Figure 2. Chest X-ray of a 45-year-old Female reveals

Right Paratracheal and Hilar Lymphadenopathy

DISCUSSION

Sarcoidosis today is being more frequently recognised than earlier and is now seen as an important emerging disease in India. The true burden of sarcoidosis in India is not clearly known due to underreporting caused by its resemblance to TB. In the present study, 46.7% cases have been misdiagnosed as tuberculosis and had taken ATT before coming to our hospital.

The ATS/ERS/WASOG statement states that sarcoidosis consistently shows a predilection for adults under age 40; peaking in those aged 20-29 years.¹ However, studies done in Scandinavian countries and Japan report a second peak in incidence in women aged over 50 years.^13-14 Other studies from western countries also report more than 70% patients of sarcoidosis to be of less than 40 years of age.¹⁵ A study done from India among sarcoidosis patients revealed the average age of 46 years (range) and 70% of them were in 4^th/5^th decades.¹⁶ Rajkumar et al reported average age of 43 years (range 22-70) in sarcoidosis patients and majority were aged more than 40 years.⁶ Another study from India reported average age of 40 years in sarcoidosis patients.¹⁷ In present study, the mean age of study population was 34.8 years (range: 27-61 years) and majority were in between 30-49 years.

Studies done globally report slightly higher disease rate for women in sarcoidosis.^1,18 In the only population-based incidence study of sarcoidosis in the United States, rates were 5.9 per 100,000 person-years for men and 6.3 per 100,000 person-years for women.¹⁹ Various studies from India reported male predominance.^20-21 Similar observations have been found in present case series also.

Till date the most accepted proposed pathogenic hypothesis is that various antigens could promote sarcoidosis in genetically susceptible individuals.^1,22 It appears to occur more frequently in non-smokers. This inverse relationship between smoking and sarcoidosis has been observed in various other studies.^23-24 In our study also, majority (73.3 %) of patients were non-smokers.

Cough, dyspnoea, dry cough and chest pain have been reported in one-third to one-half of the patients and haemoptysis rarely occurred.^1,18,25 In the present study, pulmonary symptoms were the most common complaints with the predominance of dyspnoea (100%) which was followed by cough (93.3%) and chest pain in 16.6% of the sarcoidosis patients.

A negative Mantoux test has a high sensitivity value for the diagnosis of sarcoidosis. Even the Bacillus Calmette-Guerin vaccination administered during childhood has been found to have no correlation with a negative Mantoux reaction.²⁶ A positive Mantoux test (irrespective of the size of reaction) in a suspected case of sarcoidosis should arouse strong suspicion of an alternate or an additional diagnosis of TB.²⁷ In our study also, we found that Mantoux test was negative in 93.3% patients.

Certain laboratory tests such as serum angiotensin converting enzyme (ACE) level, while often helpful in corroborating the diagnosis, did not make the diagnosis of sarcoidosis definitive.²⁸ Serum ACE levels are increased in 30%-80% of patients with sarcoidosis and may be a surrogate marker of total granuloma burden as noted by studies from western countries.²⁹ In previous Indian studies, elevated serum ACE levels were documented in 70.5% patients.^30-31 In the present study, elevated levels of serum ACE were observed in 86.6% of cases.

Hypercalcaemia occurs in about 10% of the patients with sarcoidosis and hypercalciuria is about three times more frequent and are due to dysregulated production of 1,25-(OH) 2-D3 (calcitriol) by activated macrophages trapped in pulmonary alveoli and granulomatous inflammation.^32-33 In present study, the hypercalcaemia and hypercalciuria were observed in 33.3% and 26.6% cases of sarcoidosis respectively.

