Emerging Countries and Tuberculosis Constriction
Despite great advances in tackling tuberculosis (TB), the challenge posed by the disease in the developing world remains a significant one. This is further exacerbated by the persistence of the HIV/AIDS pandemic despite effective anti-retroviral therapy. TB ranks alongside HIV as the biggest causes of worldwide mortality, with a significant majority of these deaths occurring in the developing world.1 Tuberculous pericarditis is the commonest manifestation of TB in the cardiovascular system, and pericardial constriction is a dreaded sequelae, occurring in approximately 8% of affected individuals despite effective anti-TB therapy.2,3 TB is, by far, the most common cause of pericardial constriction in the developing world, accounting for about 40-90% of cases seen in different series.4 By contrast, less than 5% of cases of pericardial constriction in the developed world are attributable to TB.5
Clinical presentation is usually with signs and symptoms of predominantly right heart failure (i.e. peripheral edema, ascites and elevated central venous pressure) due to impaired diastolic filling of the heart by either an acutely inflamed and thickened pericardium (transient constrictive pericarditis), a combination of fluid and a thickened pericardium (effusive-constrictive pericarditis) or a thickened and fibrosed pericardium with/without calcification (chronic pericarditis). Without ready access to diagnostic aids such as echocardiography, it is not uncommon for patients in the developing world to present with clinical evidence of advanced disease such as gross congestive heart failure, protein-losing enteropathy or cardiac cirrhosis.6 Advanced imaging techniques such as CT scanning and cardiac MRI are also not readily available to assist in reaching a diagnosis of constrictive pericarditis in the developing world.
Renewed interest in tuberculous pericarditis in the developing world over the past 20 years has given rise to ground-breaking research that is revolutionising our understanding of the condition and its management. Historically, a 6-month course of anti-tuberculous chemotherapy and pericardiectomy, when necessary, formed the cornerstone of managing tuberculous constrictive pericarditis.7 Towards the end of the 20th century, the addition of steroids to anti-TB therapy was advocated by Strang and colleagues, whose studies showed reduction of adverse outcomes with this strategy compared to anti-tuberculous therapy alone.8,9 The turn of the 21st century necessitated a re-examination of the understanding and management of the condition, as hitherto, HIV/AIDS and TB/AIDS co-infection had not been major factors at play in tuberculous constrictive pericarditis.
Ntsekhe and colleagues showed that HIV/AIDS was associated with a lower risk of pericardial constriction in patients with presumed tuberculous pericarditis.10 The effect of CD4+ T cell count, as a marker of immunosuppression, in determining this reduced risk is not known. The Investigation into the Management of Pericarditis (IMPI) trial was a contemporary large double-blind randomized controlled trial from multiple centres in the developing world comparing steroids and immunomodulatory Mycobacterium indicus pranii in addition to standard anti-TB therapy to standard anti-TB therapy alone in patients with tuberculous pericarditis.3 The study showed no benefit for adjunctive steroids or M. Indicus pranii in preventing the primary outcome of a composite of death, tamponade requiring pericardiocentesis or constrictive pericarditis. Both steroids and M. Indicus pranii were, in fact, significantly associated with a higher risk of malignancy in those with HIV/AIDS. However, in a pre-specified sub-group analysis, steroids showed significant benefit in reducing pericardial constriction rates compared to placebo.3 These contemporary data show that steroids still have a beneficial role in the management of tuberculous constrictive pericarditis in HIV-negative patients in the developing world.11 While the benefit of steroids in transient constrictive pericarditis and effusive-constrictive pericarditis is clearly the prevention of progression to chronic constrictive pericarditis, the role of steroids in chronic constrictive pericarditis is not known.12
If anti-TB therapy and/or adjuvant steroids (when indicated) fail to prevent or reverse pericardial constriction after 4-8 weeks of therapy, surgical excision of the pericardium (pericardiectomy) is indicated to relieve the symptoms of pericardial constriction.7 While readily accessible in the developed world, pericardiectomy remains an expensive, high risk and poorly accessible procedure in many parts of the developing world.13 We have recently shown that although effective at relieving symptoms of constriction, pericardiectomy in the TB endemic region of Western Cape (South Africa )has a high peri-operative mortality of 14% (n=17/121)that is not influenced by HIV status.4 This figure is the highest reported in contemporary studies from the developing world with low output cardiac syndrome accounting for most early mortalities (n=11/17, 64.7%). Pre-operative New York Heart Association (NYHA) Functional Class IV symptoms and hyponatraemia were found to be predictors of peri-operative mortality in this study.4 In a study from India in whom 351 of 395 (88.9%) patients who underwent pericardiectomy had tuberculous constrictive pericarditis, peri-operative mortality was 7.6% with most early deaths attributable to peri-operative low-output syndrome (14/30, 47%). Pre-operative high right atrial pressure, hyperbilirubinemia, renal dysfunction, atrial fibrillation, pericardial calcification, thoracotomy approach and partial pericardiectomy were significant risk factors for death with partial pericardiectomy conferring a 4.5 higher risk of death than total pericardiectomy in this series.14 Only 7 (1.7%) patients underwent pericardiectomy on cardiopulmonary bypass in this series. In both these studies, tuberculous aetiology did not confer a higher risk of perioperative mortality. Table 1 highlights mortality and predictors of mortality after pericardiectomy for constrictive pericardiectomy in a selection of studies from developing countries where tuberculous aetiology for constrictive pericarditis still predominates.
