Pulmonary sarcoidosis

Sarcoidosis (Besnier-Beck-Schaumann disease) is a systemic disease characterized by the development of productive inflammation with the formation of epithelioid cell granulomas without necrosis resulting in resorption or fibrosis.

Sarcoidosis is characterized by the formation of noncaseating granulomas in one or more organs or tissues; the etiology is unknown. The lungs and lymphatic system are most commonly affected, but sarcoidosis can affect any organ. Symptoms of pulmonary sarcoidosis range from none (limited disease) to dyspnea on exertion and, rarely, respiratory or other organ failure (disseminated disease). The diagnosis is usually first suspected when the lungs are involved and is confirmed by chest radiography, biopsy, and exclusion of other causes of granulomatous inflammation. Glucocorticoids are first-line treatment. The prognosis is very good for limited disease but poor for more widespread disease.

Sarcoidosis primarily affects people aged 20 to 40 years, but occasionally occurs in children and older adults. Worldwide, the prevalence is highest in African Americans and northern Europeans, especially Scandinavians. The global prevalence of sarcoidosis averages 20 per 100,000 population (with rates ranging from 10 to 40 in different countries). Manifestations of the disease vary widely by racial and ethnic background, with African Americans and Puerto Ricans more likely to have extrathoracic manifestations. For unknown reasons, pulmonary sarcoidosis is slightly more common in women.

The incidence increases during the winter and early spring.

Pulmonary sarcoidosis is a systemic disease that affects the intrathoracic lymph nodes, lungs, bronchi, serous membranes, liver, spleen, skin, bones and other organs.

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What causes pulmonary sarcoidosis?

Sarcoidosis is thought to result from an inflammatory response to an environmental factor in genetically susceptible individuals. Viral, bacterial, and mycobacterial infections and inorganic (eg, aluminum, zirconium, talc) or organic (eg, pine pollen, clay) substances have been suggested as triggers, but these have not been proven. Unknown antigens trigger a cellular immune response characterized by accumulation of T cells and macrophages, release of cytokines and chemokines, and formation of granulomas. Sometimes a family history or increased incidence in certain communities suggests genetic predisposition, certain exposures, or, less likely, person-to-person transmission.

The inflammatory process results in the formation of noncaseating granulomas, a characteristic feature of sarcoidosis. Granulomas are collections of mononuclear cells and macrophages that have differentiated into epithelioid and multinucleated giant cells surrounded by lymphocytes, plasma cells, mast cells, fibroblasts, and collagen. Granulomas occur most commonly in the lung and lymph nodes but can develop in many other organs, including the liver, spleen, eye, sinuses, skin, bone, joints, skeletal muscle, kidneys, reproductive organs, heart, salivary glands, and nervous system. Granulomas in the lung are located along lymphatics, most commonly in the peribronchiolar, subpleural, and perilobular areas.

Symptoms of pulmonary sarcoidosis

Symptoms of pulmonary sarcoidosis depend on the location and extent of the lesion and change over time, ranging from spontaneous remission to chronic asymptomatic disease. Therefore, regular examinations are necessary to detect new symptoms in various organs.

