- Email: [email protected]
Methotrexate in acute persistent humoral rejection: an option for graft rescue
Ann Thorac Surg 2003;76:607–10
1. Blood donors in communities with active WNV transmission should be encouraged to report flulike illnesses associated with fever (⬎ 38.3°C) during the 2 weeks after blood donations. 2. On receipt of postdonation information of a suspected WNV infection (flu-like symptoms and fever ⬎ 38.3°C), retrieval and quarantine should be made of the extant products collected from 14 days before and 28 days after the onset of illness. 3. A donor with a diagnosis of WNV infection should be deferred for 14 days after they have recovered or 28 days from the onset of illness (whichever time period is longer). 4. In order to have a blood sample for investigations of suspected WNV transmission by blood products, the blood centers should maintain all retention samples for 90 days or more after the donation date. Clinicians should remain vigilant for the possibility of patients who have WNV infection develop after receiving blood transfusions within the month preceding illness onset in communities where the WNV infection is active.
References 1. Petersen LR, Roehig JT, Hughes JM. West Nile virus encephalitis. N Engl J Med 2002;347:1225–6. 2. Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. The West Nile virus outbreak of 1999 in New York: The Flushing Hospital experience. Clin Inf Dis 2000;30:413–8. 3. CDC. West Nile virus activity—United States. MMWR 2002; 51:999 –1000. 4. Southam CM, Moore AE. Induced virus infections in man by the Egypt isolates of West Nile virus. Am J Trop Med Hyg 1954;3:19 –50. 5. Biggerstaff BJ, Petersen LR. Estimated risk of West Nile virus © 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
607
transmission through blood transfusion during an epidemic in Queens, New York City. Transfusion 2002;42:1019 –26. 6. CDC. Update investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion. MMWR 2002;51:833–6. 7. CDC. Public Health Dispatch. Investigations of West Nile virus infections in recipients of blood transfusions. MMWR 2002;51:973–4. 8. Information regarding West Nile virus (www.cdc.gov/od/oc/ media/wncount.htm [accessed 11/14/02]).
Methotrexate in Acute Persistent Humoral Rejection: An Option for Graft Rescue Fernando Bacal, MD, Gustavo L. Sodre´ , MD, Daniela A. Fernandes, MD, Vera D. Aiello, MD, Noedir Stolf, MD, Edimar Bocchi, MD, and Giovanni Bellotti, MD Heart Failure Department, Heart Institute, University of Sa˜ o Paulo Medical School, Sa˜ o Paulo, Brazil
Humoral response emerges as an important component in acute graft rejection and a new challenge to clinicians in posttransplant care. Management of recurrent episodes and persistent activation of the humoral component of the immune system, despite the usual therapeutic approach to rejection, remains unknown. This article describes the successful use of methotrexate as an option for rescuing a graft in this worrisome situation. (Ann Thorac Surg 2003;76:607–10) © 2003 by The Society of Thoracic Surgeons
S
ince the advent of heart transplantation, it has been recognized that acute rejection is a cell-mediated phenomenon. However, studies [1] have suggested a role for humoral mechanisms in acute allograft rejection, and its frequency is greater than predicted in initial descriptions. A relationship has previously been shown between the consequences of episodes of humoral rejection on the durability of grafts and the development of coronary artery disease in transplanted organs. It has been shown that they were more aggressive and precocious than those mediated through T-lymphocytes, which significantly changed a patient’s prognosis [1]. New approaches, such as plasmapheresis, or cyclophosphamide therapy [2], and the use of high doses of human intravenous immunoglobulin (Ig) have been proposed to treat patients with humoral graft rejection in association, or not, with cellular rejection. However, some patients have persistent graft rejection or recurrent episodes with a humoral component of the immune
Accepted for publication Jan 19, 2003. Address reprint requests to Dr Bacal, Rua Joa˜ o Castaldi, 217 Apto 42, Moema, Sa˜ o Paulo–SP 04517-050, Brazil; e-mail: [email protected].
