ACTA FAC

Tatjana Pejčić¹, Ivana Stanković¹, Milan Rančić ¹, Ivanka Đorđević¹, Ljiljana Isaković², Lidija Ristić¹

¹ Clinic for lung disaese and tuberculosis, Clinical center Niš,
² Special hospital for rehabilitation of lung diseases, Sokobanja

    Sarcoidosis is a systemic granulomatous disorder of unknown etiology, characterized by bilateral hilar adenopathy (BHA), lung parenchyma infiltrations, skin and eyes changes or other organs involvement. Histological characteristic of sarcoidosis is the presence of non- caseating granulomas, which can resorb or evolve into fibrosis. Immunological tests show a depression of delayed hypersensitivity reaction, amplified activity of Th1 immune response on affected organs, hyperreactivity of B lymphocytes and elevated values of circulated immune complexes (1).
    This disease is well-known around the world, yet, with quite different prevalence and incidence ranging. In Sweden the prevalence ranging is 64/100000, in Norway 26,7/100000 and in USA 11/100000. There is no precise data about the frequency of sarcoidosis in Serbia and Montenegro, but the areas of Sandzak and West Serbia (2,3) are considered to be predilactive. As early as 1905 M. Boeck described sarcoidosis as "a bacillary infections disease ", but until now its etiology hasn't been explained. The possible etiological causes are induced unorgans agents (cirkonium, aluminium, talc), viruses (herpes virus 8, rethrovirus, Epstein- Barr virus), mycobacteria (M. tuberculosis, M. paratuberculosis, other mycobacteria) and other bacterias considered to be capable of producing granuloma. Until now, there have been no infective agents isolated from affected tissue; so, this hypothesis is questionable. Sarcoidosis frequently affects younger women between 20-30 years of age. A family connection was observed as far as illness is concerned, with more frequent relation between brother and sister as well as mother and children. This confirms the theses about the presence of genetics in sarcoidosis appearance. The connection between sarcoidosis and HLA-1, HLA-B8 and HLA-DR4 has been confirmed. A good clinical outcome of disease is associated with HLA-D3, whereas only pulmonary sarcoidosis is associated with HLA-B27 (4,5).
    Depending on the period of symptoms appearing, sarcoidosis is clinically classified as acute and chronic form. Acute forms are characterised by symptoms over two year period, and chronic one by symptoms lasting more than two years. General symptoms of disease are frequently expressed by fever, weakness, loss of weight, while specific symptoms of disease are related to organ involvement. In more than a half of the patients respiratory tract is affected; so, the most dominant symptoms are dry cough and chest pain. The most common acute manifestation of sarcoidosis is Lofgren's syndrome, characterized by fever, weakness arthritis, erythema nodosum and BHA on chest x - ray. Sarcoidosis is considered as a disease with good prognosis; 90% of the patients show spontaneous remission of all symptoms in a two year period, and also, there are cases with permanent BHA. The most predominant extrapulmonary symptoms of acute sarcoidosis are eye disorders (conjuctivitis, photophobia and sight disturbance) and skin disorders. Sarcoidosis of cardiac and abdominal organs and changes of central nervous system are substantialy rare. Pheripherial lymphoadenopathia can be present in 60-75%. Erythema nodosum and acute inflammation manifestation (fever and polyarthritis), are indicators of good prognosis (2,6).
    Chronic course of sarcoidosis is present in patients with symptoms lasting more than two years. On the basis of literature data, chronic sarcoidosis appears in about 10-30 % of the patients. Spontaneous remission in this group occurs in two thirds of the patients, and thus, chronic course of disease persists in 10-30% of the patients.
    Severe extrapulmonary localisation of sarcoidosis (involvement of myocard, CNS, liver, spleen) is present in 4-7% of the patients in the onset of disease and its atypical beginning are the first signs of bad prognosis and chronic course of disease (7).
    Symptoms of chronic sarcoidosis depend on organs involvement and functional symptoms. On the basis of radiographical involvement of pulmonary sarcoidosis (Wurm - Reindell - Helmeyer) the first stage is characterised by bilateral hilar lymphadenopathy, the second one by BHA as well as lung parenchyma infiltrations, whereas the third one is characterised only by parenchymal infiltrations with or without interstitial fibrosis, and finally the fourth refers to radiological stage including fibrous lines spreading up from the hilus. Relaps of the disease is defined as repeated appearance of symptoms and signs of disease after the end of previous treatment or as reappearance of disease besides treatment of morbostatic doses of glucocorticoides (5-10mg) (7,8).

