Case of the Month:Case of the Month:

Is it a Mystery???Is it a Mystery???

32 y/o post-doctoral student at UT, who 32 y/o post-doctoral student at UT, who moved from India 3 years ago for moved from India 3 years ago for academic reasons.academic reasons.

The patient presents with one month of The patient presents with one month of febrile illness (not quantified), general febrile illness (not quantified), general malaise, weakness, non-productive cough, malaise, weakness, non-productive cough, weight loss (10 lbs estimation). Few days weight loss (10 lbs estimation). Few days prior to admission her symptoms have prior to admission her symptoms have been worsening, as well as new SOB.been worsening, as well as new SOB.

The SOB is at rest, but it worsens on The SOB is at rest, but it worsens on exertion. Denies orthopnea, PND or LE exertion. Denies orthopnea, PND or LE edema.edema.

Because of her symptoms, she went to Because of her symptoms, she went to Student Health, where a CXR was Student Health, where a CXR was obtained, a PPD was placed and PO obtained, a PPD was placed and PO antibiotics were administered.antibiotics were administered.

The CXR preliminary report was read as The CXR preliminary report was read as cardiomegaly and “suspicious” appearing cardiomegaly and “suspicious” appearing right apex.right apex.

The PPD was (+).The PPD was (+). The patient was referred from Student The patient was referred from Student

Health to the Med ED for further Health to the Med ED for further evaluation.evaluation.

PMHx: malaria when she was 10 yoaPMHx: malaria when she was 10 yoa

Otherwise negativeOtherwise negative Soc Hx: Denies smoking, ETOH or Soc Hx: Denies smoking, ETOH or

recreational drugsrecreational drugs Meds: Ciprofloxacin 200mg PO BIDMeds: Ciprofloxacin 200mg PO BID FHx: Non-contributoryFHx: Non-contributory

ROS:ROS: Denies CP. Denies SOB prior to current Denies CP. Denies SOB prior to current

illness. Good exercise tolerance.illness. Good exercise tolerance. Denies frequent cough, in the past. Denies Denies frequent cough, in the past. Denies

hemoptysis. Denies unexplained febrile hemoptysis. Denies unexplained febrile illness or weight loss in the past. Denies illness or weight loss in the past. Denies night sweats.night sweats.

Denies arthralgias or myalgias.Denies arthralgias or myalgias.

Has been a healthy adult until now.Has been a healthy adult until now.

PEX:PEX:

BP: 115/70 HR: 105 T: 101 F RR: 21 BP: 115/70 HR: 105 T: 101 F RR: 21 SO2: 100%SO2: 100%

Patient is in mild distress because of Patient is in mild distress because of respiratory difficulty. AAOX3 able to respiratory difficulty. AAOX3 able to provide history.provide history.

(+) 7 cm JVD, no carotid bruits heard.(+) 7 cm JVD, no carotid bruits heard.

Heart: RR no S3, S4 no murmurs or rubs.Heart: RR no S3, S4 no murmurs or rubs. Lungs: Bibasilar crackles, otherwise clear.Lungs: Bibasilar crackles, otherwise clear. Abd: soft, non tender, BS +, no guarding.Abd: soft, non tender, BS +, no guarding. NO LE edema.NO LE edema.

CXR: Cardiomegaly. Bilateral pleural CXR: Cardiomegaly. Bilateral pleural effusions. NO pulmonary nodules.effusions. NO pulmonary nodules.

CT scan chest: Large pericardial effusion. CT scan chest: Large pericardial effusion. Moderate bilateral pleural effusions. Moderate bilateral pleural effusions. Bilateral atelectasis.Bilateral atelectasis.

The cardiology fellow on call, “Dr. Z” was The cardiology fellow on call, “Dr. Z” was called.called.

He noted on his physical exam a He noted on his physical exam a pulsus pulsus paradoxusparadoxus of 20 mmHg. of 20 mmHg.

He performed STAT EKG and echo.He performed STAT EKG and echo.

