, canceled. However, the maximum response to methotrexate may occur after 6-12 months. In such cases, the dose of prednisolone should decrease more slowly. Serial blood tests and liver enzyme tests should be performed first every 1-2 weeks and then every 4 to 6 weeks as soon as a stable dose is achieved. Folic acid (1 mg orally once a day) is recommended for patients taking methotrexate.

The effectiveness of other drugs is shown in a small number of patients who are resistant to glucocorticoids or who have adverse events. These drugs include azathioprine, cyclophosphamide, chlorambucil, chloroquine or hydroxychloroquine, thalidomide, pentoxifylline and inflleximab.

Hydroxychloroquine orally 200 mg 3 times a day can be as effective as glucocorticoids, for the treatment of disfiguring skin lesions in sarcoidosis and the attraction of hypercalciuria. Although immunosuppressants are often more effective in resistant cases, relapse often occurs after discontinuation of treatment.

There are no drugs available that consistently prevent pulmonary fibrosis.

Lung transplantation is an option for patients with terminal lung injury, although the disease can recur in the transplanted organ.

What is the prognosis of lung sarcoidosis?

Although spontaneous recovery often occurs , the severity and manifestations of the disease are extremely variable, and many patients require repeated courses of glucocorticoids. Thus, regular monitoring to identify relapses is mandatory. Approximately 90% of patients who experience spontaneous recovery develop within the first 2 years after diagnosis; less than 10% of these patients have relapses after 2 years. Those patients who do not develop remission within 2 years are likely to have a chronic disease.
 
Lung sarcoidosis is considered chronic in 30% of patients, and 10-20% of the disease has a constant course. Sarcoidosis is fatal for 1-5% of patients. Pulmonary fibrosis with respiratory failure is the most common cause of death worldwide, followed by pulmonary hemorrhage due to aspergilloma. However, in Japan, the most frequent cause of death is infiltrative cardiomyopathy, which causes heart failure and cardiac arrhythmias.

The prognosis is worse for patients with extrapulmonary sarcoidosis and for those of the Negroid race. Recovering occurs in 89% of Caucasians and 76% of patients of the Negroid race without extrathoracic disease and in 70% of Caucasians and 46% of patients of Negroid race with extrathoracic manifestations. The presence of erythema nodosum and acute arthritis is a sign of a favorable prognosis. Uveitis, pernio lupus, chronic hypercalcemia, neurosarcoidosis, nephrocalcinosis, myocardial disease and extensive pulmonary lesion are unfavorable prognostic symptoms of pulmonary sarcoidosis. However, there was a slight difference in the long-term outcome of the treated and untreated patients, and after the end of treatment, a relapse is often observed.