Pulmonary sarcoidosis : presentation in India

1. Pulmonary sarcoidosis : presentation in India ASHOK SHAH Professor of Respiratory Medicine Vallabhbhai Patel Chest Institute University of Delhi

2. Sarcoidosis is a : Complex disease Chronic disease Occurs globally • Seen in : both sexes all age groups all races

3. Sarcoidosis : a multisystem disorder

4. It was assumed that the disease was born in northern Europe, and was once called “ Scandinavian disease ”

5. Sarcoidosis : clinical picture Clinical manifestations depend on : Ethnicity Duration of the illness Site and extent of organ involvement Activity of the granulomatous process

6. Ethnic variations Marked variation in disease presentation and severity among different ethnic and racial groups The presentation of sarcoidosis in India is often at variance with the classical descriptions found in standard western texts

7. Presentation in Caucasians High incidence of asymptomatic isolated bilateral hilar adenopathy Erythema nodosum : ? in Europeans Scandinavian countries : second peak incidence in women > 50 years

8. Presentation in African - Americans 10 - 17 times more common * A more severe course Chronic diffuse lung disease : - dyspnoea , lymphadenopathy , - systemic manifestations Extrathoracic : chronic uveitis , skin # Less amenable to treatment

9. Presentation in Japan Incidence rates per 100,000 Japan 1972 1.3 1984 1.3 Yamaguchi M et al . Sarcoidosis 1989 ; 6 : 138 - 146 Higher incidence of : cardiac and ocular sarcoidosis Erythema nodosum : uncommon Second peak incidence in women > 50 years

10. The Joint Statement still considers sarcoidosis to be a rare clinical entity in India

11. Pioneers in India “ Looking for sarcoidosis in the so - called Mantoux negative tuberculosis cases ” S C Chakravarty Vallabhbhai Patel Chest Institute, University of Delhi

12. History of sarcoidosis in India Ghose BC & Chakravarti G : first report, Indian J Pediatr 1953 ; 20 : 280 - 284 Burdwan, West Bengal Ghosh PK & Chakraborty AN : Calcutta Bull School Trop Med ( Calcutta ) 1956 ; 4 : 142 - 143 Rajam RV & colleagues : first case of Indian J Dermatol 1957 ; 23 : 95 - 135 cutaneous sarcoidosis Vishwanathan R & : first report from Chakravarty SC V P Chest Institute , Indian J Chest Dis 1959 ; 1 : 64 - 68 University of Delhi

13. 15 - year - old boy Generalized lymphadenopathy and hepatomegaly Roentgenology - chest : bilateral hilar adenopathy - hand : cystic changes in phalanges Diagnosis - cervical lymph node biopsy The first case of sarcoidosis from India

15. Presentation in India In India, almost all of the reported cases suggest that the presentation of sarcoidosis is akin to that of African - Americans Indians also have a chronic fibrosing relapsing type of the disease that is less amenable to treatment

16. In contradistinction to the African - Americans , sarcoidosis in Indians occurs far less frequently , is less severe , and is still regarded as uncommon

17. In the West, about 50% of patients with sarcoidosis are asymptomatic at the time of diagnosis, whereas in India almost all patients are symptomatic on presentation

18. Clinical presentation( West : India ) Age at presentation : West - 20 - 40 yrs India * - 5th decade Children and elderly are also affected Gender distribution Females = males : West Males > females : India #

19. Constitutional symptoms West India Fever : 15 - 22 % 22 - 57 % Weight loss : 20 - 30 % 27 - 38 % Loss of appetite : not available 22 - 32 % Fatigue : 20 - 30 % 24 - 100 %

20. Pulmonary symptoms West India Dyspnoea : 30 - 50 % 38 - 100 % Cough : 30 - 50 % 55 - 100 % Sputum production : 10 - 12 % 26 % Chest pain : 30 - 50 % 11 - 34 % Haemoptysis : 1 - 3 % 2 - 10 %

21. Pulmonary signs West India Crepitations : < 20 % 33 – 36 % Wheeze : - 8 - 18 % Airway hyperreactivity : 20 % not available

22. Although not pathognomonic , many radiological features are highly suggestive of sarcoidosis , especially when they occur concurrently

23. Thoracic sarcoidosis : radiographic staging Stage 0 : no demonstrable abnormality Stage I : hilar and mediastinal lymph node enlargement unassociated with pulmonary abnormality Stage II : hilar and mediastinal lymph node enlargement associated with pulmonary abnormality Stage III : diffuse pulmonary disease unassociated with node enlargement Stage IV : pulmonary fibrosis