EchocardiogramEchocardiogram

Na: 141Na: 141 K: 3.5K: 3.5 Cl:106Cl:106 CO2: 29CO2: 29 BUN: 13BUN: 13 Crea: 0.7Crea: 0.7 T Prot: 6.0T Prot: 6.0 Alb: 2.6Alb: 2.6 Bili: 0.7Bili: 0.7 SGOT: 26SGOT: 26 SGPT: 63SGPT: 63 AlP: 175AlP: 175 GGT: 141GGT: 141 PT: 14.7PT: 14.7 PTT: 34.9PTT: 34.9 INR: 1.16INR: 1.16

WBC: 14.9 (18)KWBC: 14.9 (18)K Hgb: 11Hgb: 11 Hct: 33Hct: 33 Plt: 614 KPlt: 614 K N: 77% N: 77% L: 14%L: 14% M: 9%M: 9% E: 1%E: 1% MCV: 80.9MCV: 80.9 MCH: 27MCH: 27 RDW: 15.1RDW: 15.1 Fe: 24Fe: 24 TIBC: 308TIBC: 308 Ferritin: 115Ferritin: 115

CRP: 8.1CRP: 8.1 ESR: 98ESR: 98 TSH: 1.560TSH: 1.560 Anti RNP: 36Anti RNP: 36 RF: 11.4RF: 11.4 ANA: (-)ANA: (-) Smith AB: 29Smith AB: 29 Hep A, B, C (-)Hep A, B, C (-)

Pericardial FluidPericardial Fluid

Glucose: 41Glucose: 41 LDH: 2432LDH: 2432 pH: 7.5pH: 7.5 Protein: 6.8Protein: 6.8 WBC:10.5 KWBC:10.5 K RBC: 5.4 KRBC: 5.4 K N: 46%N: 46% L: 14%L: 14% M: M:

10%10% AFB smear: (-)AFB smear: (-) Fungal cx: (-)Fungal cx: (-) Aerobic cx: (-)Aerobic cx: (-) AFB cx: PendingAFB cx: Pending

Adenosine Deaminase: 44.4Adenosine Deaminase: 44.4

PCR for PCR for M.tuberculosisM.tuberculosis: (-): (-)

Pericardial Biopsy: Reactive mesothelial Pericardial Biopsy: Reactive mesothelial cells, underlying adipose tissue and cells, underlying adipose tissue and paucicellular fibro connective tissue with paucicellular fibro connective tissue with foci of chronic inflammation consistent with foci of chronic inflammation consistent with chronic pericarditis. Granulomatous chronic pericarditis. Granulomatous inflammation is not identified.inflammation is not identified.

Special stains are Pending.Special stains are Pending.

Microbiology:Microbiology: AFB smear (sputum): (-) X 3AFB smear (sputum): (-) X 3 AFB cxs (sputum): PendingAFB cxs (sputum): Pending Blood cxs: (-) X3Blood cxs: (-) X3

SO??SO??

Tuberculous PericarditisTuberculous Pericarditis

Tuberculous pericarditis occurs in 1 to 2 % of Tuberculous pericarditis occurs in 1 to 2 % of patients with pulmonary tuberculosis patients with pulmonary tuberculosis

Diagnosis of tuberculous etiology in pericardial Diagnosis of tuberculous etiology in pericardial effusions is important since the prognosis is effusions is important since the prognosis is excellent with specific treatment. excellent with specific treatment.

Clinical features may not be distinctive and the Clinical features may not be distinctive and the diagnosis could be missed. With the spread of diagnosis could be missed. With the spread of HIV infection the incidence has increased. HIV infection the incidence has increased.

Usually presents as a slowly progressive febrile Usually presents as a slowly progressive febrile illness. When it presents as an acute illness. When it presents as an acute pericarditis, which is uncommon, or as cardiac pericarditis, which is uncommon, or as cardiac tamponade, which is frequent, the diagnosis is tamponade, which is frequent, the diagnosis is more likely to be delayed or missed. more likely to be delayed or missed.

The delay from hospital admission to diagnosis The delay from hospital admission to diagnosis was 5.2 weeks; diagnosis was first made only at was 5.2 weeks; diagnosis was first made only at necropsy in 17% of patients.necropsy in 17% of patients.1,21,2

1.Sagrista-Sauleda J. Am Coll Cardiol 1988;2:724–8 2. Rooney JJ. Ann Intern Med 1970;72:73–8

Chronic idiopathic effusions in which no Chronic idiopathic effusions in which no etiology could be established are a etiology could be established are a common cause of tamponade varying from common cause of tamponade varying from 11%–32%.11%–32%.