0003-4975/03/$30.00 PII S0003-4975(03)00143-7
CASE REPORTS
with donations that tested positive by polymerase chain reaction or donors that seroconverted after donation. All recipients received components from multiple donors (mean, 42 donors) and 42% (14 cases) underwent surgical procedures of which 50% were coronary artery bypass surgeries. Reducing the risk of WNV infection from blood transfusions when there is active WNV transmission in the community is an important public health issue. Although prior estimates of the risk are viewed as small (perhaps 1:10,000), subsequent infections may be fatal. In addition, patients undergoing procedures (such as open heart surgery) in which multiple blood product transfusions may be necessary are at higher risk. Screening donor blood for WNV serology would not be an effective strategy, as the period of viremia may antedate appearance of antibodies and immunoglobulin M antibodies against WNV may persist for more than 500 days. Nucleic amplification testing, which is currently used to screen blood for human immunodeficiency virus and hepatitis C virus, is not available and is not recommended for WNV yet. In lieu of additional information from ongoing studies of WNV transmission by blood products, the American Association of Blood Banks recommends the following [8]:
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
608
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
Ann Thorac Surg 2003;76:607–10
CASE REPORTS
response (findings which are probably related to a shorter surveillance of the transplanted organ, high mortality, cost of treatment, and development of graft coronary artery disease), reflecting a poor prognosis. Antimetabolite effects of methotrexate, through its potent inhibition of dihydrofolate reductase and interruption in purine synthesis, promote a breakdown in replication and function of T lymphocytes, and possibly B cells, because of relatively selective action on DNA replication [3–5]. The latter should be the principal component in modulation of humoral response. In a previous article [6], our group reported on 6 patients with persistent acute cellular rejection treated with methotrexate who experienced an important reduction in episodes of graft rejection. Therefore, a reduction in the number of recurrences of humoral-mediated immune response against a transplanted heart must be expected. The aim of this report is to show the first use of methotrexate, as a rescue treatment, in recurrent humoral rejection of a patient undergoing standard treatment. The transplant recipient is a white man, 33 years old, who had idiopathic dilated cardiomyopathy. His blood type is AB negative. He never received blood transfusions, and serologies for cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and 2 were negative. Panel reaction was 0%. The donor, a black woman, age 46, blood type B, died as consequence of stroke. She was hypertensive; other comorbidities and her obstetric history were not described. She had never received blood components. Serologies for Chagas disease, cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and -2 were negative. A crossmatch was performed and all studies were negative An orthotopic heart transplant was performed on December 26, 2000, without sequelae. The patient received standard treatment with corticosteroids, cyclosporine (4 mg/kg/d), and azathioprine (2.5 mg/kg/d) to prevent rejection. His serum level of cyclosporine was 549 ng/mL on the seventh day after transplantation. On postoperative day 9, the echocardiogram showed mild left ventricular hypertrophy with normal function, mild global dysfunction of the right ventricle, and mild tricuspid and mitral insufficiency. An endomyocardial biopsy was performed on the same day, and the sample showed acute cellular rejection grade IIIB (ISHLT [International Society of Heart–Lung Transplantation]) with an associated humoral immunity component: IgG negative, IgM⫹⫹, C3⫹⫹⫹ and fibrinogen ⫹⫹⫹ (Fig 1). Treatment for acute rejection was initiated with methylprednisolone intravenously at a dose of 1 g for 3 days, and horse antithymocyte globulin was used (dosage, 10 mg/kg/min for 10 days) (Fig 2). The patient was hemodynamically and clinically stable. A new endomyocardial biopsy was performed on postoperative day 17 after transplantation, with an identical grade of cellular and humoral immune response. No
Fig 1. Immunofluorescence of myocardial tissue: (A) Focal positivity for immunoglobulin G in a small vessel (white arrow) (original magnification, ⫻400.) (B) Granular pattern of positivity for C3 in the interstitium (original magnification, ⫻400.) (C) Diffuse positivity for fibrinogen in the interstitium (original magnification, ⫻200).
changes occurred in the echocardiographic findings of the first examination. The patient was removed to the intensive care unit and
Ann Thorac Surg 2003;76:607–10
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
609
CASE REPORTS
Fig 2. Immunosuppression therapy used to treat the rejection in a patient with persistent cellular and humoral components. (ATGAM ⫽ polyclonal antibodies; FK506 ⫽tacrolimus; MMF ⫽mycophenolate mofetil; OKT3 ⫽ monoclonal antibodies; Rej ⫽ rejection.)
