American Journal of Emergency Medicine 33 (2015) 1712.e1–1712.e2
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Cardiac tamponade caused by paradoxical immune reconstitution inflammatory syndrome☆,☆☆,★ Abstract Cardiac tamponade is a constellation of hemodynamic crises, usually characterized by an increase in pericardial pressure due to aberrant accumulation of various fluid components. Even with expeditious intervention, it will carry a high risk of in-hospital morbidity and mortality if the corresponding etiology is not recognized. Herein, we describe a 38-year-old woman with severe cardiac tamponade caused by paradoxical immune reconstitution inflammatory syndrome. Corticosteroid therapy combined with echo-guided subxiphoid percutaneous pericardiocentesis achieved a favorable outcome. This report profiles clinical features, therapeutic strategies, and pathogenetic bases and reinforces the need for physicians to maintain heightened vigilance of this distinct manifestation. In particular, the prevalence of highly active antiretroviral therapy paralleled by increased worldwide incidence of human immunodeficiency virus and tuberculosis coinfection warrants a timely approach to immune reconstitution inflammatory syndrome in general practice. A 36-year-old woman presented with severe respiratory distress. She had a 5-year history of silent human immunodeficiency virus (HIV)-1 infection. Three months previously, she received standard antituberculous quadruple-drug formulations for treating cervical tuberculosis lymphadenitis. No major adverse events occurred. After 6 weeks, she started highly active antiretroviral therapy because of oral candidiasis, intractable diarrhea, and weight loss with increased plasma virus load to 1 025 520 RNA copies/mL and a CD4 T-cell count of 40/mm 3. Two weeks before coming to the hospital, she had experienced progressive exercise intolerance and intermittent low-grade fever. Upon examination, she was tachypneic and had a jugular venous distention, muffled heart sounds, and a blood pressure of 90/60 with 25 mm Hg of pulsus paradoxus. Laboratory investigation was shown in the Table. Computed tomographic scan of the chest (Figure) along with echocardiographic features of right cavities diastolic collapse confirmed cardiac tamponade. Emergent echo-guided subxiphoid percutaneous pericardiocentesis allowed the aspiration of 1100 mL of a straw-colored fluid. Cultures from pericardial effusion samples grew Mycobacterium tuberculosis. A stepwise approach of hypercalcemia disclosed hypercalciuria (urine fractional excretion of calcium, 3.8%; urine calcium-creatinine ratio, 0.41 mg/mg), high serum calcitriol (1,25(OH)2D3 (188 pmol/L)), and suppressed intact parathyroid
☆ Funding: none. ☆☆ Potential conflicts of interest: none. ★ Patient consent: obtained.
0735-6757/© 2015 Elsevier Inc. All rights reserved.
hormone (3.0 ng/L), consistent with absorptive hypercalcemia. The newly developed pericardial effusion and hypercalcemia after starting highly active antiretroviral therapy (HAART) indicate that these clinical features were attributable to paradoxical immune reconstitution inflammatory syndrome (IRIS). The patient responded well to a shortterm course of oral prednisolone (1 mg/kg per day for 2 weeks), achieving rapid and complete resolution of pericardial effusion. She was discharged 4 weeks later and was normocalcemic at a 1-year follow-up. Immune reconstitution inflammatory syndrome is defined as a paradoxical worsening of preexisting or smoldering opportunistic infections in HIV-infected patients on HAART due to the recuperating of immune system. The temporal association between initiation of HAART and the development of an unusual manifestation often provides a strong evidence of IRIS. Immune reconstitution inflammatory syndrome can be classified into 2 forms, paradoxical or unmasking. Paradoxical IRIS is defined as the recurrent, new, or worsening symptoms of a treated opportunistic infection. In contrast, unmasking IRIS is a HAART-associated inflammatory manifestation of a subclinical infection with an accelerated presentation. The risk factors of paradoxical treatment reactions in IRIS include extrapulmonary and disseminated tuberculosis, a lower CD4 lymphocyte count and higher viral load before commencing HAART, and a greater reduction in viral load and greater expansion of CD4 T cell during HAART [1]. Tuberculosis is the most important HIV/ acquired immunodeficiency syndrome (AIDS)-related opportunistic disease globally and is the leading cause of HIV/AIDS-related mortality, accounting for an estimated 25% of such deaths [2]. Paradoxical reactions in tuberculosis-associated IRIS are constitutionally pertaining to