Tb Pericarditis

A lecture on diagnosis and treatment of TB pericarditis tailored to practitioners in the Global South.

1. Tuberculous Pericarditis Zhenya Krapivinsky, MD By Yale Rosen from USA (Tuberculous pericarditis Uploaded by CFCF) [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)], via Wikimedia Commons

2. HEALTH 4 THE WORLD . ORG . INSERT PICTURE Zhenya Krapivinsky, MD Assistant Clinical Professor, Division of Hospital Medicine University of California, San Francisco

3. HEALTH 4 THE WORLD . ORG . No disclosures or conflicts of interest FACULTY DISCLOSURE Health4TheWorld is not responsible for, and to the extent not prohibited by law, disclaims all liability relating to, the information, content and materials included by medical professionals in their lectures.

4. 01 02 03 04 05 PATHOPHYSIOLOGY SIGNS AND SYMPTOMS DIAGNOSIS PATIENT EVALUATION TREATMENT SUB-TOPICS

5. Learning Objectives Be able to correctly identify a patient presenting with symptoms of TB pericarditis. Be able to recognize physical exam findings of TB pericarditis, constrictive pericarditis and tamponade. Be able to order appropriate investigations for a patient with suspected TB pericarditis Be able to list the diagnostic criteria for definite and presumptive diagnoses of TB pericarditis Be able to order and interpret appropriate investigations of pericardial fluid in a patient with suspected TB pericarditis. Be able to appropriately treat TB pericarditis and determine when steroids and/or pericardiectomy are indicated.

6. HEALTH 4 THE WORLD . ORG . BACKGROUND AND PATHOPHYSIOLOGY

7. Tuberculous Pericarditis Important Complication of Tuberculosis Diagnosis is difficult and often delayed Pericardial effusion is the most common clinical presentation Delayed diagnosis can lead to constrictive pericarditis with limited treatment options.

8. TB Pericarditis: epidemiology # 1 Cause of pericarditis on the African continent Mortality 50% Most common cause of pericardial effusion Constrictive pericarditis 40%, leading cause of death.

9. 3 Clinical Stages Effusive Stage Effusive-Constrictive Stage Constrictive Stages

10. TB pericarditis : 4 Stages of pathogenesis Serous effusion Exudative effusion, many neutrophils, lots of bacteria Serosanguinous effusion (tamponade & heart failure) First clinically recognizable phase Lymphocyte predominant, high protein Fibrosis (benefit from steroids) No effusion, calcified pericardium on CT Constriction (need surgery)

11. Effusive Constrictive Pericarditis Combination of tamponade ands constriction leg edema, ascites and hypotension, raised JVP Diagnose: after pericardiocentesis elevated RA pressure or elevated JVP CT: effusion + calcified pericardium Pericardial Effusion Calcified pericardium: enhanced with IV contrast By K.Yamazak, General Thoracic and Cardiovascular Surgery, 2012, Volume 60, Number 5, Page 297

12. Risk Factors - Weakened Immune System HIV infection Diabetes mellitus Severe kidney disease Low body weight Head and neck cancer Medical treatments such as corticosteroids or organ transplant Specialized treatment for rheumatoid arthritis or Crohn’s disease Older Age

13. HEALTH 4 THE WORLD . ORG . SIGNS AND SYMPTOMS

14. Mr R. is a 45-year-old man, who presented to the hospital with shortness of breath (SOB) and right upper quadrant abdominal pain . 2 months of increasing SOB and dyspnea on exertion. Decreased exercise tolerance, only able to walk a few steps before getting SOB. Orthopnea , could only sleep sitting up in a chair. No cough, hemoptysis, or chest pain + Leg edema Dull, constant right upper abdominal pain without nausea, vomiting or diarrhea. 7kg weight loss over the past 3 months with fevers and sweats. He had a history of unprotected sex with multiple female partners His family history was significant for 2 siblings who had died from AIDS

15. Symptoms Dyspnea Chest Pain improves leaning forward Cough Fevers Sweats Weight Loss

16. Symptoms of Constrictive Pericarditis Right upper abdominal pain From liver congestion Ascites Leg edema Hypotension from tamponade

17. Back to Mr. R. General: Cachectic man in respiratory distress , sitting upright in bed. Vital signs: Temp 38.9ºC, HR 105 BP 98/60, RR 30, O 2 Sat 98% Head: bitemporal wasting, no icterus, conjunctival pallor, no thrush Neck: no adenopathy. JVP seen with patient sitting upright without respiratory variation Lungs: clear to auscultation bilaterally. Heart: regular tachycardia , no murmurs and no S3 heart sound and no pericardial rub, but the heart sounds are distant . Abdomen: tender hepatomegally with liver edge palpated at 4 cm below the costal margin. Abdomen soft and without fluid wave or splenomegaly. Extremities: No edema.