underwent four sessions of plasmapheresis, methylprednisolone pulse therapy (1 g/d); immunosuppressive drugs had been changed to cyclophosphamide (200 mg/ d), tacrolimus (0.16 mg/kg/d), and OKT3 (Orthoclone, Janssen-Cilag, Brazil) (monoclonal antibodies, 5 mg/d). The patient had febrile episodes occur, but without evidence of infectious illness. No changes occurred in the patient’s clinical state or in the hemodynamic findings. On postoperative day 29, a new biopsy showed improvement in histologic findings, with grade IA (ISLHT) cellular rejection, and a mild humoral response on immunofluorescence. The serum level of FK506 (Prograf, Janssen-Cilag, Brazil) (tacrolimus) was 9.4 ng per mL. On postoperative day 30, cyclophosphamide was replaced by mycophenolate mofetil (CellCept, Roche, Brazil) (1 g/d). The patient remained asymptomatic. Another biopsy was performed on postoperative day 40 after the transplantation showed a mild progression in the cellular grade of rejection grade IB (ISLHT), and recurrent humoral findings were graded as IgG negative on immunofluorescence, IgM⫹/III, C3⫹/III, and fibrinogen ⫹⫹⫹. On postoperative day 49, another endomyocardial biopsy showed acute cellular rejection grade IIIA (ISHLT); humoral rejection was graded as IgG negative, IgM⫹/IV, C3⫹⫹/IV, and fibrinogen ⫹⫹/IV. Methylprednisolone pulse therapy was tried again, and antimetabolite methotrexate was included in the therapeutic regimen. A dosage of 15 mg per week was used the first week, then 10 mg per week thereafter. The patient remained asymptomatic without changes in echocardiographic findings. A biopsy was performed on postoperative day 55, which showed a cellular rejection grade A (ISLHT), and immunofluorescence of IgG⫹/IV, IgM⫹/IV, C3⫹/IV, and fibrinogen ⫹/IV. A week later, an endomyocardial biopsy showed no evidence of rejection (humoral or cellular), and the echocardiography study was normal. Histologic findings remained without alterations, and the patient was stable and asymptomatic in ambulatory care at 24 months of follow-up.
Comment The role of humoral immunity in acute cardiac allograft rejection is an area of recent interest, thus predisposing factors and prognosis for this kind of rejection remains largely unknown [1]. The treatment performed was validated by literature data. Prophylaxy was used in the postoperative period, with a triple-drug immunosuppressive regimen added of corticosteroids, azathioprine, and cyclosporine. Standard treatment was maintained during the first episode of acute rejection, when methylprednisolone pulse therapy and monoclonal antibodies were prescribed; however, biopsies were still showing acute rejection patterns. Based on the patient’s response, we decided to gear the therapeutic goal to the humoral branch of immune response. Cyclophosphamide and plasmapheresis were then tried, as other authors had previously advocated [2]. The lack of efficacy for a standard treatment and the persistence of humoral and cellular response led us to initiate a new immunosuppressive regimen. Despite no reports in the literature pertaining to the use of methotrexate in humoral rejection treatment, we aimed at a new approach that allowed prolongation of xenograft survival to guarantee the patient’s well being. We took into account previous reports about the association of methotrexate as an adjuvant therapy in persistent acute cellular rejection. Therefore, we initiated a folic acid analogue that would play an important role by inhibiting T lymphocytes through interruption of purine synthesis, reducing cellular response [3, 4], as well as B cells, inhibiting humoral factors [4]. Results of the present case have reflected our expectations; reverse of rejection and maintenance of this pattern thus far (24 months after institution of this new therapy). It is clear that the case reported in this article cannot lead us to hasty conclusions. Further studies are needed to determine the real effectiveness and reliability of the proposed regimen. However, this report may have im-
610
CASE REPORT POLITO ET AL EMPYEMA IN A PATIENT WITH A TOTAL ARTIFICIAL HEART
portant implications involving a novel therapeutic treatment.
References
CASE REPORTS
1. Costanzo-Nordin MR, Heroux AL, Radvany R, et al. Role of humoral immunity in acute cardiac allograft dysfunction. J Heart Lung Transplant 1993;12:S143–6. 2. Grauhan O, Mu¨ ller J, v Baeyer H, et al. Treatment of humoral rejection after heart transplantation. J Heart Lung Transplant 1998;17:1184 –94. 3. Hosenpud JD, Hershberger RA, Ratkovec RR, et al. Methotrexate for the treatment of patients with multiple episodes of acute cardiac allograft rejection. J Heart Lung Transplant 1992;11:739 –45. 4. Costanzo-Nordin MR, Grusk BB, Silver MA, et al. Reversal of recalcitrant cardiac allograft rejection with methotrexate. Circulation 1998;78(Suppl III):III-47–57. 5. Rosenthal GJ, Weigand GW, Germolec DR. Suppression of B cell function by methotrexate and trimetrexate: evidence of inhibition of purine biosynthesis as a major mechanism of action. J Immunol 1988;141:410 –6. 6. Bacal F, Veiga VC, Fiorelli AE, et al. Treatment of persistent rejection with methotrexate in stable patients undergoing heart transplantation. Arq Bras Cardiol 2000;74:141–4.