intensification of cell-mediated immunity and may be associated with conversion of pre-HAART immune anergy to a positive response after antituberculosis treatment. Human immunodeficiency virus and mycobacteria co-infection disrupt cell-mediated immune responses by impairing both the recruitment and function of the effective macrophages and CD4 T lymphocytes [3]. Interleukin 2– mediated CD4 lymphocyte activation and proliferation are inhibited along with the unregulated imbalance of type 1 and type 2 cytokine secretions. These changes drive the humoral arm of the immune system and dampened cell-mediated immunity. Through these defects, progressive HIV-associated immunodeficiency results in abrogation of granuloma formation and unbridled mycobacteria in infected tissues. Subsequently, patients with AIDS may develop active infection with very high mycobacteria burden but only have few clinical symptoms [4]. The restoration of the granulomatous host response toward M tuberculosis infection is a delayed-type hypersensitivity mediated by T helper type 1 cell cytokines. Highly dynamic antigen-specific CD4 T-cell interferon gamma responses can occur in the first weeks after HAART initiation in both tuberculosis-associated immune reconstitution inflammatory
1712.e2
Y.-T. Tsao et al. / American Journal of Emergency Medicine 33 (2015) 1712.e1–1712.e2
Table Laboratory investigation on admission Tests
Results
Reference
Hemoglobin level Leukocyte Platelet Blood urea nitrogen Creatinine Sodium Potassium Calcium, ionized Phosphate Uric acid CRP ALT AST Creatine kinase MB fraction Troponin I D-dimers
14.7 g/dL 10.4 × 109/L 523 × 109/L 32 mg/dL 0.8 mg/dL 136 mmol/L 4.1 mmol/L 6.2 mg/dL 6.7 mg/dL 7.5 mg/dL 1.02 mg/dL 31 U/L 36 U/L 49 U/L 6 U/L 0.02 ng/mL 17
12.2-14.7 g/dL 4.5-11.0 × 109/L 189-287 × 109/L 8-25 mg/dL 0.7-1.5 mg/dL 135-145 mmol/L 3.3-4.9 mmol/L 4.5-5.1 mg/dL 2.5-4.5 mg/dL 3-8 mg/dL 0-0.9 mg/dL 7-53 U/L 11-47 U/L 30-200 U/L 0-7 U/L b0.05 ng/mL 0-200 μg/L
Arterial blood gas (room air) pH PO2 PCO2 HCO3−
7.46 77.2 mm Hg 29.8 mm Hg 28.3 mmol/L
7.35-7.45 80-105 mm Hg 35-45 mm Hg 22-32 mmol/L
Abbreviations: CRP, C-reactive protein; ALT, alanine aminotransferases; AST, aspartate aminotransferases; HCO3−, sodium bicarbonate.
calcium metabolism. However, if unregulated production of excessive 1,25(OH)2D3 supervenes through a time course–dependent manner, absorptive hypercalcemia will occur [7]. Of interest, abnormal calcium metabolism against mycobacterial granuloma does not always correlate with the serum level of 1,25(OH)2D3, the type of infection, the extent of granulomatous destruction, or the duration of chemotherapeutic treatment. Differences in circulating vitamin D levels, intakes of calcium, and the amount of sun exposure had been postulated to explain the regional variations in the prevalence of hypercalcemia observed in mycobacterial infection. The critical role of 1,25(OH)2D3 manifesting a local positive feedback defense mechanism from restored granulomatous response in IRIS and a systemic negative feedback immune inhibition in the presence of chronic HIV infection should require in-depth investigations. The current paradigm in the management of IRIS is aimed at obviating inappropriate control of opportunistic or masked pathogens during HAART. Corticosteroids are the mainstay of treatment for disordered calcium homeostasis in tuberculosis-associated IRIS. Nevertheless, in the era of HAART paralleled by increased worldwide incidence and prevalence of HIV infection, the management of IRIS can be quite challenging because of its protean manifestations. It should be addressed that maintaining a heightened awareness of this presentation is indispensible and invaluable in emergency practice. Yu-Tzu Tsao, MD Department of Critical Care Medicine, Taoyuan General Hospital Ministry of Health and Welfare, Taoyuan, Taiwan Division of Nephrology, Department of Medicine Taoyuan General Hospital, Ministry of Health and Welfare Taoyuan, Taiwan Jui-Chang Chen, MD Department of Critical Care Medicine, Taoyuan General Hospital Ministry of Health and Welfare, Taoyuan, Taiwan Wei-Chi Tsai, MD Department of Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan Corresponding author at: Department of Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, No. 553, Junxiao Rd Zuoying Dist, Kaohsiung City 813, Taiwan. Tel.: +886 2 87927213 fax: +886 2 87927134 E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2015.03.015 References
Figure. Computed tomography scan of the chest showing massive pericardial effusion with compression of the cardiac chambers, angulation of the interventricular septum, and distention of the superior vena cava, consistent with cardiac tamponade.