18. Physical Exam Vitals: Lower Blood Pressure, +/- weak pulse, +/- fever Gen: Thin, Dyspneic Neck: Raised JVP ( Kussmaul’s sign) CV: Distant heart sounds , Pericardial Rub (ask patient to hold breath), Pericardial nock (high pitch S3, diaphragm) Abd: Ascites & tender hepatomegaly Ext: Leg edema

19. Back to our case of Mr. R.: Laboratory tests: WBC 5,000 cells/mL with an absolute lymphocyte count 6500 cells/uL (normal 1300 - 3500 cells/uL) . ESR: 75 An HIV test was ordered. Chest X ray: A very enlarged cardiac silhouette, with a cardiothoracic ratio of approximately 75%. No pulmonary infiltrates, effusions, or hilar lymphadenopathy seen.

20. HEALTH 4 THE WORLD . ORG . PATIENT EVALUATION

21. Pericardial TB: My Diagnostic Approach Chest x-ray ECG Echocardiogram Consider CT of the chest to eval lymph nodes Obtain sputum and urine for AFB and Gene- Xpert Pericardiocentesis (smear, culture and PCR) HIV testing

22. Pericardial TB: Chest X-ray Enlarged cardiac silhouette 30% pleural effusion Calcified pericardium No Hilar Adenopathy Image courtesy of James Heilman, MD (Own work) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0) , via Wikimedia Commons

23. Pericardial TB pleural effusion calcified pericardium

24. ECG: concave ST elevation

25. ECG: Large pericardial effusion

26. ECG: Tamponade

27. Back to our case of Mr. R.: Laboratory tests: WBC 5,000 cells/mL with an absolute lymphocyte count 6500 cells/uL (normal 1300 - 3500 cells/uL) . ESR: 75 An HIV test was ordered. Chest X ray: A very enlarged cardiac silhouette, with a cardiothoracic ratio of approximately 75%. No pulmonary infiltrates, effusions, or hilar lymphadenopathy seen.

28. Diagnosis Definitive Diagnosis: Gold Standard Detection of TB bacilli in smear or culture of pericardial fluid Detection of TB bacilli on or caseating granulomas on histological exam of excised pericardium Presumptive Diagnosis TB is diagnosed in another body area in a patient with a pericardial effusion. Lymphocyte predominant pericardial effusion (exudate) or an elevated level of Adenosine Deaminases (ADA) in the pericardial fluid (ADA > 40U/L) Mediastinal (non-hilar)lymph nodes on chest computed tomography with hypodense centre and matting + positive tuberculin skin test (matting  =  coalescing of adjacent lymph nodes). Appropriate response to anti-TB therapy

29. Pericardial TB: Echocardiogram Pericardial effusion Calcified pericardium Fibrin stranding RV collapse in tamponade PE = pericardial effusion Image courtesy of Kalumet (Own work) [GFDL(http:// www.gnu.org /copyleft/ fdl.html ), via Wikimedia Commons

30. Pericardial Stranding Seen in up to 60% of patients with TB pericardial effusion

31. Normal Echocardiogram Apical 4 chamber view- Normal "Echo Apical 4 Chamber View- Normal." YouTube. N. p., 2019. Web. 24 Jan. 2019. RV

32. Cardiac Tamponade RV collapse Image courtesy of Kalumet (Own work) [GFDL(http://www.gnu.org/copyleft/fdl.html), via Wikimedia Commons

33. Diagnosis Definitive Diagnosis: Gold Standard Detection of TB bacilli in smear or culture of pericardial fluid Detection of TB bacilli on or caseating granulomas on histological exam of excised pericardium Presumptive Diagnosis TB is diagnosed in another body area in a patient with a pericardial effusion. Lymphocyte predominant pericardial effusion (exudate) or an elevated level of Adenosine Deaminases (ADA) in the pericardial fluid (ADA > 40U/L) Mediastinal (non-hilar)lymph nodes on chest computed tomography with hypodense centre and matting + in a patient with pericardial effusion Appropriate response to anti-TB therapy

34. Pericardial TB: CT Chest Mediastinal Lymph Nodes No hilar nodes Lymph nodes > 10mm Hypodense center (due to necrosis)

35. Diagnosis Definitive Diagnosis: Gold Standard Detection of TB bacilli in smear or culture of pericardial fluid Detection of TB bacilli on or caseating granulomas on histological exam of excised pericardium Presumptive Diagnosis TB is diagnosed in another body area in a patient with a pericardial effusion. Lymphocyte predominant pericardial effusion (exudate) or an elevated level of Adenosine Deaminases (ADA) in the pericardial fluid (ADA > 40U/L) Mediastinal (non-hilar)lymph nodes on chest computed tomography with hypodense centre and matting + in a patient with pericardial effusion Appropriate response to anti-TB therapy