Successful Management of Empyema in a Patient With a Total Artificial Heart William F. Polito, MD, Francisco A. Arabia, MD, Pei H. Tsau, MD, Venki Paramesh, MD, Daniel S. Woolley, MD, Raj K. Bose, MD, Gulshan K. Sethi, MD, and Jack G. Copeland, MD University of Arizona Sarver Heart Center, Tucson, Arizona, and Gunderson Lutheran Hospital, LaCross, Wisconsin
A description of successful management of a patient who developed an empyema as a postoperative complication following the insertion of a CardioWest total artificial heart (TAH) as a bridge to cardiac transplantation is presented. By using traditional methods of management, the patient recovered and went on to transplant. (Ann Thorac Surg 2003;76:610 –1) © 2003 by The Society of Thoracic Surgeons
W
ith the increasing number of patients needing cardiac transplantation for end-stage heart disease, and the number of donors remaining constant, the use of mechanical circulatory support has evolved as a new standard for bridge to transplant (BTT). The main complications of these devices include infection and thromboembolic events. We report a case of a patient who was treated for empyema while on the total artificial Accepted for publication Jan 8, 2003. Address reprint requests to Dr Arabia, University of Arizona Sarver Heart Center, PO Box 245071, Tucson, AZ 85724-5071; e-mail: [email protected].
© 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
Ann Thorac Surg 2003;76:610 –1
heart (TAH). He recovered, received an orthotopic heart transplant, and was discharged home without significant sequelae. A 52 year-old male admitted with congestive heart failure (CHF) secondary to ischemic cardiomyopathy was referred for transplantation after failing medical management. He required the placement of an automatic implantable cardioverter device for malignant ventricular arrhythmias. An echo revealed a left ventricular ejection fraction (LVEF) 10% to 20%. He was stabilized, evaluated, and accepted for heart transplantation. During the next few months he had multiple admissions for CHF. Right heart catheterization revealed: CVP (central venous pressure) ⫽ 18 mm Hg; PCW (pulmonary capillary wedge pressure) ⫽ 29 mm Hg; CI ⫽ 1.9 L/min per m2; and systemic blood pressure ⫽ 82/52 (mean ⫽ 65 mm Hg), while on dopamine at 2.5 mcg/kg per min, dobutamine at 10 mcg/kg per min, and milrinone at 0.6 mcg/kg per min. Despite this aggressive support the patient continued to deteriorate and CardioWest TAH (CardioWest Technologies, Tucson, AZ) was implanted as BTT. The operation was performed via a median sternotomy utilizing cardiopulmonary bypass. The pleural spaces were not entered during the implantation, and the device was protected with fashioned PTFE (polytetrafluoroethylene) membranes. Mechanical ventilation was discontinued on postoperative day 1 (POD 1). He was reintubated 2 days later for respiratory failure as a result of right lower lobe pneumonia. Initial sputum cultures identified the organism Klebsiella pneumoniae. Antibiotics were continued according to susceptibilities. Anticoagulation consisting of heparin initially then followed by warfarin, persantine, and aspirin was initiated. He was extubated 2 weeks following surgery, and was recovering slowly. Over the next 2 weeks he developed a right pleural effusion. A computed tomographic (CT) guided 12-French pigtail catheter was placed on POD 34 with evacuation of 1200 cc of serous fluid that revealed 2⫹ PMNs but no organisms. Pleural fluid recultured 5-days later revealed mixed anaerobic flora. Chest CT scan demonstrated a thickened fluid collection with a rind consistent with empyema (Fig 1). On POD 43 he underwent a right thoracotomy with decortication; INR at this time was 2.4, with a bleeding time of 19.5 minutes. He developed a right hemothorax 4-days later requiring a second exploration and evacuation of the hemothorax. He recovered and was relisted as UNOS (United Network for Organ Sharing) status 1A for heart transplantation on POD 75. He underwent orthotopic heart transplantation on POD 159. He recovered without complications and was discharged home after 11 days. The CardioWest TAH is currently used as a BTT and is under an investigation device exemption from the Food and Drug Administration. It is a pneumatically driven device consisting of two polyurethane prosthetic ventricles that are placed in an orthotopic position via a median sternotomy. Blood and air are separated by a four-layer diaphragm that retracts 0003-4975/03/$30.00 PII S0003-4975(03)00157-7
1. Blood donors in communities with active WNV transmission should be encouraged to report flulike illnesses associated with fever (⬎ 38.3°C) during the 2 weeks after blood donations. 2. On receipt of postdonation information of a suspected WNV infection (flu-like symptoms and fever ⬎ 38.3°C), retrieval and quarantine should be made of the extant products collected from 14 days before and 28 days after the onset of illness. 3. A donor with a diagnosis of WNV infection should be deferred for 14 days after they have recovered or 28 days from the onset of illness (whichever time period is longer). 4. In order to have a blood sample for investigations of suspected WNV transmission by blood products, the blood centers should maintain all retention samples for 90 days or more after the donation date. Clinicians should remain vigilant for the possibility of patients who have WNV infection develop after receiving blood transfusions within the month preceding illness onset in communities where the WNV infection is active.