Systemic symptoms of sarcoidosis

System	Frequency of defeat	Comments
Pleuropulmonary (lungs, pleura)	> 90%	Granulomas form in the alveolar septa, bronchiolar and bronchial walls, causing diffuse lung involvement; pulmonary arteries and veins are also involved Often asymptomatic. Resolves spontaneously in many patients, but can cause progressive pulmonary dysfunction leading to activity limitations, respiratory failure, and death in a few patients. Leads to the development of lymphocytic exudative effusions, usually bilateral
Lymphatic	90%	Hilar or mediastinal involvement is discovered incidentally on chest radiography in most patients. Others have mild peripheral or cervical lymphadenopathy.
Gastrointestinal tract Liver Splenic Others	40-75%	Usually asymptomatic; manifests as moderate increases in liver function tests, decreased drug accumulation on CT with contrast Rarely leads to clinically significant cholestasis, cirrhosis The distinction between sarcoidosis and granulomatous hepatitis, where sarcoidosis only affects the liver, is unclear Usually asymptomatic, manifested by pain in the left upper quadrant of the abdomen, thrombocytopenia, an unexpected finding on X-ray or CT Rare reports of gastric granulomas, rare intestinal involvement; mesenteric lymphadenopathy may cause abdominal pain
The organ of vision	25%	Most commonly uveitis with visual impairment, photophobia and lacrimation. May cause blindness, but most often resolves spontaneously Conjunctivitis, iridocyclitis, chorioretinitis, dacryocystitis, lacrimal gland infiltration leading to dry eyes, optic neuritis, glaucoma and cataracts also occur. Ocular involvement is more common in African Americans and Japanese For early detection of eye pathology, examination is recommended once or twice a year.
Musculoskeletal	50-80%	Asymptomatic disease with/without enzyme elevation in most patients; occasionally silent or acute myopathy with muscle weakness Ankle, knee, wrist, elbow are the most common sites of arthritis; may cause chronic arthritis with Jaccoud deformities or dactylitis Löfgren's syndrome - a triad of symptoms including acute polyarthritis, erythema nodosum, and hilar lymphadenopathy. Has variable features; more common in Scandinavian and Irish women, often responsive to NSAIDs and often self-limited; low recurrence rate Osteolytic or cystic lesions; osteopenia
Dermatological	25%	Erythema nodosum: red, hard, tender nodules on the front of the legs; more common in Caucasians, Puerto Ricans, and Mexicans; usually resolves in 1-2 months; surrounding joints often arthritic (Lofgren's syndrome); may be a good prognostic sign Non-specific skin lesions; macules, macules and papules, subcutaneous nodules and hypopigmentation and hyperpigmentation are also common Lupus pernio: raised patches on nose, cheeks, lips, and ears; more common in African Americans and Puerto Ricans; often associated with pulmonary fibrosis; poor prognostic sign
Neurological	<10%	Neuropathy of the cranial nerves, especially the 7th (causing facial paralysis) and 8th (hearing loss). Peripheral neuropathy and optic neuropathy are also common. Any pair of cranial nerves may be affected. CNS involvement, with nodular lesions or diffuse meningeal inflammation typically in the cerebellum and brainstem region Hypothalamic diabetes insipidus, polyphagia and obesity, thermoregulatory disorders and changes in libido
Renal	10%	Asymptomatic hypercalciuria most common; interstitial nephritis; chronic renal failure caused by nephrolithiasis and nephrocalcinosis requiring kidney transplantation (dialysis or transplantation) in some patients
Cordial	5%	Conduction blocks and arrhythmias are most common and may cause sudden death; heart failure due to restrictive cardiomyopathy (primary) or pulmonary arterial hypertension (secondary) is also possible. Transient dysfunction of papillary muscles and rarely pericarditis More common in Japanese people, where cardiomyopathy is the most common cause of death from sarcoidosis
Reproductive	Rarely	There are reports of damage to the endometrium, ovaries, epididymis and testicles. Does not affect fertility. The disease may subside during pregnancy and recur after childbirth.
Oral cavity	<5%	Asymptomatic swelling of the parotid glands is most common; mumps with xerostomia is also possible; may be a component of keratoconjunctivitis sicca Hereford syndrome (also called uveoparotid fever): uveitis, bilateral swelling of the parotid glands, facial paralysis, and chronic fever Lupus pernio of the oral cavity can disfigure the hard palate and affect the cheeks, tongue and gums
Nasal sinuses	<10%	Acute and chronic granulomatous inflammation of the sinus mucosa produces symptoms indistinguishable from simple allergic and infectious sinusitis. Biopsy confirms the diagnosis. More common in patients with lupus pernio
Endocrine	Rarely	Infiltration of the hypothalamic zone and pituitary stalk may cause panhypopituitarism; may cause thyroid infiltration without dysfunction; secondary hypoparathyroidism due to hypercalcemia
Mental	10%	Depression develops frequently. It is doubtful if this is the first manifestation of sarcoidosis, more often it is a reaction to the long course of the disease and frequent relapses
Hematological	<5-30%	Lymphopenia; anemia of chronic disease; anemia due to granulomatous infiltration of bone marrow, sometimes leading to pancytopenia; splenic sequestration leading to thrombocytopenia; leukopenia

Most cases are likely to be asymptomatic and therefore remain undiagnosed. Pulmonary involvement occurs in more than 90% of adult patients with sarcoidosis.