26. Radiological staging of sarcoidosis in India Stage 0 1.1 - 3.4 % Stage I 24 - 44.8 % Stage II 29 - 79 % Stage III 11.1 - 32 %

27. Abnormal chest radiograph : 90 – 95 % Joseph PL III et al. Clin Chest Med 1997 ; 18 : 755 – 785 Common abnormalities encountered : - lymph node enlargement : ~ two thirds - parenchymal involvement : 25 – 50 % Plain roentgenologic appearances

28. Lymphadenopathy Nodes commonly involved : - hilar - paratracheal - tracheobronchial Commonest presentation : - symmetrical bilateral hilar lymphadenopathy : 75 – 85 %

29. A 30 - year - old man with bilateral lymph node enlargement and fine reticulations in both lung fields

30. A 50 - year - old man with bilateral asymmetrical hilar lymph nodes with lobulated border on the right side . Bilateral reticulonodular opacities are also visible Bilateral asymmetrical hilar nodes

31. Radiograph shows striking asymmetric enlargement of mediastinal lymph nodes ‘ potato nodes ’

32. Paratracheal lymph nodes Paratracheal adenopathy : 71 % - usually with hilar adenopathy Left paratracheal adenopathy : less commonly seen on chest x - ray - located more posteriorly - smaller in size and fewer in number - obscured by aorta and brachiocephalic vessels

33. 1 - 2 - 3 sign or Garland’s / pawnbroker’s sign Radiograph of 34 - year - old man shows bilateral hilar and right paratracheal lymph nodes enlargement ( ‘1 - 2 - 3 sign’ ). Also visible is bilateral parenchymal involvement with reduced lung volumes

34. Unilateral hilar adenopathy Unilateral hilar lymph node enlargement West $ : 3 - 5 % of cases India @ : 43 % of cases

35. Postero - anterior chest radiograph in a 42 - year - old man with sarcoidosis shows a left hilar lymph node and consolidation in right upper and mid zones mistaken for tuberculosis Unilateral hilar adenopathy

36. Regression of lymphadenopathy and progression of pulmonary lesion

37. Calcification of hilar nodes Seen in 5 - 20 % Usually a late manifestation Probably indicative of burnt out hyalinized lymph nodes Reported to be associated with advanced disease and steroid therapy “ Eggshell ” calcification : rarely seen

38. Parenchymal involvement Parenchymal infiltrates : - often symmetrical bilaterally - preferentially involve - central regions - posterior and apical segments of upper lobes, especially in the fibrotic stage Unilateral disease is a rarity * * Mesbahi SJ , Davies P. Clin Radiol 1981 ; 32 : 283 – 287

39. Unilateral disease Radiograph of 49 - year - old woman shows predominantly unilateral disease involving left side with cavities ( arrows ) and features of parenchymal fibrosis in the left upper zone as evidenced by the pulled - up left hilum & tracheal deviation

40. Parenchymal lesions Parenchymal nodules Linear / Reticular shadows Nodular or reticulo - nodular shadows Alveolar / Acinar pattern Cavitation Fibrosis / Atelectasis and Bronchiectasis, cysts , bullae and honeycombing are seen in advanced disease

41. Parenchymal nodules Most frequent radiological observation Caused by accumulation of many granulomas May be large and dense May simulate a metastatic neoplasm Rarely, a miliary pattern ( 1 % ) may also be seen Commonly : in combination with reticular pattern infiltration varies from purely reticular to purely nodular

42. Parenchymal nodules

43. Reticulations : - seen in 46 % patients * - may form a very fine or very coarse network Linear infiltrates : - are common and may extend fanwise from the hilum Mottled opacities have better prognosis than streaky opacities in Indian studies # Other parenchymal lesions

44. Reticulations Chest radiograph in a 40 - year - old man shows bilateral reticulations. Pleural thickening ( arrow ) is also seen in the left upper zone

45. Alveolar sarcoidosis or acinar pattern Atypical manifestation of sarcoidosis : 10 - 20 % - may be discrete or coalescent - multifocal , bilateral segmental consolidation with air bronchograms - frequently associated with reticulonodular pattern

46. Pulmonary sarcoidosis : alveolar pattern

47. Alveolar pattern : 11 years post treatment

48. Alveolar sarcoidosis with subpleural nodules HRCT of a 30 – year – old man through the level of left lower lobe bronchus showing alveolar pattern of involvement on the left side. Also visible are bilateral sub - pleural nodules (arrows)

49. Stage IV sarcoidosis : 50 - year - old woman - beaded appearance of bronchovascular bundles with - perihilar concentration of fibrosis and lobular distortion