syndrome and control patients in response to early secretory mycobacterial antigens [5]. Recuperation from immunosuppression through HAART has the potential to cause a rebound in interferon gamma, which promotes granuloma formation and facilitates the eradication of infection. In particular, overproduction of active 1,25(OH)2D3 caused by increased macrophagic 1α-hydroxylase activity in granulomatous lesions can cause a disruption of mineral homeostasis [6]. It is believed that 1,25(OH)2D3 produced by macrophages probably has only a local effect in enhancing cell-mediated immunity and should not normally affect
[1] Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008;22:601–10. [2] Lawn SD, Churchyard G. Epidemiology of HIV-associated tuberculosis. Curr Opin HIV AIDS 2009;4:325–33. [3] Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002;4:635–46. [4] Leone S, Nicastri E, Giglio S, Narciso P, Ippolito G, Acone N. Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review. Int J Infect Dis 2010;14:e283–91. [5] Meintjes G, Wilkinson KA, Rangaka MX, Skolimowska K, van Veen K, Abrahams M, et al. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med 2008; 178:1083–9. [6] Monkawa T, Yoshida T, Hayashi M, Saruta T. Identification of 25-hydroxyvitamin D3 1α-hydroxylase gene expression in macrophages. Kidney Int 2000;58:559–68. [7] Messa P, Alfieri C, Rastaldi MP. Recent insights into vitamin D and its receptor. J Nephrol 2011;24:S30–7.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Case Report
Cardiac tamponade caused by paradoxical immune reconstitution inflammatory syndrome☆,☆☆,★ Abstract Cardiac tamponade is a constellation of hemodynamic crises, usually characterized by an increase in pericardial pressure due to aberrant accumulation of various fluid components. Even with expeditious intervention, it will carry a high risk of in-hospital morbidity and mortality if the corresponding etiology is not recognized. Herein, we describe a 38-year-old woman with severe cardiac tamponade caused by paradoxical immune reconstitution inflammatory syndrome. Corticosteroid therapy combined with echo-guided subxiphoid percutaneous pericardiocentesis achieved a favorable outcome. This report profiles clinical features, therapeutic strategies, and pathogenetic bases and reinforces the need for physicians to maintain heightened vigilance of this distinct manifestation. In particular, the prevalence of highly active antiretroviral therapy paralleled by increased worldwide incidence of human immunodeficiency virus and tuberculosis coinfection warrants a timely approach to immune reconstitution inflammatory syndrome in general practice. A 36-year-old woman presented with severe respiratory distress. She had a 5-year history of silent human immunodeficiency virus (HIV)-1 infection. Three months previously, she received standard antituberculous quadruple-drug formulations for treating cervical tuberculosis lymphadenitis. No major adverse events occurred. After 6 weeks, she started highly active antiretroviral therapy because of oral candidiasis, intractable diarrhea, and weight loss with increased plasma virus load to 1 025 520 RNA copies/mL and a CD4 T-cell count of 40/mm 3. Two weeks before coming to the hospital, she had experienced progressive exercise intolerance and intermittent low-grade fever. Upon examination, she was tachypneic and had a jugular venous distention, muffled heart sounds, and a blood pressure of 90/60 with 25 mm Hg of pulsus paradoxus. Laboratory investigation was shown in the Table. Computed tomographic scan of the chest (Figure) along with echocardiographic features of right cavities diastolic collapse confirmed cardiac tamponade. Emergent echo-guided subxiphoid percutaneous pericardiocentesis allowed the aspiration of 1100 mL of a straw-colored fluid. Cultures from pericardial effusion samples grew Mycobacterium tuberculosis. A stepwise approach of hypercalcemia disclosed hypercalciuria (urine fractional excretion of calcium, 3.8%; urine calcium-creatinine ratio, 0.41 mg/mg), high serum calcitriol (1,25(OH)2D3 (188 pmol/L)), and suppressed intact parathyroid
☆ Funding: none. ☆☆ Potential conflicts of interest: none. ★ Patient consent: obtained.