Stages of pulmonary sarcoidosis

Stage	Definition	Spontaneous remission rate
0	Normal chest x-ray	Remission is common; no correlation with prognosis
1	Bilateral lymphadenopathy of the roots, paratracheal and mediastinal lymph nodes without parenchymatous infiltrates	60-80%
2	Bilateral hilar/mediastinal lymphadenopathy with interstitial infiltrates (usually upper lung fields)	50-65%
3	Diffuse interstitial infiltrates without root adenopathy	< 30%
4	Diffuse fibrosis, often associated with fibrous confluent formations, traction dilation of the bronchi, traction cysts	0%

Symptoms of pulmonary sarcoidosis may include shortness of breath, cough, chest discomfort, and wheezing. Fatigue, malaise, weakness, anorexia, weight loss, and low-grade fever are also common; sarcoidosis is a common cause of fever of unknown origin. Often the only sign is lymphadenopathy, which is enlarged but nontender lymph nodes. Systemic manifestations cause a variety of symptoms of sarcoidosis, which vary with race, sex, and age. Blacks are more likely to have involvement of the eyes, liver, bone marrow, peripheral lymph nodes, and skin (but not erythema nodosum). Women are more likely to have erythema nodosum and to have involvement of the nervous system or eyes. Men and older patients are more likely to have hypercalcemia. In children under 4 years of age, arthritis, rash, and uveitis are the most common manifestations. In this age group, sarcoidosis may be confused with juvenile rheumatoid arthritis.

Classification of pulmonary sarcoidosis

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

Unfortunately, K. Wurn's classification does not reflect all clinical aspects of sarcoidosis. In particular, there are no indications of the possibility of combining pulmonary and extrapulmonary manifestations of sarcoidosis, and the activity of the pathological process is not reflected. In this regard, A. G. Khomenko's classification deserves much attention.

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Classification of respiratory sarcoidosis (K. Wurm, 1958)

• I Isolated enlargement of intrathoracic lymph nodes (mediastinal lymphadenopathy)
• II Combined lesion of intrathoracic lymph nodes and lungs
  • II-A Increased pulmonary pattern, its mesh deformation (excessive, looped pattern in the root and lower parts of the lungs)
  • II-B Widespread bilateral small focal shadows in the lungs (miliary type)
  • II-B Widespread bilateral mid-focal shadows (3-5 mm in diameter) in the lungs
  • II-G Widespread bilateral large-focal shadows (diameter 9 mm or more) in the lungs
• III Combination of mediastinal lymphadenopathy with pronounced widespread fibrosis and large confluent formations:
  • III-A in the lower parts of the lungs
  • III-B in the upper and middle parts of the lungs

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Diagnosis of pulmonary sarcoidosis

Pulmonary sarcoidosis is most often suspected when hilar lymphadenopathy is incidentally detected on chest radiography. These changes are the most common radiographic features of the disease and are also predictive of spontaneous remission in patients with pulmonary involvement. Therefore, chest radiography should be the first test performed in patients suspected of having sarcoidosis if it has not already been performed.

Because pulmonary involvement is so common, a normal chest radiograph generally excludes the diagnosis. In cases where the disease is still suspected despite a normal chest radiograph, a high-resolution chest CT scan should be obtained, which is more sensitive for detecting hilar and mediastinal lymphadenopathy. CT findings in later stages (II–IV) include thickening of the bronchovascular junctions and bronchial walls; nodular change of the interlobular septa; ground-glass infiltration; parenchymal nodules, cysts, or cavities; and/or tractional bronchial dilation.

When imaging studies suggest sarcoidosis, the diagnosis is confirmed by identifying noncaseating granulomas on biopsy and excluding alternative causes of granulomatous disease. Diagnosis requires proper biopsy site selection, exclusion of other causes of granulomatous disease, and determination of disease severity and extent to assess need for therapy.

Biopsy sites can be identified by physical examination and palpation; peripheral lymph nodes,
skin lesions, and conjunctiva are readily accessible for biopsy. However, in patients with intrathoracic lymphadenopathy, bronchoscopic transbronchial biopsy is preferred because sensitivity approaches 90% when performed by an experienced operator. Video-assisted thoracoscopy can provide access to lung tissue when bronchoscopic transbronchial biopsy is nondiagnostic. Mediastinoscopy is sometimes performed if hilar or mediastinal lymphadenopathy exists in the absence of pulmonary infiltrate, particularly if lymphoma is a differential diagnosis. However, even in patients with mediastinal lymphadenopathy only on radiograph or CT, transbronchial biopsies are often diagnostic. Open lung biopsy is another option for obtaining tissue but requires general anesthesia and is now rarely performed. Clinical and radiographic findings may be accurate enough to diagnose stage I or II disease when biopsy is not possible.