50. Pulmonary sarcoidosis : simultaneous ground glass & honeycombing HRCT through right lower lobe bronchus shows : air bronchogram ( arrow ) ground glass opacities

51. Endobronchial sarcoidosis Usually asymptomatic May manifest with : cough , wheezing & haemoptysis Projections into bronchial lumen often described as : “ wart - like excrescences” or “bleb – like elevations” Nodular elevations : 2 – 3 mm Stage 1 : 40 % Stages 2 and 3 : 70 % Narrowing of bronchi : - atelectasis - infections distal to obstruction

52. Pleura in sarcoidosis : uncommon Clinically significant manifestations : 2 % - 4 % May manifest as : - pleural effusion : previously thought to exclude sarcoidosis - pneumothorax - pleural thickening - hydropneumothorax - trapped lung - haemothorax - chylothorax

53. Pleural effusion Prevalence : < 3 % Right : 45 % - Left : 33 % - Bilateral : 22 %

54. Pleura : a 35 - year - old man with a non - resolving pleural effusion

55. Well circumscribed noncaseating granuloma consisting of epitheloid cells and multinucleated giant cells ( H & E ? 100 )

56. Spontaneous pneumothorax Chest radiograph in a 45 - year - old woman with sarcoidosis shows pneumothorax ( arrows ) along with b / l hilar prominence, reticular opacities in lower zones

57. Extrapulmonary features in pulmonary sarcoidosis West India Peripheral : 30 % 27 - 45 % lymphadenopathy Erythema nodosum : 33 % 1.5 - 20 % Other skin lesions : 25 % 4.6 - 42 % Ocular lesions : 11 - 83 % 8 - 40 % Arthralgia : 25 - 39 % 18 - 51 %

59. Sarcoidosis : skin lesions

60. Pulmonary sarcoidosis :extrapulmonary features West India Hepatomegaly : < 20 % 34 - 46 % Splenomegaly : not available 12 - 19 % Clubbing : rare 3 - 12 % Cardiac involvement : 5 % 5 - 12 % Neurological : < 10 % 8 - 13 % involvement Parotid gland : 6 % 8 - 15 % involvement

61. In India , sarcoidosis is infrequently recognised and is often mistaken for tuberculosis

62. Diagnostic dilemma with tuberculosis Remarkable similarities to tuberculosis : - Clinical - Radiologic - Histopathologic - Immunologic

63. Miliary involvement In India , presence of miliary lesions is almost always presumed to be due to tuberculosis

64. Sarcoidosis : miliary pattern in a 40 - year - old man

65. A 65 - year - old lady with cavitation9 months prior to referral

66. Aspergilloma formation in a sarcoid cavity1 ¾ - year after commencement of therapy for sarcoidosis

67. Tuberculosis and sarcoidosis : occurrence in same patient Sporadic case reports of both diseases Chronologically it can be either : - concomitant occurrence - sarcoidosis followed by tuberculosis - tuberculosis followed by sarcoidosis

68. A 35 - year - old lady presented with a history of dry cough , fever and weight loss for one month Chest X - ray showed bilateral symmetrical hilar lymphadenopathy FOB done elsewhere : inconclusive

69. On presentation : investigated for pulmonary sarcoidosis Spirometry : mixed obstruction with restriction , diffusion per unit volume normal Serum ACE : 25.7 IU / ml ( 8 – 52 IU / ml ) Mantoux test : 20 mm x 22 mm ( 1 TU )

70. Patient went out of town and reported later with persistent fever and productive cough Chest X - ray revealed a cavity in the right middle zone All three consecutive samples for AFB were positive Sputum culture : positive Bronchial aspirate culture by BACTEC : positive

71. She complained of ? dyspnoea Chest X- ray : shrunken lung fields PFT : restrictive pattern with diffusion defect

72. A final diagnosis of sarcoidosis was established on the basis of a transbronchial lung biopsy which showed non caseating granulomas with Schaumann bodies The patient was subsequently initiated on oral corticosteroids to which she responded favourably

73. Both are chronic multisystem diseases : affect lungs , lymph nodes , skin , eye , liver , spleen , brain , musculo - skeletal system etc. Both can have acute presentations Both characterised by granulomatous inflammation Both present as a constellation of symptoms : - fever , weight loss , anorexia , malaise , weakness , chronic cough , etc. Sarcoidosis and Tuberculosis : similarities

74. Sarcoidosis and Tuberculosis : differences Sarcoidosis Tuberculosis Clinical course remissions & progressive exacerbations Pleural effusion rare very common Tuberculin test anergic positive Granuloma non - caseating caseating Serum ACE ? not raised Treatment corticosteroids ATT

