M. kansasii occurs in water and milk, though not in soil.
Disease caused by this mycobacterium has mainly been described in Europe and the USA. It rarely causes a relatively benign type of human pulmonary disease, usually in middle-aged males. Men working in dusty jobs (e.g. miners) apear to be especially at risk, as are those who have underlying chronic bronchitis and emphysema. M.avium intracellulare is an important cause of pulmonary infection in AIDS patients
GRANULOMATOUS LUNG DISEASE
A granuloma is a mass or nodule composed of chronically inflamed tissue formed by the response of the mononuclear phagocyte system (macrophage/histiocyte) to a slowly soluble antigen or irritant. If the foreign substance is inert (e.g. an inhaled dust), the phagocytes turn over slowly; if the substance is toxic or reproducing, the cells turn over raster, producing a granuloma. A granuloma is characterized by epithelioid multinucleate giant cells, as seen in tuberculosis. Granulomas may be caused by:
• Fungal and helminthic infections
• Hypersensitivity reactions
They are also found in disorders with no known cause, such as sarcoidosis.
Sarcoidosis is a multisystem granulomatous disorder, commonly affecting young adults and usually presenting with bilateral hilar lymphadenopathy, pulmonary infiltration and skin or eye lesions. The diagnosis is confirmed on the histological evidence of widespread, non-caseating, epithelioid granulomas in more than one organ. Poisoning with beryllium can rarely produce a clinical and histological picture identical to sarcoidosis, though contact with this element is now strictly controlled.
EPIDEMIOLOGY AND AETIOLOGY
Sarcoidosis is a common disease that is often detected by mass X-ray studies. There is great geographical variation. The prevalence in the UK is approximately 19 in 100000 of the population. It is common in the USA but is uncommon in Japan. The course of the disease is much more severe in American Blacks than in Whites. There is no relation with any histocompatibility antigen, but cases of sarcoidosis are seen within families, possibly suggesting an environmental factor. Other aetiological factors suggested are an atypical mycobacterium or fungus, the Epstein-Barr virus and occupational, genetic, social or other environmental factors (a higher incidence occurs in rural rather than in urban populations); none have been substantiated.
TYPICAL SARCOID GRANULOMAS consist of focal accumulations of epithelioid cells, macrophages and lymphocytes, mainly T cells.
DEPRESSED CELL-MEDIATED REACTIVITY to tuberculin and other antigens such as Candida albicans is present.
OVERALL LYMPHOPENIA-circulating T lymphocytes are low but B cells are slightly increased.
BRONCHOALVEOLAR LAVAGE shows a great increase in the number of cells; lymphocytes (particularly CD4 helper cells) are greatly increased.
ALVEOLAR MACROPHAGEs-the number is increased but they represent a reduced percentage of the total number of cells.
TRANSBRONCHIAL BIOPSIES show infiltration of the alveolar walls and interstitial spaces with mononuclear cells, mainly T cells, prior to granuloma formation. It seems likely that the decrease in circulating T lymphocytes and changes in delayed hypersensitivity responses are the result of sequestration of lymphocytes within the lung. There is no evidence to suggest that patients with sarcoidosis suffer from an overall defect in cellular immunity, since the frequency of fungal, viral and bacterial infections is not increased and there is no substantiated evidence of a greater risk of developing malignant neoplasms.
The peak incidence is in the third and fourth decades, with a female preponderance. Sarcoidosis can affect many different organs of the body. The commonest presentation is with respiratory symptoms or abnormalities found on chest X-rays (50%). Fatigue or weight loss occurs in 5%, peripheral lymphadenopathy in 5% and a fever in 4%. A chest X-ray may be negative in up to 20% of non-respiratory cases, though lesions may be detected later.
BILATERAL HILAR LYMPHADENOPATHY is a characteristic feature of sarcoidosis. It is often symptomless and simply detected on a routine chest X-ray. Occasionally, the bilateral hilar lymphadenopathy is associated with a dull ache in the chest, malaise and a mild fever. Although the chest X-ray may not show any evidence of infiltration in the lung fields, evidence from CT scanning, transbronchial biopsies and bronchoalveolar lavage indicate that the lung parenchyma is nearly always involved.
The differential diagnosis of the bilateral hilar lymphadenopathy
LYMPHOMA-though it is rare for this only to affect the hilar lymph nodes.
PULMONARY TUBERCULOSIS-though it is rare for the hilar lymph nodes to be symmetrically enlarged.
CARCINOMA OF THE BRONCHUS with malignant spread to the contralateral hilar lymph nodes-again it is rare for this to give rise to a typical symmetrical picture.
In the early stages it may be difficult to distinguish enlarged lymph nodes on the chest X-ray from the pulmonary arteries, and lymph node enlargement is not always symmetrical. It is for these reasons that, in the absence of additional erythema nodosum, histological confirmation of the disease process is advisable.
This type of sarcoidosis may be progressive and may lead to increasing effort dyspnoea and eventually cor pulmonale and death. The chest X-ray shows a mottling in the mid-zones proceeding to generalized fine nodular shadows. Eventually, widespread pulmonary line shadows develop, reflecting the underlying fibrosis. A honeycomb appearance can occasionally occur. Pulmonary function tests show a typical restrictive lung defect. It is possible to have a normal chest X-ray with abnormal lung function tests; conversely, lung infiltration may be present on the X-ray with lung function tests in the normal range.