Exclusion of other diagnoses is mandatory, especially when the symptoms of pulmonary sarcoidosis and radiographic signs are minimal, since granulomatous inflammation can be caused by many other diseases. Biopsy tissue should be cultured for fungi and mycobacteria. A history of occupational hazards (silicates, beryllium) and environmental factors (crushed hay, birds and other antigen triggers of hypersensitivity pneumonitis) should be analyzed; tests for infectious antigens (tuberculosis, coccidioidomycosis, histoplasmosis) should be performed. Tuberculin skin tests with anergy control should be performed as early as possible.

Disease severity is assessed by pulmonary function and pulse oximetry. Pulmonary function tests are often normal in the early stages but show restriction and decreased diffusing capacity for carbon monoxide (DL^) in advanced disease. Airflow obstruction is also sometimes seen, which may indicate bronchial mucosal involvement. Pulse oximetry is often normal when measured at rest but may show desaturation with exercise if lung involvement is more extensive. Resting and exercise arterial blood gas analysis is more sensitive than pulse oximetry.

Recommended screening tests for extrapulmonary disease include ECG, slit-lamp ophthalmologic examination, and routine renal and hepatic function tests. Echocardiography, brain imaging, lumbar puncture, bone or MRI scans, and electromyography may be helpful when symptoms suggest cardiac, nervous system, or rheumatic involvement. Abdominal CT with radiocontrast is not usually recommended but may show evidence of liver or splenic involvement such as enlarged organs and hyperintensity lesions.

Laboratory tests play an additional role in establishing the diagnosis and the extent of organ involvement. A blood count, electrolytes (including calcium ), blood urea nitrogen, creatinine, and liver function tests are usually helpful in identifying extrathoracic lesions. A blood count may reveal anemia, eosinophilia, or leukopenia. Serum calcium may be elevated because of production of vitamin D analogues by activated macrophages. Blood urea nitrogen, creatinine, and liver function tests may be elevated in renal and hepatic sarcoidosis. Total protein may be elevated because of hypergammaglobulinemia. An elevated ESR is nonspecific. A24-hour urine calcium collection is recommended to exclude hypercalciuria, even in patients with normal serum values. Elevated serum angiotensin-converting enzyme (ACE) levels also suggest sarcoidosis but are not specific; levels may be decreased in patients taking ACE inhibitors or increased in a variety of other conditions (eg, hyperthyroidism, Gaucher disease, silicosis, mycobacterial infection, hypersensitivity pneumonitis). ACE testing may be useful in monitoring disease activity and response to therapy in patients with confirmed sarcoidosis. Elevated ACE levels in cerebrospinal fluid may aid in the diagnosis of CNS sarcoidosis.

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

Whole-body gallium scanning may provide useful information in the absence of tissue confirmation. Symmetrical increased uptake in the mediastinal and hilar lymph nodes (lambda sign) and in the lacrimal, parotid, and salivary glands (panda sign) is particularly characteristic of sarcoidosis. A negative result in patients receiving prednisolone is not informative.

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Treatment of pulmonary sarcoidosis

Because pulmonary sarcoidosis often resolves spontaneously, asymptomatic patients and those with mild symptoms do not require treatment, although they should be monitored regularly for worsening disease. Monitoring of these patients may include periodic radiographic examinations, pulmonary function tests (including diffusion capacity), and markers of extrathoracic disease (eg, routine renal and liver function tests). Regardless of the stage of the disease, treatment is required for patients with worsening symptoms, activity limitation, markedly abnormal or deteriorating pulmonary function, worrisome changes on radiography (cavitation, fibrosis, grouped lesions, signs of pulmonary arterial hypertension), cardiac, neurologic, or ocular involvement, renal or hepatic insufficiency, or disfiguring skin or joint lesions.