Given the prohibitive cost and high mortality of pericardiectomy, prevention of tuberculous constrictive pericarditis with simple, easily accessible and cost-effective measures is a rational strategy in dealing with this problem of the developing world. Research is underway to identify ways of preventing the progression of effusive tuberculous pericarditis to a constrictive phase. Ntsekhe and colleagues have demonstrated a reduced level of Ac-SDKP (N-acetylseryl-aspartyl-lysyl-proline), an anti-fibrotic protein, in the pericardial fluid of patients with tuberculous pericarditis, compared to healthy controls.15 Mnguni and colleagues found that angiotensin converting enzyme inhibitors (ACE-I) were associated with increased levels of Ac-SDKP in human plasma.16 These findings suggest a potential role for ACE-I therapy in preventing tuberculous pericardial constriction and studies are underway in our center to investigate this potential therapeutic strategy. Furthermore, there is some evidence that intra-pericardial fibrinolytic agents in purulent and tuberculous pericarditis can prevent progression to constrictive pericarditis17 and we are currently involved in research aimed at fully establishing the role of intrapericardial fibrinolytic agents in preventing constrictive pericarditis in tuberculous and other forms of pericarditis.18
In summary, tuberculous constrictive pericarditis remains a major problem in the developing world. The role of anti-tuberculous chemotherapy in managing the condition is well-established. Recent evidence shows a role for the safe use of adjunctive steroids in preventing pericardial constriction in HIV negative individuals with tuberculous pericardial effusion. This benefit is outweighed by the risk of HIV-associated malignancy when steroids are used to prevent the condition in HIV positive individuals.3,11 Pericardiectomy in the developing world is associated with prohibitively high cost and peri-operative mortality and is not readily accessible. As such, prevention is a sensible strategy in the management of tuberculous constrictive pericarditis. ACE-I therapy and intra-pericardial fibrinolytic agents are potential new strategies for preventing tuberculous constrictive pericarditis that are being investigated in the developing world.Table 1: Pericardiectomy for constrictive pericarditis in the developing world: aetiology, mortality and predictors of mortality.
|Author, period||Region||Number of cases||Aetiology||Peri-operative mortality (%)||Late mortality (%)||Predictors of peri-operative mortality||Predictors of late mortality|
|Bashi, 1954-85||India||118||TB (61%)||16||_||Pre-operative NYHA III and IV||_|
|Cinar, 1990-05||Turkey||70||TB (100%)||8.6||10.1; 5 yr|
17.6; 10 yr
|Ascites, duration of symptoms||Ascites|
|Lin, 2005-10||China||51||TB (65%), idiopathic (25%), prior cardiac surgery (6%), CTD (2%), post-trauma (2%)||3.9||6.3; 1yr||_||High ESR, elevated creatinine, LCOS, pleural effusion|
|Arsan, 1983-93||Turkey||105||TB (38%), malignancy (15%), uraemia (11.4%), CTD (10.5%)||10.5||_||_|
|Chowdhury, 1984-2004||India||395||TB (88.9%), purulent (6.3%), idiopathic (3.7%), malignancy (1%)||7.6||*High RAP, hyperbilirubinaemia, AF, renal dysfunction, pericardial calcification, thoracotomy approach, partial pericardiectomy|
|Mutyaba, 1990-2014||South Africa||121||TB (91.2%), idiopathic (4.9%)||14||_||NYHA IV symptoms, hyponatraemia||_|
- Dheda K, Barry 3rd CE, Maartens G. Tuberculosis. The Lancet 2016;387:1211-1226.
- Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in Africa. Circulation 2005;112:3602-3607.
- Mayosi BM, Ntsekhe M, Bosch J et al. Prednisolone and Mycobacterium indicus pranii in Tuberculous Pericarditis. New England Journal of Medicine 2014;371:1121-1130.
- Mutyaba AK, Balkaran S, Cloete R et al. Constrictive pericarditis requiring pericardiectomy at Groote Schuur Hospital, Cape Town, South Africa: Causes and perioperative outcomes in the HIV era (1990-2012). The Journal of Thoracic and Cardiovascular Surgery 2014;148:3058-3065.e1.
- Imazio M. Constrictive Pericarditis. Myopericardial Diseases: Diagnosis and Management. Cham: Springer International Publishing, 2016:131-140.
- Commerford PJ, Strang JIG. Tuberculous pericarditis. In: Coovadia HM, Benatar SR, editors. A century of tuberculosis: South African perspectives. Cape Town: Oxford University Press, 1991:123-36.
- Mayosi BM, Burgess LJ, Doubell AF. Tuberculous pericarditis. Circulation 2005;112:3608-3616.
- Strang JI, Kakaza HH, Gibson DG, Girling DJ, Nunn AJ, Fox W. Controlled trial of prednisolone as adjuvant in treatment of tuberculous constrictive pericarditis in Transkei. Lancet 1987;2:1418-1422.
- Strang JI, Kakaza HH, Gibson DG et al. Controlled clinical trial of complete open surgical drainage and of prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1988;2:759-766.
- Ntsekhe M, Wiysonge CS, Gumedze F et al. HIV Infection Is Associated with a Lower Incidence of Constriction in Presumed Tuberculous Pericarditis: A Prospective Observational Study. PLoS ONE 2008;3:e2253.
- Adler Y, Charron P, Imazio M et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC)Endorsed by: The European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2015;36:2921-2964.
- Ntsekhe M, Wiysonge C, Volmink JA, Commerford PJ, Mayosi BM. Adjuvant corticosteroids for tuberculous pericarditis: promising, but not proven. QJM 2003;96:593-599.
- Mirabel M, Grimaldi A, Freers J, Jouven X, Marijon E. Access to cardiac surgery in sub-Saharan Africa. Lancet 2015;385:606.
- Chowdhury UK, Subramaniam GK, Kumar AS et al. Pericardiectomy for constrictive pericarditis: a clinical, echocardiographic, and hemodynamic evaluation of two surgical techniques. Ann Thorac Surg 2006;81:522-9.
- Ntsekhe M, Matthews K, Wolske J et al. Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) and Galectin-3 levels in tuberculous pericardial effusion: implications for pathogenesis and prevention of pericardial constriction. Heart 2012;98:1326-1328.
- Mnguni AT, Engel ME, Borkum MS, Mayosi BM. The Effects of Angiotensin Converting Enzyme Inhibitors (ACE-I) on Human N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) Levels: A Systematic Review and Meta-Analysis. PLoS One 2015;10:e0143338.
- Cui HB, Chen XY, Cui CC et al. Prevention of pericardial constriction by transcatheter intrapericardial fibrinolysis with urokinase. Chin Med Sci J 2005;20:5-10.
- Kakia A, Wiysonge CS, Ochodo EA, Awotedu AA, Ristic AD, Mayosi BM. The efficacy and safety of complete pericardial drainage by means of intrapericardial fibrinolysis for the prevention of complications of pericardial effusion: a systematic review protocol. BMJ open 2016;6:e007842.
- Bashi VV, John S, Ravikumar E, et al. Early and late results of pericardiectomy in 118 cases of constrictive pericarditis. Thorax 1988;43:637-641.
- Cinar B, Enc Y, Goksel O et al. Chronic constrictive tuberculous pericarditis: risk factors and outcome of pericardiectomy. PG - 701-6. Int J Tuberc Lung Dis 2006;10:701-706.
- Lin Y, Zhou M, Xiao J, Wang B, Wang Z. Treating constrictive pericarditis in a chinese single-center study: a five-year experience. Ann Thorac Surg 2012;94:1235-40.
- Arsan S, Mercan S, Sarigül A et al. Long-term experience with pericardiectomy: analysis of 105 consecutive patients. Thorac Cardiovasc Surg 1994;42:340-344.
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