References 1. Petersen LR, Roehig JT, Hughes JM. West Nile virus encephalitis. N Engl J Med 2002;347:1225–6. 2. Asnis DS, Conetta R, Teixeira AA, Waldman G, Sampson BA. The West Nile virus outbreak of 1999 in New York: The Flushing Hospital experience. Clin Inf Dis 2000;30:413–8. 3. CDC. West Nile virus activity—United States. MMWR 2002; 51:999 –1000. 4. Southam CM, Moore AE. Induced virus infections in man by the Egypt isolates of West Nile virus. Am J Trop Med Hyg 1954;3:19 –50. 5. Biggerstaff BJ, Petersen LR. Estimated risk of West Nile virus © 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
607
transmission through blood transfusion during an epidemic in Queens, New York City. Transfusion 2002;42:1019 –26. 6. CDC. Update investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion. MMWR 2002;51:833–6. 7. CDC. Public Health Dispatch. Investigations of West Nile virus infections in recipients of blood transfusions. MMWR 2002;51:973–4. 8. Information regarding West Nile virus (www.cdc.gov/od/oc/ media/wncount.htm [accessed 11/14/02]).
Methotrexate in Acute Persistent Humoral Rejection: An Option for Graft Rescue Fernando Bacal, MD, Gustavo L. Sodre´ , MD, Daniela A. Fernandes, MD, Vera D. Aiello, MD, Noedir Stolf, MD, Edimar Bocchi, MD, and Giovanni Bellotti, MD Heart Failure Department, Heart Institute, University of Sa˜ o Paulo Medical School, Sa˜ o Paulo, Brazil
Humoral response emerges as an important component in acute graft rejection and a new challenge to clinicians in posttransplant care. Management of recurrent episodes and persistent activation of the humoral component of the immune system, despite the usual therapeutic approach to rejection, remains unknown. This article describes the successful use of methotrexate as an option for rescuing a graft in this worrisome situation. (Ann Thorac Surg 2003;76:607–10) © 2003 by The Society of Thoracic Surgeons
S
ince the advent of heart transplantation, it has been recognized that acute rejection is a cell-mediated phenomenon. However, studies [1] have suggested a role for humoral mechanisms in acute allograft rejection, and its frequency is greater than predicted in initial descriptions. A relationship has previously been shown between the consequences of episodes of humoral rejection on the durability of grafts and the development of coronary artery disease in transplanted organs. It has been shown that they were more aggressive and precocious than those mediated through T-lymphocytes, which significantly changed a patient’s prognosis [1]. New approaches, such as plasmapheresis, or cyclophosphamide therapy [2], and the use of high doses of human intravenous immunoglobulin (Ig) have been proposed to treat patients with humoral graft rejection in association, or not, with cellular rejection. However, some patients have persistent graft rejection or recurrent episodes with a humoral component of the immune
Accepted for publication Jan 19, 2003. Address reprint requests to Dr Bacal, Rua Joa˜ o Castaldi, 217 Apto 42, Moema, Sa˜ o Paulo–SP 04517-050, Brazil; e-mail: [email protected].