0735-6757/© 2015 Elsevier Inc. All rights reserved.
hormone (3.0 ng/L), consistent with absorptive hypercalcemia. The newly developed pericardial effusion and hypercalcemia after starting highly active antiretroviral therapy (HAART) indicate that these clinical features were attributable to paradoxical immune reconstitution inflammatory syndrome (IRIS). The patient responded well to a shortterm course of oral prednisolone (1 mg/kg per day for 2 weeks), achieving rapid and complete resolution of pericardial effusion. She was discharged 4 weeks later and was normocalcemic at a 1-year follow-up. Immune reconstitution inflammatory syndrome is defined as a paradoxical worsening of preexisting or smoldering opportunistic infections in HIV-infected patients on HAART due to the recuperating of immune system. The temporal association between initiation of HAART and the development of an unusual manifestation often provides a strong evidence of IRIS. Immune reconstitution inflammatory syndrome can be classified into 2 forms, paradoxical or unmasking. Paradoxical IRIS is defined as the recurrent, new, or worsening symptoms of a treated opportunistic infection. In contrast, unmasking IRIS is a HAART-associated inflammatory manifestation of a subclinical infection with an accelerated presentation. The risk factors of paradoxical treatment reactions in IRIS include extrapulmonary and disseminated tuberculosis, a lower CD4 lymphocyte count and higher viral load before commencing HAART, and a greater reduction in viral load and greater expansion of CD4 T cell during HAART [1]. Tuberculosis is the most important HIV/ acquired immunodeficiency syndrome (AIDS)-related opportunistic disease globally and is the leading cause of HIV/AIDS-related mortality, accounting for an estimated 25% of such deaths [2]. Paradoxical reactions in tuberculosis-associated IRIS are constitutionally pertaining to intensification of cell-mediated immunity and may be associated with conversion of pre-HAART immune anergy to a positive response after antituberculosis treatment. Human immunodeficiency virus and mycobacteria co-infection disrupt cell-mediated immune responses by impairing both the recruitment and function of the effective macrophages and CD4 T lymphocytes [3]. Interleukin 2– mediated CD4 lymphocyte activation and proliferation are inhibited along with the unregulated imbalance of type 1 and type 2 cytokine secretions. These changes drive the humoral arm of the immune system and dampened cell-mediated immunity. Through these defects, progressive HIV-associated immunodeficiency results in abrogation of granuloma formation and unbridled mycobacteria in infected tissues. Subsequently, patients with AIDS may develop active infection with very high mycobacteria burden but only have few clinical symptoms [4]. The restoration of the granulomatous host response toward M tuberculosis infection is a delayed-type hypersensitivity mediated by T helper type 1 cell cytokines. Highly dynamic antigen-specific CD4 T-cell interferon gamma responses can occur in the first weeks after HAART initiation in both tuberculosis-associated immune reconstitution inflammatory
1712.e2
Y.-T. Tsao et al. / American Journal of Emergency Medicine 33 (2015) 1712.e1–1712.e2
Table Laboratory investigation on admission Tests
Results
Reference
Hemoglobin level Leukocyte Platelet Blood urea nitrogen Creatinine Sodium Potassium Calcium, ionized Phosphate Uric acid CRP ALT AST Creatine kinase MB fraction Troponin I D-dimers
14.7 g/dL 10.4 × 109/L 523 × 109/L 32 mg/dL 0.8 mg/dL 136 mmol/L 4.1 mmol/L 6.2 mg/dL 6.7 mg/dL 7.5 mg/dL 1.02 mg/dL 31 U/L 36 U/L 49 U/L 6 U/L 0.02 ng/mL 17
12.2-14.7 g/dL 4.5-11.0 × 109/L 189-287 × 109/L 8-25 mg/dL 0.7-1.5 mg/dL 135-145 mmol/L 3.3-4.9 mmol/L 4.5-5.1 mg/dL 2.5-4.5 mg/dL 3-8 mg/dL 0-0.9 mg/dL 7-53 U/L 11-47 U/L 30-200 U/L 0-7 U/L b0.05 ng/mL 0-200 μg/L
Arterial blood gas (room air) pH PO2 PCO2 HCO3−
7.46 77.2 mm Hg 29.8 mm Hg 28.3 mmol/L
7.35-7.45 80-105 mm Hg 35-45 mm Hg 22-32 mmol/L
Abbreviations: CRP, C-reactive protein; ALT, alanine aminotransferases; AST, aspartate aminotransferases; HCO3−, sodium bicarbonate.