Without specific treatment the average Without specific treatment the average survival was 3.7 months in a report from survival was 3.7 months in a report from Africa and only 4/20 (20%) were alive at Africa and only 4/20 (20%) were alive at six months. six months.

PathogenesisPathogenesis

In a rare case there may be direct spread from In a rare case there may be direct spread from tuberculous pneumonia, it can be seeded in tuberculous pneumonia, it can be seeded in miliary tuberculosis and in such instances other miliary tuberculosis and in such instances other organ systems dominate the presentation.organ systems dominate the presentation.

Most often the spread is from the breakdown of Most often the spread is from the breakdown of infection in mediastinal nodes directly into the infection in mediastinal nodes directly into the pericardium and particularly those at the pericardium and particularly those at the tracheobronchial bifurcation. tracheobronchial bifurcation.

Lymphatic drainage of the pericardium is Lymphatic drainage of the pericardium is mainly to the anterior mediastinal, mainly to the anterior mediastinal, tracheobronchial, lateropericardial, and tracheobronchial, lateropericardial, and posterior mediastinal lymph nodes and not posterior mediastinal lymph nodes and not into the hilar nodes. into the hilar nodes.

Does not show up on routine chest Does not show up on routine chest radiographs but can be seen only on chest radiographs but can be seen only on chest computed tomography or magnetic computed tomography or magnetic resonance imaging (MRI) studies. resonance imaging (MRI) studies.

Sir William Osler concluded that caseous Sir William Osler concluded that caseous mediastinal lymph nodes were the usual mediastinal lymph nodes were the usual focus of pericardial involvement.focus of pericardial involvement.11

Rooney Rooney et alet al found that 50% of patients found that 50% of patients with TPE who were necropsied had pleural with TPE who were necropsied had pleural effusion due to tuberculous pleuritis.effusion due to tuberculous pleuritis.2 2

1.Spodick DH. Arch Intern Med 1956;98:737–49

2. Rooney JJ. Ann Intern Med 1970;72:73–8

Some authors separate tuberculous Some authors separate tuberculous pericarditis into four stages: pericarditis into four stages:

The dry stage The dry stage The effusive stage The effusive stage The absorptive phase The absorptive phase The constrictive phase The constrictive phase

Ortbals DW. Arch Intern Med 1979 Feb;139(2):231-4

DiagnosisDiagnosis

Characteristics of the pericardial fluidCharacteristics of the pericardial fluid: : The effusion in tuberculous pericarditis is The effusion in tuberculous pericarditis is

straw-colored .straw-colored . It is uniformly an exudate. The protein It is uniformly an exudate. The protein

concentration is invariably above 3.0 g/dL, concentration is invariably above 3.0 g/dL, and is greater than 5.0 g/dL in 50 to 77%. and is greater than 5.0 g/dL in 50 to 77%.

LDH level is elevated in approximately LDH level is elevated in approximately 75%, commonly exceeding 500 IU/L. 75%, commonly exceeding 500 IU/L.

Glucose concentration is usually between 60 and 100 Glucose concentration is usually between 60 and 100 mg/dL. mg/dL.

pH is virtually always less than 7.40.pH is virtually always less than 7.40. The nucleated cell count is usually between 1000 and The nucleated cell count is usually between 1000 and

6000/mm3. It is lymphocyte-predominant in 60 to 90% of 6000/mm3. It is lymphocyte-predominant in 60 to 90% of cases. Lymphocytes predominate in subacute and cases. Lymphocytes predominate in subacute and chronic tuberculous effusions, while neutrophils chronic tuberculous effusions, while neutrophils predominate in acute effusions.predominate in acute effusions.

The fluid rarely contains more than 5% mesothelial cells. The fluid rarely contains more than 5% mesothelial cells. The presence of more than 10% eosinophils usually The presence of more than 10% eosinophils usually excludes the diagnosis of tuberculous pericarditisexcludes the diagnosis of tuberculous pericarditis

Only 40 to 60 % of patients with Only 40 to 60 % of patients with tuberculous pericarditis who undergo tuberculous pericarditis who undergo pericardiocentesis have acid fast bacilli pericardiocentesis have acid fast bacilli (which are virtually diagnostic) on smear. (which are virtually diagnostic) on smear.