0003-4975/03/$30.00 PII S0003-4975(03)00143-7
CASE REPORTS
with donations that tested positive by polymerase chain reaction or donors that seroconverted after donation. All recipients received components from multiple donors (mean, 42 donors) and 42% (14 cases) underwent surgical procedures of which 50% were coronary artery bypass surgeries. Reducing the risk of WNV infection from blood transfusions when there is active WNV transmission in the community is an important public health issue. Although prior estimates of the risk are viewed as small (perhaps 1:10,000), subsequent infections may be fatal. In addition, patients undergoing procedures (such as open heart surgery) in which multiple blood product transfusions may be necessary are at higher risk. Screening donor blood for WNV serology would not be an effective strategy, as the period of viremia may antedate appearance of antibodies and immunoglobulin M antibodies against WNV may persist for more than 500 days. Nucleic amplification testing, which is currently used to screen blood for human immunodeficiency virus and hepatitis C virus, is not available and is not recommended for WNV yet. In lieu of additional information from ongoing studies of WNV transmission by blood products, the American Association of Blood Banks recommends the following [8]:
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
608
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
Ann Thorac Surg 2003;76:607–10
CASE REPORTS
response (findings which are probably related to a shorter surveillance of the transplanted organ, high mortality, cost of treatment, and development of graft coronary artery disease), reflecting a poor prognosis. Antimetabolite effects of methotrexate, through its potent inhibition of dihydrofolate reductase and interruption in purine synthesis, promote a breakdown in replication and function of T lymphocytes, and possibly B cells, because of relatively selective action on DNA replication [3–5]. The latter should be the principal component in modulation of humoral response. In a previous article [6], our group reported on 6 patients with persistent acute cellular rejection treated with methotrexate who experienced an important reduction in episodes of graft rejection. Therefore, a reduction in the number of recurrences of humoral-mediated immune response against a transplanted heart must be expected. The aim of this report is to show the first use of methotrexate, as a rescue treatment, in recurrent humoral rejection of a patient undergoing standard treatment. The transplant recipient is a white man, 33 years old, who had idiopathic dilated cardiomyopathy. His blood type is AB negative. He never received blood transfusions, and serologies for cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and 2 were negative. Panel reaction was 0%. The donor, a black woman, age 46, blood type B, died as consequence of stroke. She was hypertensive; other comorbidities and her obstetric history were not described. She had never received blood components. Serologies for Chagas disease, cytomegalovirus, toxoplasmosis, hepatitis B and C, and human immunodeficiency virus-1 and -2 were negative. A crossmatch was performed and all studies were negative An orthotopic heart transplant was performed on December 26, 2000, without sequelae. The patient received standard treatment with corticosteroids, cyclosporine (4 mg/kg/d), and azathioprine (2.5 mg/kg/d) to prevent rejection. His serum level of cyclosporine was 549 ng/mL on the seventh day after transplantation. On postoperative day 9, the echocardiogram showed mild left ventricular hypertrophy with normal function, mild global dysfunction of the right ventricle, and mild tricuspid and mitral insufficiency. An endomyocardial biopsy was performed on the same day, and the sample showed acute cellular rejection grade IIIB (ISHLT [International Society of Heart–Lung Transplantation]) with an associated humoral immunity component: IgG negative, IgM⫹⫹, C3⫹⫹⫹ and fibrinogen ⫹⫹⫹ (Fig 1). Treatment for acute rejection was initiated with methylprednisolone intravenously at a dose of 1 g for 3 days, and horse antithymocyte globulin was used (dosage, 10 mg/kg/min for 10 days) (Fig 2). The patient was hemodynamically and clinically stable. A new endomyocardial biopsy was performed on postoperative day 17 after transplantation, with an identical grade of cellular and humoral immune response. No
Fig 1. Immunofluorescence of myocardial tissue: (A) Focal positivity for immunoglobulin G in a small vessel (white arrow) (original magnification, ⫻400.) (B) Granular pattern of positivity for C3 in the interstitium (original magnification, ⫻400.) (C) Diffuse positivity for fibrinogen in the interstitium (original magnification, ⫻200).
changes occurred in the echocardiographic findings of the first examination. The patient was removed to the intensive care unit and
Ann Thorac Surg 2003;76:607–10
CASE REPORT BACAL ET AL METHOTREXATE IN PERSISTENT REJECTION
609
CASE REPORTS
Fig 2. Immunosuppression therapy used to treat the rejection in a patient with persistent cellular and humoral components. (ATGAM ⫽ polyclonal antibodies; FK506 ⫽tacrolimus; MMF ⫽mycophenolate mofetil; OKT3 ⫽ monoclonal antibodies; Rej ⫽ rejection.)