Most series have found that stage I is the most common radiographic stage, but significant variability exists.¹ Similarly, radiographic stages I and II have been reported to be the predominant stages in most studies from Scandinavia.³⁴ In contrast to this, some studies from the United States and British Isles cite a disproportionate representation of radiographic stage III and IV disease.^35-36 Previous studies from India^6,8 report that most of the radiographic abnormalities belonged to stage I and II,^{21, 37} but another study²⁶ found that stage II and III were more common.³⁸ In present study, the most common stage of sarcoidosis on presentation was found to be stage II (46.6 %) followed by stage I (40%). (The details of different radiographic stages of sarcoidosis patients in various Indian^{6,16-17,21,37,39-43} & international^{18,34,36,38,44-51} studies are summarised in table 2 and table 3).

The classic radiographic feature of sarcoidosis is bilateral hilar lymphadenopathy and is reported to be present in nearly three quarters of patients.¹ Previous studies have found that right paratracheal lymph nodes may be also be involved concomitantly.^29,34 Computed tomography (CT) may reveal the enlargement of left paratracheal, paraaortic, and subcarinal lymph node groups also.⁵² In present study, we found hilar/mediastinal lymphadenopathy on CT (n=27) in 92.6% patients. Unilateral hilar lymph node enlargement has been reported as being uncommon (seen in <10%) in the West.²⁸ In our series, it was not seen in any of the patients.

In sarcoidosis, cutaneous involvement occurs in about 25% of patients.⁵³ Two clinically important and easily recognisable skin lesions are erythema nodosum and lupus pernio. Erythema nodosum is the hallmark of acute sarcoidosis and the lesion consists of raised, red, tender bumps or nodules on the anterior aspects of the legs. Lupus pernio represents chronic sarcoidosis and consists of indurated plaques associated with discolouration of the nose, cheeks, lips, and ears. Other skin lesions in chronic sarcoidosis include plaques, maculopapular eruptions, subcutaneous nodules, changes in old scars, alopecia, and hypo- and hyperpigmented areas. In present case series, one patient had multiple subcutaneous nodules (Figure: 1). ACCESS study group found prevalence of skin involvement (excluding erythema nodosum) in United States of America to be 15.9% and erythema nodosum was observed in 8.3%.¹⁸ Yanardag H et al retrospectively evaluated the clinical features of patients diagnosed as sarcoidosis and who had skin involvement.⁵⁴ They had observed cutaneous involvement in 170 patients (136 females, 34 males) and the most frequent skin lesion was erythema nodosum (20.5%), followed by subcutaneous nodules (4.3%), maculopapular eruptions (3.7%), scar lesions (2.9%), lupus pernio (LP) (2.7%) and psoriasiform plaques (0.9%).

Joint pains occur in 25 to 39% of patients with sarcoidosis and deforming arthritis is rare.²⁹ The joints most commonly affected are knees, ankles, elbows, wrists, and small joints of the hands and feet. In present case series, 23.3% patients had symptoms of joint pain.

Ocular involvement may occur in 11 to 83% of patients with sarcoidosis.⁵⁵ Any part of the eye or orbit may be affected; uveitis is the most common of all sarcoid eye lesions. In present case series, one patient had symptoms of chronic uveitis.

In patients of suspected pulmonary sarcoidosis, the initial diagnostic procedure of choice is flexible fibreoptic bronchoscopy (FOB) with transbronchial lung biopsy (TBLB).^8,29 The bronchial mucosa in sarcoidosis may appear normal, erythematous, miliary or large nodules, yellowish nodules with a cobblestone appearance and occasionally, endobronchial granulomas form a mass-like lesion that can obstruct the bronchial lumen.^56-58

The prevalence of abnormal bronchial mucosa in sarcoidosis has been reported to vary from 33% to 70% in differentstudies.^57,59 Torrington et al reported that both black and white patients with sarcoidosis had abnormal mucosa in approximately half of the patients.⁶⁰ In present study, we found bronchial mucosa involvement in the form of erythema in 6.1%, plaques in 3.8% and nodules in 12.2 percent.