36. Why do a Pericardiocentesis? Relieves symptoms Prevents constriction To prevents/treats tamponade Echocardiographic evidence of tamponade Hypotension Presence of pulsus paradoxus (>12 mmHg) It is recommended in cases of suspected impending tamponade (severe dyspnea & resting tachycardia) Image courtesy of N. Patchett (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons

37. HEALTH 4 THE WORLD . ORG . DIAGNOSIS

38. Decision Tree for Diagnosing TB pericarditis Legend Pc-ADA, - pericardial ADA PB-WCC - peripheral WBC count Pc L/N ratio - pericardial lymphocyte/neutrophil ratio Sensitivity: 96% Specificity: 97% ** Important Slide**

39. Back to our case: Mr. R Echocardiogram with a portable ultrasound machine showed a massive pericardial effusion with fibrin strands. Pulsus paradoxus was 8 mmHg Despite normal BP & absence of pulsus paradoxus, the severity of Mr.R’s dyspnea, along with tachycardia at rest, was consistent with a high risk of impending tamponade and a pericardiocentesis was done. Pericardiocentesis: 1.2L of blood tinged pericardial fluid. Pericardial Fluid: ADA 72 AFB smear was negative WBC count elevated at 12,000 cells/ uL and 5600 lymphocytes & 1200 neutrophils. Pericardial fluid was sent for culture (which can take up to 6 weeks to return with results). HIV serology was positive.

40. Decision Tree for Diagnosing TB pericarditis : Mr. R Sensitivity: 96% Specificity: 97% ADA=72U/L 5 x 10 9/ L

41. Differential Diagnosis for TB Pericarditis Infectious Bacterial (none-typhoid salmonella) Noninfectious Kaposi’s Sarcoma Lymphoma Trauma

42. Review Diagnostic Criteria: Pericardial TB Definitive Diagnosis: Gold Standard Detection of TB bacilli in smear or culture of pericardial fluid Detection of TB bacilli on or caseating granulomas on histological exam of excised pericardium Presumptive Diagnosis TB is diagnosed in another body area in a patient with a pericardial effusion. Lymphocyte predominant pericardial effusion (exudate) or an elevated level of Adenosine Deaminases (ADA) in the pericardial fluid (ADA > 40U/L) Mediastinal (non-hilar)lymph nodes on chest computed tomography with hypodense centre and matting + positive tuberculin skin test (matting  =  coalescing of adjacent lymph nodes). Appropriate response to anti-TB therapy

43. ***Review: Approach to Pericardial TB diagnosis**** Obtain samples from other sources: sputum, urine, lymph nodes etc. AFB stain, PCR, culture all other fluids Get a CXR, Echo, CT – supporting findings Check HIV status Most patients should undergo a pericardiocentesis - check ADA, follow decision tree. Empiric Therapy should be started before diagnosis is confirmed in most cases with high suspicion (in TB endemic areas and in HIV+ patients) Pericardial biopsy should be the last option and reserved for difficult cases where other etiologies (such as cancer) are high on the differential diagnosis.

44. Complications of Pericardial TB Congestive heart failure Constrictive pericarditis #1 complications that clinicians should try to prevent (with appropriate steroid use and drainage of effusion) Cardiac tamponade Congestive hepatopathy and cardiac cirrhosis

45. HEALTH 4 THE WORLD . ORG . TREATMENT

46. Pericardial TB: Treatment Six month regimen is used to treat pericardial TB - two months Isoniazid + Rifampicin + Pyrazinamide +/- Ethambutol - four months Isoniazid + Rifampicin +/- prednisolone (based on risk of constrictive pericarditis) For patients in areas where TB is endemic, when clinical suspicion of tuberculous pericarditis is high & in the case of presumptive diagnosis, initiation of empiric anti-TB therapy is appropriate prior to establishing a definitive diagnosis (culture results).

47. Pericardial TB Treatment: corticosteroids? Cochrane Review 7 RCTs, all from sub-Saharan Africa, 1959 participants, 54% HIV-positive Trials looked at adjuvant steroids vs. placebo in the treatment of TB pericarditis. Conclusions: In HIV-, corticosteroids may reduce deaths from all causes (RR 0.80, low certainty evidence ) and the need for repeat pericardiocentesis (RR 0.85, low certainty evidence ). In HIV+, corticosteroids may reduce constriction (RR 0.55, low certainty evidence ), uncertain if there is an effect on all-cause mortality (l ow certainty evidence) , there may be a slight increase in Kaposi’s Sarcoma with the use of steroids (l ow certainty evidence) ; no effect on repeat pericardiocentesis (RR 1.02, low certainty evidence ).