underwent four sessions of plasmapheresis, methylprednisolone pulse therapy (1 g/d); immunosuppressive drugs had been changed to cyclophosphamide (200 mg/ d), tacrolimus (0.16 mg/kg/d), and OKT3 (Orthoclone, Janssen-Cilag, Brazil) (monoclonal antibodies, 5 mg/d). The patient had febrile episodes occur, but without evidence of infectious illness. No changes occurred in the patient’s clinical state or in the hemodynamic findings. On postoperative day 29, a new biopsy showed improvement in histologic findings, with grade IA (ISLHT) cellular rejection, and a mild humoral response on immunofluorescence. The serum level of FK506 (Prograf, Janssen-Cilag, Brazil) (tacrolimus) was 9.4 ng per mL. On postoperative day 30, cyclophosphamide was replaced by mycophenolate mofetil (CellCept, Roche, Brazil) (1 g/d). The patient remained asymptomatic. Another biopsy was performed on postoperative day 40 after the transplantation showed a mild progression in the cellular grade of rejection grade IB (ISLHT), and recurrent humoral findings were graded as IgG negative on immunofluorescence, IgM⫹/III, C3⫹/III, and fibrinogen ⫹⫹⫹. On postoperative day 49, another endomyocardial biopsy showed acute cellular rejection grade IIIA (ISHLT); humoral rejection was graded as IgG negative, IgM⫹/IV, C3⫹⫹/IV, and fibrinogen ⫹⫹/IV. Methylprednisolone pulse therapy was tried again, and antimetabolite methotrexate was included in the therapeutic regimen. A dosage of 15 mg per week was used the first week, then 10 mg per week thereafter. The patient remained asymptomatic without changes in echocardiographic findings. A biopsy was performed on postoperative day 55, which showed a cellular rejection grade A (ISLHT), and immunofluorescence of IgG⫹/IV, IgM⫹/IV, C3⫹/IV, and fibrinogen ⫹/IV. A week later, an endomyocardial biopsy showed no evidence of rejection (humoral or cellular), and the echocardiography study was normal. Histologic findings remained without alterations, and the patient was stable and asymptomatic in ambulatory care at 24 months of follow-up.
Comment The role of humoral immunity in acute cardiac allograft rejection is an area of recent interest, thus predisposing factors and prognosis for this kind of rejection remains largely unknown [1]. The treatment performed was validated by literature data. Prophylaxy was used in the postoperative period, with a triple-drug immunosuppressive regimen added of corticosteroids, azathioprine, and cyclosporine. Standard treatment was maintained during the first episode of acute rejection, when methylprednisolone pulse therapy and monoclonal antibodies were prescribed; however, biopsies were still showing acute rejection patterns. Based on the patient’s response, we decided to gear the therapeutic goal to the humoral branch of immune response. Cyclophosphamide and plasmapheresis were then tried, as other authors had previously advocated [2]. The lack of efficacy for a standard treatment and the persistence of humoral and cellular response led us to initiate a new immunosuppressive regimen. Despite no reports in the literature pertaining to the use of methotrexate in humoral rejection treatment, we aimed at a new approach that allowed prolongation of xenograft survival to guarantee the patient’s well being. We took into account previous reports about the association of methotrexate as an adjuvant therapy in persistent acute cellular rejection. Therefore, we initiated a folic acid analogue that would play an important role by inhibiting T lymphocytes through interruption of purine synthesis, reducing cellular response [3, 4], as well as B cells, inhibiting humoral factors [4]. Results of the present case have reflected our expectations; reverse of rejection and maintenance of this pattern thus far (24 months after institution of this new therapy). It is clear that the case reported in this article cannot lead us to hasty conclusions. Further studies are needed to determine the real effectiveness and reliability of the proposed regimen. However, this report may have im-
610
CASE REPORT POLITO ET AL EMPYEMA IN A PATIENT WITH A TOTAL ARTIFICIAL HEART
portant implications involving a novel therapeutic treatment.
References
CASE REPORTS
1. Costanzo-Nordin MR, Heroux AL, Radvany R, et al. Role of humoral immunity in acute cardiac allograft dysfunction. J Heart Lung Transplant 1993;12:S143–6. 2. Grauhan O, Mu¨ ller J, v Baeyer H, et al. Treatment of humoral rejection after heart transplantation. J Heart Lung Transplant 1998;17:1184 –94. 3. Hosenpud JD, Hershberger RA, Ratkovec RR, et al. Methotrexate for the treatment of patients with multiple episodes of acute cardiac allograft rejection. J Heart Lung Transplant 1992;11:739 –45. 4. Costanzo-Nordin MR, Grusk BB, Silver MA, et al. Reversal of recalcitrant cardiac allograft rejection with methotrexate. Circulation 1998;78(Suppl III):III-47–57. 5. Rosenthal GJ, Weigand GW, Germolec DR. Suppression of B cell function by methotrexate and trimetrexate: evidence of inhibition of purine biosynthesis as a major mechanism of action. J Immunol 1988;141:410 –6. 6. Bacal F, Veiga VC, Fiorelli AE, et al. Treatment of persistent rejection with methotrexate in stable patients undergoing heart transplantation. Arq Bras Cardiol 2000;74:141–4.