The aim of our paper was to show the most frequent clinical and radiological forms of pulmonary sarcoidosis in patients treated at the Clinic for lung disease and tuberculosis in Knez Selo. Particular attention was paid to pulmonary functional tests, with reference to mutual correlation of some lung functional parameters.

We retrospectively analyzed medical and/or hospital records of 45 patients reported to Clinic for lung disease with a suspicion of having pulmonary sarcoidosis. Patients were from 30 to 62 years old, with some higher number of women (25) in relationship to men (20). We tested the onset of disease, duration of symptoms, the most frequent pulmonary, extrapulmonary as well as general symptoms of disease.
    We analyzed chest radiography (rtg) and classified radio-graphical staging of disease.
    All patients underwent pulmonary functional tests which presupposed spirometry and flow-volume curve as well as determining diffusing capacity of lungs for carbon monoxide (DLco) (Pneumo screen/ Diffusion firm Jaeger).
    On the basis of values of vital capacity (VC) and forced expiratory volume in the first second (FEV1) as well as middle expiratory flow at 50 percent of VC (FEF50) and FEF75, disturbance in ventilatory function were determined. We analyzed the correlation between lung functional parameters (FEV1, VC) and values of DLco.
    From statistical parameters middle value (x), standard deviation (SD) and coefficient of correlation (r) were used.

    The examination covered 45 patients, between 30 and 62 years of age (x 41,2±10,6), 25 women (55,5%) and 20 men (44,5%). The diagnosis of sarcoidosis in 10 patients confirmed the seizure of organs after biopsy and histological verification of changes in lymph nodes or lung parenchyma, and in 35 patients as probable criteria (without histological confirmation, but with symptoms and signs of sarcoidosis and presence of lymphocytes alveolitis in bronchoalveolar larvate (BAL) and lowered values DLco and other factors of sickness activities) (9).
    In 30 patients (66,6%) the beginning of the disease was acute with Löfgren's syndrome (higher temperature, erythema nodosum and BHA). One patient had enlarged parotids glands, front uveitis, higher temperature and paralysis nerves facials (Heefort- Waldenstrom syndrome). These patients had been having those symptoms less than two years.
    14 patients (31,2%) had symptoms more than 2 years and we marked them as those with chronic disease (figure 1).


Figure 1. Forms of sarcoidosis	Figure 2. Non lung symptoms in sarcoidosis

Besides lung symptoms patients also had: polyarthralgia (35/ 77%), mostly in wrists (30/ 66,6%), and palm wrists of both hands (10/22,2%), higher temperature (28/62%), sub febrile type, erythema nodosum 30 patients (66,6%) (figure 2). All patients were complaining of weariness and tiredness.
As far as extrapulmonary symptoms are concerned, patients mostly complained of dry cough (34/75,5%), dyspnea (13/ 28,8%) and chest pain (7/ 15,5%) (figure 3). Patients complained mostly of chest pain lasting more than 1 year in the case of 5 patients (11,1%), and the feeling of weariness (25/ 55,5%) as one of the general symptoms.
31 patients (68,8%) had radiological report of the I stadium of lung sarcoidosis. One patient had only one sided hilar adenopathy, and other had both sided hilar and mediastinal, 10 patients (22,2%) had II radiological stadium, 3 patients (6,66%) had III and 1 patient (2,2%) had IV radiological stadium of sarcoidosis (figure 4).


Figure 3. Lung symptoms of patients in sarcoidosis	Figure 4. Radiological stadium of sarcoidosis

30 patients (66,6%) had preserved lung ventilation (28 patients with acute stadium and 2 patients in the second radiological stadium). Changes in small lung airways (FEF50 and FEF75 < 60% of expected values) had third patients (6,6%) (two with acute sarcoidosis and one with chronic sarcoidosis in II radiological stadium). Five patients had obstructive disorder of ventilation (11,1%) with FEV1 from 52% to 74% (x 61,11± 11,2) (one of the patients was with I rtg stadium and four with II rtg stadium). Seven patients had restrictive disorder of ventilation (15,5%) (one in IV rtg stadium, three in III rtg stadium and three in II rtg stadium of illness). The values of VC were from 51% to 76% (x 63,1 %± 8) (figure 5).

DLco was lowered in 30 patients and values were from 46,9% to 70% (x 62,8%± 7,3 ). In one third of the patients (10 patients) with preserved lung ventilation, values of DLco were lowered below 70%. No significant statistical correlation of parameters VC and FEV1 with DLco (r =0,34, p> 0,05, and r= 0,37, p> 0,05) were found. In one patient in III rtg stadium of illness and chronic sarcoidosis, sarcoidosis of myocardia and pancreas was proved.