Treatment of pulmonary sarcoidosis is with glucocorticoids. The standard protocol is prednisolone at a dose of 0.3 to 1 mg/kg orally once daily, depending on symptoms and the severity of changes. Alternating dosing regimens (eg, prednisolone 40 to 60 mg orally once a day or every other day) are also used. Rarely, the dose exceeds 40 mg daily; however, higher doses may be required to treat complications in patients with ocular, cardiac, or neurologic involvement. Response to treatment is usually seen within 2 to 4 weeks, so symptoms of pulmonary sarcoidosis, chest radiographs, and pulmonary function tests can be reassessed at 4 and 12 weeks. Chronic, silent cases may respond more slowly. Doses are tapered to a maintenance dose (eg, prednisolone < 10 mg every other day if possible) after response, and treatment is continued for at least 12 months if resolution occurs. The optimal duration of treatment is unknown. Premature reduction of the dose may result in relapse. The drug is gradually discontinued if response is absent or equivocal. Glucocorticoids can eventually be discontinued in most patients, but because relapse occurs in 50% of cases, follow-up examinations should be performed, usually every 3 to 6 months. Glucocorticoid treatment of pulmonary sarcoidosis should be resumed if symptoms and signs recur, including dyspnea, arthralgia, fever, liver failure, cardiac arrhythmia, CNS symptoms, hypercalcemia, ocular involvement, failure to respond to topical agents, and disfiguring skin lesions.

Data regarding the use of inhaled glucocorticoids in pulmonary sarcoidosis are mixed, but some studies suggest that this route of administration may reduce cough in patients with endobronchial involvement. Topical glucocorticoids may be useful in some cases of dermatologic and ocular involvement.

Approximately 10% of patients requiring therapy are resistant to tolerated doses of glucocorticoids and require a 6-month trial of methotrexate, beginning with 2.5 mg orally weekly and then increasing to 10-15 mg weekly, maintaining a white blood cell count of >3000/μl. Methotrexate and glucocorticoids are initially given concomitantly; after 8 weeks, the glucocorticoid dose can be reduced and, in many cases, discontinued. However, the maximal response to methotrexate may take 6-12 months. In such cases, the prednisolone dose should be tapered more slowly. Serial blood counts and liver enzyme tests should be performed every 1-2 weeks initially and then every 4-6 weeks once a stable dose is achieved. Folic acid (1 mg orally once daily) is recommended for patients taking methotrexate.

Other drugs have been shown to be effective in a small number of patients who are resistant to glucocorticoids or who experience adverse effects. These drugs include azathioprine, cyclophosphamide, chlorambucil, chloroquine or hydroxychloroquine, thalidomide, pentoxifylline, and infliximab.

Hydroxychloroquine 200 mg orally 3 times daily may be as effective as glucocorticoids in treating disfiguring skin lesions of sarcoidosis and in treating hypercalciuria. Although immunosuppressants are often more effective in resistant cases, relapse often occurs after treatment is stopped.

There are no drugs available that consistently prevent pulmonary fibrosis.

Lung transplantation is an option for patients with end-stage lung disease, although the disease may recur in the transplanted organ.

What is the prognosis for pulmonary sarcoidosis?

Although spontaneous recovery is common, the severity and manifestations of the disease are extremely variable, and many patients require repeated courses of glucocorticoids. Thus, regular monitoring for relapse is essential. Approximately 90% of patients who experience spontaneous recovery do so within the first 2 years of diagnosis; less than 10% of these patients relapse after 2 years. Those patients who do not achieve remission within 2 years are likely to have chronic disease.

Pulmonary sarcoidosis is considered chronic in 30% of patients, and 10–20% have persistent disease. Sarcoidosis is fatal in 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 common cause of death is infiltrative cardiomyopathy, causing heart failure and cardiac arrhythmias.

The prognosis is worse for patients with extrapulmonary sarcoidosis and for blacks. Recovery occurs in 89% of whites and 76% of blacks without extrathoracic disease and in 70% of whites and 46% of blacks with extrathoracic manifestations. The presence of erythema nodosum and acute arthritis are favorable prognostic features. Uveitis, lupus pernio, chronic hypercalcemia, neurosarcoidosis, nephrocalcinosis, myocardial disease, and extensive pulmonary involvement are unfavorable prognostic features of pulmonary sarcoidosis. However, little difference in long-term outcome has been found between treated and untreated patients, and relapse is common after completion of treatment.