Skin and ocular sarcoidosis are the commonest extrapulmonary presentations.
SKIN SARCOIDOSIS. This is seen in 10% of cases; apart from erythema nodosum, a chilblain-like lesion known as lupus pernio is seen, as are nodules. Sarcoidosis is the commonest cause of erythema nodosum. The association of bilateral symmetrical hilar lymphadenopathy with erythema nodosum only occurs in sarcoidosis.
ANTERIOR UVEITIS. This is common and may present with misting of vision, pain and a red eye, but posterior uveitis may simply present as progressive loss of vision. Although ocular sarcoidosis accounts for about 5% of uveitis presenting to ophthalmologists, evidence of asymptomatic uveitis may be found in up to 25% of patients with sarcoidosis. Conjunctivitis may occur and retinal lesions have been recognized recently. Keratoconjunctivitis sicca and lacrimal gland enlargement may also occur. Uveoparotid fever is a syndrome of bilateral uveitis and parotid gland enlargement together with occasional development of facial nerve palsy and is sometimes seen with sarcoidosis.
METABOLIC MANIFESTATIONS. It is rare for sarcoidosis to present with problems of calcium metabolism, though hypercalcaemia is found in 10% of established cases. Hypercalcaemia and hypercalciuria can lead to the development of renal calculi and nephrocalcinosis. The cause of the hypercalcaemia has been shown to be high circulating 1,25-dihydroxy vitamin D3, with the l ohydroxylation occurring in sarcoid macrophages in the lung in addition to that taking place in the kidney.
THE CENTRAL NERVOUS SYSTEM. Involvement of the CNS is rare (2%) but can lead to severe neurological disease.
BONE AND JOINT INVOLVEMENT. Arthralgia without erythema nodosum is seen in 5% of cases. Bone cysts are found, particularly in the digits, with associated swelling. In the absence of swelling, routine X-rays of the hands are unnecessary.
HEPATOSPLENOMEGALY. Sarcoidosis is a cause of hepatosplenomegaly, though it is rarely of any clinical consequence.
CARDIAC INVOLVEMENT. Cardiac involvement is rare (3%). Ventricular dysrhythmias, conduction defects and cardiomyopathy with congestive cardiac failure may be seen.
FULL BLOOD COUNT. Mild normochromic, normocytic anaemia with raised ESR.
SERUM BIOCHEMISTRy-raised serum calcium and hypergammaglobulinaemia.
TRANSBRONCHIAL BIOPSY is the most useful investigation. Positive results are seen in 90% of cases of pulmonary
sarcoidosis with or without X-ray evidence of lung involvement. The test provides positive histological evidence of a granuloma in approximately one-half of patients with clinically extrapulmonary sarcoidosis in whom the chest X-ray is normal.
THE KVEIM TEST, which involved an intradermal injection of sarcoid tissue, was regularly used for confirmation of the diagnosis. It should not now be used because of the risk of transmission of infection. It is less sensitive and less specific than transbronchial biopsy which has superseded it.
TUBERCULIN TEST is negative in 80% of patients with sarcoidosis; it is of no diagnostic value.
SERUM LEVEL OF ACE is two standard deviations above the normal mean value in over 75% of patients with untreated sarcoid. Raised (but lower) levels are also seen in patients with lymphoma, pulmonary tuberculosis, asbestosis and silicosis, rendering the test of no diagnostic value. However, it is a simple test and is of use in assessing the activity of the disease and therefore as a guide to treatment with corticosteroids. Reduction of serum ACE during treatment with corticosteroids has not, however, yet been proved to reflect resolution of th e disease.
LUNG FUNCTION TESTS show a restrictive lung defect with pulmonary infiltration. There is a decrease in TLC, a decrease in both FEV! and FVC and a decrease in gas transfer.
Both the need to treat and the value of corticosteroid therapy are contested in many aspects of this disease. Hilar lymphadenopathy on its own with no evidence of chest X-ray involvement of the lungs or decrease in lung function tests does not require treatment. Persisting infiltration on the chest X-ray or abnormal lung function tests are unlikely to improve without corticosteroid treatment. If the disease is not improving spontaneously 6 months after diagnosis, treatment should be started with prednisolone 30 mg for 6 weeks, reducing to alternate day treatment with prednisolone 15 mg for 6-12 months. Although there are no controlled trials that have proved the efficacy of such treatment, it is difficult to withhold corticosteroids when there is continuing deterioration of the disease.
Topical or systemic prednisolone should be given for patients suffering from involvement of the eyes or the presence of persistent hypercalcaemia. The erythema nodosum of sarcoidosis will respond rapidly to a short course of prednisolone 5-15 mg for 2 weeks. Myocardial sarcoi dosis and neurological manifestations are also treated with prednisolone, and uveoparotid fever responds rapidly to steroids.
Sarcoidosis is a much more severe disease in certain racial groups, particularly American Blacks, where death rates of up to 10% have been recorded. It is probable that the disease is fatal in less than 1 in 20 individuals in the UK, most often as a result of respiratory failure and cor pulmonale but, rarely, from myocardial sarcoidosis and renal damage. The chest X-ray provides a guide to prognosis. The disease remits by 2 years in over two-thirds of patients with hilar lymphadenopathy alone, in approximately one-half with hilar lymphadenopathy plus chest X-ray evidence of pulmonary infiltration, but in only one-third of patients with X-ray evidence of infiltration without any demonstrable lymphadenopathy.