48. Recommendations: steroids to prevent constrictive pericarditis Corticosteroids may prevent constrictive pericarditis, and should be used in all HIV- patients. Recommend using steroids in HIV+ patients at highest risk for constrictive pericarditis In those with large effusion In those with high WBC in the pericardial fluid In those with early signs of constriction on echocardiogram Corticosteroid Regimen Prednisolone 60 mg/day for 4 weeks. Prednisolone 30 mg/day for 4 weeks Prednisolone 15 mg/day for 2 weeks Prednisolone 5 mg/day for 1 week A shorter course of 60 mg of prednisone daily, tapering by 10/mg day each week for 6 weeks has been shown to be effective in HIV+ patients.

49. Constrictive Pericardial TB Treatment: Pericardiectomy Surgical resection of the pericardium is indicated for those with echo findings of pericardial constriction after 6-8 weeks of treatment and in those who remain symptomatic after 6-8 weeks of treatment with steroids and ATB. Important: all patients should have a repeat echocardiogram after 6-8 weeks of initiating treatment. Fibrous Pericardium Photo curtesy of Anatomist90 (Own work) [CC BY-SA 3.0 (https:// creativecommons.org /licenses/by- sa /3.0)], via Wikimedia Commons

50. Back to Mr. R. A presumptive diagnosis of TB pericarditis due to a lymphocyte predominant, exudative pericardial fluid was made. Mr. R’s symptoms improved dramatically following pericardiocentesis. His exercise tolerance returned to baseline and he was immediately able to lay flat on the bed. His tachycardia immediately resolved His Abdominal Pain improved over the course of 1 week. A repeat echocardiogram done 5 days later revealed no reaccumulation of pericardial fluid. Mr.R was started on empiric 4-drug anti-TB therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol) and adjunctive prednisolone as his large pericardial effusion put him at high risk for developing constrictive pericarditis. He was discharged from the hospital on these medications & a repeat echo at 6 weeks after discharge. .

51. Take Home Summary Symptoms: fever, weight loss, cough, dyspnea, chest pain, Echocardiogram: do urgently if TB pericarditis suspected. Pericardiocentesis should always be pursued if possible. Send pericardial fluid for ADA, AFB, culture & PCR “Presumptive diagnosis ”: use the S. Africa decision tree.

52. Take Home Points Empiric treatment Steroids : can decrease mortality and prevent constriction in:” All HIV - patients with pericardial TB should receive adjuvant steroids Only HIV+ patients with established constrictive pericarditis or those at a high risk of developing it (high WBCs in pericardial fluid, large effusion) should receive adjuvant steroids. Follow-up echocardiogram at 6 weeks to evaluate for constriction.

53. References Diagnostic Value of Adenosine Deaminase Activity in TB serositis. P.C. Mathur et. al. Indian J Tuberc 2006; 53:92-95 Tuberculous pericarditis and myocarditis in adults and children, Bongani M Mayosi et. al. Tuberculosis, 2009 Pericardial Diseases, William C. Little, Jae K. Oh, in Goldman's Cecil Medicine (Twenty Fourth Edition), 2012 Clinical and Microbiologic Criteria for Diagnosis of Lung Disease Due to Nontuberculous Mycobacteria . Nicholas Walter, Charles L. Daley; Clinical Respiratory Medicine (Fourth Edition) , 2012 H. Reuter, L. Burgess, W. van Vuuren, A. Doubell; Diagnosing tuberculous pericarditis, QJM: An International Journal of Medicine, Volume 99, Issue 12, 1 December 2006, Pages 827–839 Advanced effusive-constrictive pericarditis rescued by the aggressive waffle procedure. Akira Marui, MD, PhD; Gen Thorac Cardiovasc Surg (2012) 60:297–301 Wiysonge CS, Ntsekhe M, Thabane L, Volmink J, Majombozi D, Gumedze F, Pandie S, Mayosi BM. Interventions for treating tuberculous pericarditis. Cochrane Database of Systematic Reviews 2017, Issue 9. Tuberculous Pericarditis. Bongani M. Mayosi, Lesley J. Burgess and Anton F. Doubell. Circulation. 2005;112:3608-3616, originally published December 5, 2005 Management of Effusive and Constrictive Pericardial Heart Disease. Circulation Journal of American Heart Association 2002;105;2939-2942 Brian D. Hoit Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: a prospective study. Pandie et al. BMC Medicine 2014, 12:101 Etiological Profile, Clinical Features and Medical Management of Acute, Pericarditis in Burkina Faso. Yameogo et al., J Trop Dis 2013, 1:3 Tuberculosis. Thomas R Frieden, Timothy R Sterling, Sonal S Munsiff, Catherine J Watt, Christopher Dye. Lancet 2003; 362: 887–99