Fibreoptic bronchoscopy is a safe and minimal invasive procedure, available to make the diagnosis, including needle aspiration, BAL, transbronchial biopsy, open-lung biopsy, and mediastinoscopy.²⁵ Each of these techniques has advantages and disadvantages. BAL is safe, minimally invasive, and provides useful information for the diagnosis of sarcoidosis. The characteristic findings in BAL for sarcoidosis are normal or only mildly elevated total cell count with a predominance of lymphocytes, usually a normal percentage of eosinophils and neutrophils, and an absence of plasma cells and foamy alveolar macrophages.⁶¹ Drent M et al reported that no single cell type present in bronchoalveolar lavage (BAL) fluid appears to be predictive for sarcoidosis. They also highlighted that in sarcoidosis the majority of cases have an increased number of lymphocytes and a normal number of eosinophils/neutrophils and in severe cases the number of neutrophils can be increased as well.⁶² The cell discrimination findings of BALF in the present study were revealed the predominance of lymphocytic plus neutrophilic and lone lymphocytic alveolitis.

Bronchoalveolar lavage CD4/CD8 ratios may be of diagnostic value in sarcoidosis, obviating the need of biopsy in 40–60% of patients and it may depend on the individual facilities, knowledge and skill of the investigators involved in the various diagnostic techniques.¹ Costabel et al reported that a BAL fluid CD4/CD8 ratio of 3.5 or greater had a sensitivity of 52% and specificity of 94% in 117 consecutive patients with biopsy-proven sarcoidosis.¹² Winterbauer et al described that a ratio of 4.0 or greater distinguished²⁷ patients with sarcoidosis from 28 patients with other interstitial lung diseases with a sensitivity of 59% and a specificity of 96%.⁶³ Thomeer and Demedts compared⁴² patients with sarcoidosis and 90 patients with other forms of diffuse lung disease and found that a CD4/CD8 ratio of greater than 4.0 had a sensitivity of 55% and a specificity of 94%.⁶⁴ These three studies reached similar conclusions: in patients with a clinical picture typical of sarcoidosis, an elevated CD4/CD8 ratio in BAL may prove diagnostic of sarcoidosis and obviate the need for confirmation by additional biopsy. It is important to note that in the study of Winterbauer et al, transbronchial biopsy had a specificity of 89% for the distinction between sarcoidosis and other forms of diffuse lung disease and was thus not better than the CD4/CD8 ratio in this respect.⁶³ SP Kantrow et al reported that in pulmonary sarcoidosis BAL fluid CD4/CD8 ratio is highly variable and these authors found that only 42% in a population of 86 patients with biopsy-proven sarcoidosis had a ratio greater than 4.0, and that 12% had an inversed ratio below 1.0.⁶⁵

Danila E et al prospectively evaluated diagnostic role of BALF CD4/CD8 ratio in pulmonary sarcoidosis manifested in different radiographic and clinical forms and they found Normal BALF cell counts in 7% of sarcoid patients. They also found that optimal cut-off points for CD4/CD8 ratio are 3.5 and 4.0 for asymptomatic and symptomatic patients, respectively.⁶⁶ In the present study, TBLB was performed in 36.6% of the patients (i.e. 11/30) and more than half of them were diagnostic (i.e.8/11).

Conclusion

Sarcoidosis is a chronic granulomatous inflammatory disorder of unknown origin with heterogeneous outcome and not uncommon in India. The clinical and radiological features of sarcoidosis closely resemble tuberculosis and in countries with high prevalence of TB, like India, it is often misdiagnosed. In present study, bilateral hilar lymphadenopathy plus pulmonary opacity was the most common radiological presentation of sarcoidosis. In present study, TBLB was performed in 11 patients only (i.e. 11/30); histopathological examination revealed non-caseating granulomas in 8 (72.7%) patients. The present study also highlighted that the CD4 to CD8 of BAL fluid levels were raised in all cases of sarcoidosis and are easy to perform and helpful in supporting diagnosis of sarcoidosis along with clinical and radiological features.