75. Treatment issues and difficulties Risk of precipitation of tuberculosis following corticosteroid therapy for sarcoidosis Occasionally , a patient misdiagnosed as sarcoidosis may later develop tuberculosis attributed to a delay in the diagnosis rather than steroid therapy Lillibaek T , Thomsen VO. Scand J Infect Dis 2000 ; 32 : 218 - 220

76. Treatment issues and difficulties in India Not uncommon for a healthy adult Indian to harbour quiescent tubercular foci ( tuberculin positivity : 64 - 85 % * ) Indian patients with either tuberculin positivity or with difficult to distinguish features : invariably prescribed antituberculous therapy along with corticosteroids * Bull World Health Organ 1979 ; 57 : 819 - 827 Indian J Med Res 1979 ; 70 : 349 - 363

77. Mantoux test : - < 10 mm : 123 ( 96 % ) - > 10 mm : 4 ( 3 % ) History of antituberculous therapy : 69 ( 54 % ) Shah A et al. Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005 Sarcoidosis : review of 128 Indian patients

78. Mantoux test in sarcoidosis Tuberculin anergy in sarcoidosis is not influenced by the rate of Mantoux positivity Tuberculin negativity in : healthy controls = 23 % sarcoidosis = 90.2 % Mantoux positivity in a suspected case of sarcoidosis an alternate or an additional diagnosis of tuberculosis

79. Issues in India Patient - dependent factors Reluctance to accept diagnosis Doctor shopping Reluctance to undergo invasive procedures Partial symptomatic relief with intermittent unregulated steroid therapy

80. Issues in India Physician - dependent factors Lack of awareness Lack of easy, standardised diagnostic criterion Reluctance to perform invasive procedures Lack of a standardised treatment protocol The overwhelming presence of tuberculosis

81. Sarcoidosis, in India, in contrast to world data, is more often seen in males, generally occurs after forty years of age and is usually of the chronic relapsing fibrotic type

84. Sarcoidosis : review of 128 Indian patients 1986 - 2000 * 2001 - 2005 No. of patients 73 55 Mean age 42.8 yrs 43.2 yrs Males : females 42 : 31 20 : 35 Mean duration 1.8 yrs 2.2 yrs of disease Onset of disease 60 % 58 % after 40 yrs . of age Paediatric age group 0 1

85. Respiratory symptoms Cough : 99 ( 77 % ) Breathlessness : 98 ( 76 % ) Sputum : 54 ( 42 % ) Wheezing : 31 ( 24 % ) Chest pain : 24 ( 19 % ) Haemoptysis : 13 ( 10 % ) Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005

86. Other symptoms Fever : 73 ( 57 % ) Weight loss : 50 ( 39 % ) Anorexia : 45 ( 35 % ) Skin lesions : 42 ( 33 % ) Arthralgia : 33 ( 26 % ) Eye lesions : 26 ( 20 % ) Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005

87. Clinical signs Clubbing : 9 ( 7 % ) Crepitations : 39 ( 30 % ) Wheezing : 21 ( 16 % ) Lymphadenopathy : 40 ( 31 % ) Hepatomegaly : 31 ( 24 % ) Splenomegaly : 17 ( 13 % ) Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005

88. Other associated medical problems Nasal symptoms : 38 ( 30 % ) Hypertension : 21 ( 16 % ) Diabetes mellitus : 18 ( 14 % ) Cardiac involvement : 4 ( 3 % ) Renal calculi : 4 ( 3 % ) Chronic cholecystitis with cholelithiasis : 3 ( 2 % ) Hypothyroidism : 3 ( 2 % ) Epididymitis : 1 ( 0.8 % ) Giant cell ataxia : 1 ( 0.8 % )

89. Lofgren’s syndrome : 2 ( 1.6 % ) Mantoux test < 10 mm : 123 ( 96 % ) > 10 mm : 4 ( 3 % ) History of antituberculous therapy : 69 ( 54 % ) Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005

90. Biochemical tests 24 - hour urinary : ? 54 / 127 ( 43 % ) calcium Serum calcium : ? 9 / 125 ( 7 % ) Serum A C E : ? 55 / 92 ( 60 % ) Study presented in part at the 8th WASOG Congress , Denver , Colorado , USA , June 12 - 15 , 2005

91. Chest roentgenogram

92. Demonstration of noncaseating granuloma Bronchoscopy : 93 / 102 Skin biopsy : 17 Lymph node biopsy : 7 Kveim test : 7 Liver biopsy : 2 Thoracotomy : 1 Trans - thoracic FNAC : 1

93. Pulmonary function testing

94. Response to therapy