calcium metabolism. However, if unregulated production of excessive 1,25(OH)2D3 supervenes through a time course–dependent manner, absorptive hypercalcemia will occur [7]. Of interest, abnormal calcium metabolism against mycobacterial granuloma does not always correlate with the serum level of 1,25(OH)2D3, the type of infection, the extent of granulomatous destruction, or the duration of chemotherapeutic treatment. Differences in circulating vitamin D levels, intakes of calcium, and the amount of sun exposure had been postulated to explain the regional variations in the prevalence of hypercalcemia observed in mycobacterial infection. The critical role of 1,25(OH)2D3 manifesting a local positive feedback defense mechanism from restored granulomatous response in IRIS and a systemic negative feedback immune inhibition in the presence of chronic HIV infection should require in-depth investigations. The current paradigm in the management of IRIS is aimed at obviating inappropriate control of opportunistic or masked pathogens during HAART. Corticosteroids are the mainstay of treatment for disordered calcium homeostasis in tuberculosis-associated IRIS. Nevertheless, in the era of HAART paralleled by increased worldwide incidence and prevalence of HIV infection, the management of IRIS can be quite challenging because of its protean manifestations. It should be addressed that maintaining a heightened awareness of this presentation is indispensible and invaluable in emergency practice. Yu-Tzu Tsao, MD Department of Critical Care Medicine, Taoyuan General Hospital Ministry of Health and Welfare, Taoyuan, Taiwan Division of Nephrology, Department of Medicine Taoyuan General Hospital, Ministry of Health and Welfare Taoyuan, Taiwan Jui-Chang Chen, MD Department of Critical Care Medicine, Taoyuan General Hospital Ministry of Health and Welfare, Taoyuan, Taiwan Wei-Chi Tsai, MD Department of Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan Corresponding author at: Department of Medicine, Zuoying Branch of Kaohsiung Armed Forces General Hospital, No. 553, Junxiao Rd Zuoying Dist, Kaohsiung City 813, Taiwan. Tel.: +886 2 87927213 fax: +886 2 87927134 E-mail address: [email protected] http://dx.doi.org/10.1016/j.ajem.2015.03.015 References
Figure. Computed tomography scan of the chest showing massive pericardial effusion with compression of the cardiac chambers, angulation of the interventricular septum, and distention of the superior vena cava, consistent with cardiac tamponade.
syndrome and control patients in response to early secretory mycobacterial antigens [5]. Recuperation from immunosuppression through HAART has the potential to cause a rebound in interferon gamma, which promotes granuloma formation and facilitates the eradication of infection. In particular, overproduction of active 1,25(OH)2D3 caused by increased macrophagic 1α-hydroxylase activity in granulomatous lesions can cause a disruption of mineral homeostasis [6]. It is believed that 1,25(OH)2D3 produced by macrophages probably has only a local effect in enhancing cell-mediated immunity and should not normally affect
[1] Murdoch DM, Venter WD, Feldman C, Van Rie A. Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study. AIDS 2008;22:601–10. [2] Lawn SD, Churchyard G. Epidemiology of HIV-associated tuberculosis. Curr Opin HIV AIDS 2009;4:325–33. [3] Lawn SD, Butera ST, Shinnick TM. Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 2002;4:635–46. [4] Leone S, Nicastri E, Giglio S, Narciso P, Ippolito G, Acone N. Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review. Int J Infect Dis 2010;14:e283–91. [5] Meintjes G, Wilkinson KA, Rangaka MX, Skolimowska K, van Veen K, Abrahams M, et al. Type 1 helper T cells and FoxP3-positive T cells in HIV-tuberculosis-associated immune reconstitution inflammatory syndrome. Am J Respir Crit Care Med 2008; 178:1083–9. [6] Monkawa T, Yoshida T, Hayashi M, Saruta T. Identification of 25-hydroxyvitamin D3 1α-hydroxylase gene expression in macrophages. Kidney Int 2000;58:559–68. [7] Messa P, Alfieri C, Rastaldi MP. Recent insights into vitamin D and its receptor. J Nephrol 2011;24:S30–7.