Successful Management of Empyema in a Patient With a Total Artificial Heart William F. Polito, MD, Francisco A. Arabia, MD, Pei H. Tsau, MD, Venki Paramesh, MD, Daniel S. Woolley, MD, Raj K. Bose, MD, Gulshan K. Sethi, MD, and Jack G. Copeland, MD University of Arizona Sarver Heart Center, Tucson, Arizona, and Gunderson Lutheran Hospital, LaCross, Wisconsin
A description of successful management of a patient who developed an empyema as a postoperative complication following the insertion of a CardioWest total artificial heart (TAH) as a bridge to cardiac transplantation is presented. By using traditional methods of management, the patient recovered and went on to transplant. (Ann Thorac Surg 2003;76:610 –1) © 2003 by The Society of Thoracic Surgeons
W
ith the increasing number of patients needing cardiac transplantation for end-stage heart disease, and the number of donors remaining constant, the use of mechanical circulatory support has evolved as a new standard for bridge to transplant (BTT). The main complications of these devices include infection and thromboembolic events. We report a case of a patient who was treated for empyema while on the total artificial Accepted for publication Jan 8, 2003. Address reprint requests to Dr Arabia, University of Arizona Sarver Heart Center, PO Box 245071, Tucson, AZ 85724-5071; e-mail: [email protected].
© 2003 by The Society of Thoracic Surgeons Published by Elsevier Inc
Ann Thorac Surg 2003;76:610 –1
heart (TAH). He recovered, received an orthotopic heart transplant, and was discharged home without significant sequelae. A 52 year-old male admitted with congestive heart failure (CHF) secondary to ischemic cardiomyopathy was referred for transplantation after failing medical management. He required the placement of an automatic implantable cardioverter device for malignant ventricular arrhythmias. An echo revealed a left ventricular ejection fraction (LVEF) 10% to 20%. He was stabilized, evaluated, and accepted for heart transplantation. During the next few months he had multiple admissions for CHF. Right heart catheterization revealed: CVP (central venous pressure) ⫽ 18 mm Hg; PCW (pulmonary capillary wedge pressure) ⫽ 29 mm Hg; CI ⫽ 1.9 L/min per m2; and systemic blood pressure ⫽ 82/52 (mean ⫽ 65 mm Hg), while on dopamine at 2.5 mcg/kg per min, dobutamine at 10 mcg/kg per min, and milrinone at 0.6 mcg/kg per min. Despite this aggressive support the patient continued to deteriorate and CardioWest TAH (CardioWest Technologies, Tucson, AZ) was implanted as BTT. The operation was performed via a median sternotomy utilizing cardiopulmonary bypass. The pleural spaces were not entered during the implantation, and the device was protected with fashioned PTFE (polytetrafluoroethylene) membranes. Mechanical ventilation was discontinued on postoperative day 1 (POD 1). He was reintubated 2 days later for respiratory failure as a result of right lower lobe pneumonia. Initial sputum cultures identified the organism Klebsiella pneumoniae. Antibiotics were continued according to susceptibilities. Anticoagulation consisting of heparin initially then followed by warfarin, persantine, and aspirin was initiated. He was extubated 2 weeks following surgery, and was recovering slowly. Over the next 2 weeks he developed a right pleural effusion. A computed tomographic (CT) guided 12-French pigtail catheter was placed on POD 34 with evacuation of 1200 cc of serous fluid that revealed 2⫹ PMNs but no organisms. Pleural fluid recultured 5-days later revealed mixed anaerobic flora. Chest CT scan demonstrated a thickened fluid collection with a rind consistent with empyema (Fig 1). On POD 43 he underwent a right thoracotomy with decortication; INR at this time was 2.4, with a bleeding time of 19.5 minutes. He developed a right hemothorax 4-days later requiring a second exploration and evacuation of the hemothorax. He recovered and was relisted as UNOS (United Network for Organ Sharing) status 1A for heart transplantation on POD 75. He underwent orthotopic heart transplantation on POD 159. He recovered without complications and was discharged home after 11 days. The CardioWest TAH is currently used as a BTT and is under an investigation device exemption from the Food and Drug Administration. It is a pneumatically driven device consisting of two polyurethane prosthetic ventricles that are placed in an orthotopic position via a median sternotomy. Blood and air are separated by a four-layer diaphragm that retracts 0003-4975/03/$30.00 PII S0003-4975(03)00157-7