Strang JI. Lancet 1988 Oct 1;2(8614):759-64 Fowler NO. Prog Cardiovasc Dis 1973;

16:323

Polymerase chain reaction (PCR)Polymerase chain reaction (PCR)PCR technology has been used for nucleic PCR technology has been used for nucleic acid amplification. Overall accuracy of acid amplification. Overall accuracy of PCR approached the results of PCR approached the results of conventional methods. The sensitivity for conventional methods. The sensitivity for pericardial fluid was poor and false pericardial fluid was poor and false positive results with PCR remain a positive results with PCR remain a concern.concern.

Sensitivity in pleural fluid is 42-81%.Sensitivity in pleural fluid is 42-81%.

Cegielskyi JP. J Clin Microbiol 1997;35:3254–7

Lee JH. Am J Med 2002;113:519–21

SerodiagnosisSerodiagnosisELISA: A sensitivity of 61% (at 96% ELISA: A sensitivity of 61% (at 96% specificity) was achieved. It is unlikely that specificity) was achieved. It is unlikely that this technology will be widely applied. this technology will be widely applied.

NG TT. Q J Med 1995;88:317–20

Adenosine deaminaseAdenosine deaminase Adenosine deaminase levels are believed to Adenosine deaminase levels are believed to reflect T-cell activity. The levels with TPE have reflect T-cell activity. The levels with TPE have varied from 10–303 U/l, and with a cut off level varied from 10–303 U/l, and with a cut off level of 30 U/l the sensitivity was 94% and specificity of 30 U/l the sensitivity was 94% and specificity 68% with a positive predictive accuracy of 80%.68% with a positive predictive accuracy of 80%. 1 1

High ADA levels that may occur in other High ADA levels that may occur in other conditions, like rheumatoid, empyema, conditions, like rheumatoid, empyema, mesothelioma, lung cancer, parapneumonic, and mesothelioma, lung cancer, parapneumonic, and hematologic malignancies.hematologic malignancies.

1. Burgess LJ. Chest 2002;122:900–5 2. Komsuogluo B. Eur Heart J 1995;16:1126–30

Interferon-gammaInterferon-gamma Median concentration in TPE Median concentration in TPE was >1000 pg/l and significantly higher was >1000 pg/l and significantly higher than malignancy or non-tuberculous than malignancy or non-tuberculous effusions (p<0.0005). A cut off value of effusions (p<0.0005). A cut off value of 200 pg/l for interferon-gamma resulted in a 200 pg/l for interferon-gamma resulted in a sensitivity and specificity of 100% for the sensitivity and specificity of 100% for the diagnosis of TPE. diagnosis of TPE.

Burgess LJ. Chest 2002;122:900–5

Histological evidenceHistological evidenceHistological evidence of a tuberculous Histological evidence of a tuberculous granuloma with the demonstration of acid fast granuloma with the demonstration of acid fast bacilli would be a definite diagnostic criterion. bacilli would be a definite diagnostic criterion.

The typical granuloma is however not always The typical granuloma is however not always found and the pericardial biopsy may show non-found and the pericardial biopsy may show non-specific findings even when specific findings even when M tuberculosisM tuberculosis is is found in the pericardial fluid. Strang found in the pericardial fluid. Strang et alet al reported 29% of non-specific findings on patients reported 29% of non-specific findings on patients whom whom M tuberculosisM tuberculosis was recovered from the was recovered from the pericardial fluid.pericardial fluid.

Strang JIG. Lancet 1988;ii:759–64.

Myocardium with epicardium and part of the pericardium. In the epi- and pericardium a granuloma is present (right half of image), with caseous necrosis, lymphocytes, and epitheloid cells. The myocardium (left quarter of image) is not involved in the inflammatory process.

Chest computed tomographyChest computed tomographyEnlarged mediastinal lymph nodes >10 Enlarged mediastinal lymph nodes >10 mm detected on chest computed mm detected on chest computed tomography have been reported recently tomography have been reported recently in virtually 100% of patients with TPE. in virtually 100% of patients with TPE. They were found in all 22 patients with They were found in all 22 patients with TPE and none of a control group with TPE and none of a control group with large viral/idiopathic or postoperative large viral/idiopathic or postoperative pericardial effusion. pericardial effusion.