    Immunopathogenesis of sarcoidosis includes initial agents as a possible trigger for the beginning of disease. CD4+ T lymphocytes and mononuclear phagocytes have the leading role in that. The sarcoid granuloma is considered to be the consequence of induced immune response to unknown agent which persists on active affected sites, probably due to low solubility or demolition.The first pathological manifestation of disease is accumulation of immunocompetent cells (mostly CD4-lymphocytes and macrophages) followed by producing lymphocytes alveolitis. The next step is the formation of granulomas, which originates from high- differentiated mononuclear phagocytes (epitheloid and multinucleated gigant cells) and lymphocytes. The giant cells are formed by IL-2, IFN g and IL 1ß. In the centre of sarcoid granuloma CD4+ cells are dominated, and on the periphery there are scatterd CD8+, CD4+, B cells, fibroblastes, mastocytes and other cells. The evidences pointed out that sarcoidosis is a consequence of defective cellular immune response, triggering by specific antigen related to genetic disorder. In the early phase of disaese, at the site of sarcoid lessions, there is marked enhancement of number of Th1 lymphocytes, which cytokines increased the growth of granuloma by inhibition of fibrosis. Depending on organism tendency, getting into Th2-lymphocites response leading to progression of sarcoidosis and appearing of fibrosis. By cytokines realising throught Th2 lymphocytes fibroblaste hyperplasio originated with amplified formation and deposition of extracellulare matrix components in the surrounding granulomas inflamation (6,4,1).
    We showed 45 patients with sarcoidosis, among whom the most dominant were those with acute form of illness in I rtg stadium (31/ 68,8%). According to literature facts 50% - 60% of the patients had acute beginning of illness, while there was less number of patients with chronic sarcoidosis (in our environment even to 30% with is similar to our research (2 , 7). Although it is rarely found, we had one patients with Heefort - Walenstrom syndrome, and one patient with one sided hilar adenopathy.
    Löfgren's syndrome dominated out of all extrapulmonary symptoms (higher temperature, erythema nodosum, BHA). Polyarthralgies were longer during the illness.
    Lung symptoms are non characteristic for lung sarcoidosis (dry cough, chest pain and dyspnea) but coupled with other symptoms and radiological results, they can easily initiate doubts of lung sarcoidosis. The diagnosis of sarcoidosis in our patients is confirmed by gland biopsy or biopsy of lung parenchyma (definitive diagnosis), but in most patients, it was proved according to BAL analysis together with clinical and radiological parameters (probably criteria). The BAL analysis is very important in diagnosis and in the following stadium of lung sarcoidosis activity (1, 9,5).
    Radiological lung result found in our patients is usual for this ratio of acute and chronic sarcoidosis. The majority of those with II, III and IV stadium of illness are patients having asymptomatic onset of illness (10/ 22,2%), which was non spontaneously regarded but changed into chronicle form of illness. We found heart and pancreas sarcoidosis in one patient, while all other had only chronic lung sarcoidosis. This can be explained by the fact that we examined newly found patients. Though until recently we described that because of distinctive granulomatosa process of lung parenchyma, the restrictive disorder of ventilation can be expected, our results show the significant number of patients with obstructive lung changes (3 with changes in small air way and 5 with obstructive ventilation disorder), which continues that small air way, but also larger, was covered with the process of sarcoidosis. The very important result was the lowered value of DLco and even in those patients with the preserved lung ventilation. This shows that the changes in interstitial can be present, even the rtg results of lung function can be in normal values. We have to pay attention to this group of patients and more often examine the illness activity (serum values of angiotezine convertase, Ca in urine and serum) (10,11,12).
    We didn't find any correlation between DLco and parameters of lung function (VC, FEV1, FEF50 and FEF75), which confirms the previous result that DLco has bigger sensitivity in determining the changes in lung interstitial than radiography and parameters of lung function.

According to our analysis we concluded that the frequency of acute sarcoidosis was dominant in relation to chronic form of illness. Acute onset of disease was registered in 68,8% of cases. Respiratory tract symptoms were the most frequent. In one third of the patients spirometry disorders were found whereas obstructive and restrictive ventilatory disorders were significantly present. Restrictive changes follow up the advanced pulmonary disorders. Obstructive changes in bronchi at the beginning of diseases are frequent in the cases of decreased flow in small airways. It is very important to examine more often the value of DLco, which decreased values means changer in lung interstitial. Also, this parameter has to be considered in following up of sarcoidosis activity. The role of functional examination in diagnosis and follow up of sarcoidosis is significant only in combination with other diagnostic methods. Overall examination enables the estimate of activity and prognosis of disease, which is significant for sarcoidosis treatment.

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