Cherian G. Am J Med 2003;114:319–22

Features of Mediastinal Nodes in TPE:Features of Mediastinal Nodes in TPE:

Aortopulmonary, paratracheal, and carinal Aortopulmonary, paratracheal, and carinal nodes most often involved.nodes most often involved.Typically coalesced (matted) with hypodense Typically coalesced (matted) with hypodense center.center.Hilar nodes rare and inconspicuous.Hilar nodes rare and inconspicuous.Nodes seen only on chest computed Nodes seen only on chest computed tomography or MRI.tomography or MRI.Nodes disappear or regress on specific Nodes disappear or regress on specific treatment. treatment.

EchocardiographyEchocardiographyThe pericardial exudate is thick and The pericardial exudate is thick and fibrinous with a tendency to form fibrinous with a tendency to form adhesions and in some instances adhesions and in some instances constriction. On echocardiography there constriction. On echocardiography there are patchy deposits with "fibrinous" are patchy deposits with "fibrinous" strands criss crossing the pericardial strands criss crossing the pericardial space. space.

LIU PY. Am J Cardiol 2001;87:1133–5

Large pericardial effusion Large pericardial effusion and inversion of the right and inversion of the right atrium, caused by atrium, caused by elevated pericardial elevated pericardial pressure, in late diastole pressure, in late diastole and early systole. and early systole.

A parasternal short-axis A parasternal short-axis view shows that the right view shows that the right ventricular outflow tract is ventricular outflow tract is compressed in diastole compressed in diastole because of the elevated because of the elevated pericardial pressure. pericardial pressure.

Nardell E. N Engl J Med 2004; 351:1804-1805

Culture of mycobacterium tuberculosisCulture of mycobacterium tuberculosisRecovery from the pericardial fluid has Recovery from the pericardial fluid has varied from 30%–100%. Strang using varied from 30%–100%. Strang using special techniques was able to culture special techniques was able to culture M M tuberculosistuberculosis from all patients. The from all patients. The specimens were cultured in double specimens were cultured in double strength Kirchner culture medium after strength Kirchner culture medium after bedside inoculation and also conventional bedside inoculation and also conventional culture in Stonebrink medium. culture in Stonebrink medium.

Strang JIG. J Infect 1994;28:251–4.

Role of corticosteroidsRole of corticosteroids In active constrictive pericarditis, the addition of In active constrictive pericarditis, the addition of

corticosteroids to standard antituberculous corticosteroids to standard antituberculous chemotherapy reduced mortality and the need chemotherapy reduced mortality and the need for subsequent pericardiocentesis. for subsequent pericardiocentesis.

A similar effect is observed on pericarditis with A similar effect is observed on pericarditis with effusion, when coupled by initial pericardial effusion, when coupled by initial pericardial drainage.drainage.

Prednisone 60 mg/day for four weeks, 30 Prednisone 60 mg/day for four weeks, 30 mg/day for four weeks, 15 mg/day for two mg/day for four weeks, 15 mg/day for two weeks, then 5 mg/day for week eleven. weeks, then 5 mg/day for week eleven.

SUGGESTED APPROACHSUGGESTED APPROACH Ascertain if there is a prior history of tuberculosis, tuberculosis Ascertain if there is a prior history of tuberculosis, tuberculosis

exposure, of prior PPD skin test reactivity, or if the patient is exposure, of prior PPD skin test reactivity, or if the patient is immunocompromised. immunocompromised.

Perform an intermediate strength PPD skin test on all patients Perform an intermediate strength PPD skin test on all patients If the PPD skin test is positive or the patient is immunocompromised If the PPD skin test is positive or the patient is immunocompromised

and an alternate cause (eg, lupus, malignancy, trauma) is not and an alternate cause (eg, lupus, malignancy, trauma) is not present, empiric antituberculous and prednisone therapy can be present, empiric antituberculous and prednisone therapy can be initiated. initiated.

If, however, there is hemodynamic impairment, subxiphoid If, however, there is hemodynamic impairment, subxiphoid pericardial biopsy and sampling of pericardial fluid should be pericardial biopsy and sampling of pericardial fluid should be performed. performed.

If the biopsy shows granulomatous changes and/or AFB, smear of If the biopsy shows granulomatous changes and/or AFB, smear of the pericardial fluid is positive for AFB, or the probability of the pericardial fluid is positive for AFB, or the probability of tuberculosis is highly likely. tuberculosis is highly likely.

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