T tation remains high and is reported as 38% [l]. The

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1 Pneumocystis carinii Pneumonia After Heart Transplantation Hideaki Saigenji, MD, Mitsunori Kaneko, MD, Birger Rhenmen, MD, Richard J. Williams, MD, M. Andre Vasu, MD, Timothy B. Icenogle, MD, and Jack G. Copeland, MD Section of Cardiovascular and Thoracic Surgery, Department of Surgery, University of Arizona, Tucson, Arizona Five patients with Pneumocystis carinii pneumonia after heart transplantation are reported. Four had severe clinical symptoms, whereas 1 was asymptomatic. Mechanical ventilatory support was necessary in 1 because of respiratory distress. Pneumocystis carinii infection developed in 4 patients within the first 4 postoperative months, and 1 patient had clinical disease 1 year after transplantation with a recurrence 9 months later. All were treated with trimethoprim-sulfamethoxazole either orally or intravenously (10 to 20 mg * kg-' * day-' of trimethoprim). All patients recovered from infection and received the same drug prophylactically for 2 to 20 months after the infection. All patients are doing well after Pneumocystis carinii infection except 1 who died after an acute myocardial infarction 4 years after infection. We conclude that trimethoprim-sulfamethoxazole is an effective agent for the treatment of Pneumocystis carinii pneumonia after heart transplantation. (Ann Thoruc Surg ) he mortality rate due to infection after heart transplan- T tation remains high and is reported as 38% [l]. The organisms seen after heart transplantation can be universal [2, 31. When diffuse infiltrates in the lung of the immunocompromised host appear in the chest roentgenogram, Pneumocystis curinii infection is the most likely infecting agent [4]. From the beginning of our heart transplant program in March 1979 to March 1988, 159 heart and six heart and lung transplantation procedures were performed. Of this group, Pneumocystis curinii infection developed in 5 patients. This article reports the clinical picture of Pneumocystis curinii pneumonia (PCP) in our series. The problems of diagnosis and treatment of PCP after heart transplantation are also discussed. Material and Methods From March 1979 to March 1988, 158 orthotopic and one heterotopic heart transplantation (HTX) were performed in 139 male and 20 female patients ranging from 2 to 65 years of age. Of those patients, 6 (3 patients in each group) were undergoing a second HTX due to graft failure and graft atherosclerosis. The initial indication for HTX was end-stage heart disease, primary or secondary to ischemic or idiopathic cardiomyopathy. Pneumocystis curinii pneumonia developed in 5 of the 153 heart transplant patients. Accepted for publication March 20, Dr Saigenji's present address is The Second Department of Surgery, Kagoshima University Faculty of Medicine, Sakuragaoka, Kagoshima 890, Japan. Address reprint requests to Dr Copeland, Section of Cardiovascular and Thoracic Surgery, University of Arizona Health Sciences Center, 1501 N Campbell Ave, Tucson, AZ Immunosuppressive regimens for all patients were described in detail previously [2, 3, 51. From 1979 to 1982, immunosuppression consisted of the administration of, and rabbit antithymocyte globulin. From 1983 to 1984, cyclosporin A,, and rabbit antithymocyte globulin were used, and a regimen of cyclosporin A,, and rabbit antithymocyte globulin was followed from 1985 to present. The serum concentration of cyclosporin A 12 hours after the previous dose as measured by radioimmunoassay was maintained at 200 to 250 ng/ml for the first postoperative month and then 100 to 150 ng/ml after the first month. Azathioprine was given at a dose of 2 mg - kg-' - day-' orally and titrated so that a white blood cell count of at least 5 x 109/L (5,OOO/pL) was maintained. Five hundred milligrams of intravenous methylprednisolone was administered intraoperatively, and then 125 mg was given every 12 hours until oral administration was begun. Prednisone was given orally at 1.5 mg * kg-' - day-' and was tapered to 0.5 mg - kg-'.day-' the first month, 0.25 mg. kg-' -day-' at 3 months, and mg - kg-' - day-' at 1 year. In patients suspected of having lung infection after HTX, a transtracheal aspiration was performed in an attempt to isolate the infecting agents. Bronchoscopy and bronchoalveolar lavage were performed under general anesthesia in 1 patient. The specimens obtained by transtracheal aspiration or bronchoalveolar lavage were sent for an immediate Gram stain and KOH preparation for fungi. Cultures for anaerobic and aerobic bacteria, as well as fungi, Legionella, acid-fast bacteria, viruses, mycoplasma, nocardia, and chlamydia were obtained. Part of the specimen was also sent for a silver stain for Pneumocystis curinii and fluorescent antibody stain for Legionella. If by The Society of Thoracic Surgeons /91/$3.50

2 108 SAICENJI ET AL PNEUMOCYSTIS CARINII PNEUMONIA Ann Thorac Surg Table 1. Clinical Pictures Onset of PCP After I m m u n o - Patient Age HTX suppressive No. (y) Sex (mo) Regimens Clinical Pictures 1 25 M 12 Azathioprine, 21 Azathioprine, 2 49 M 2 Cyclosporin A, 3 54 M 4 Cyclosporine A, 4 52 M 2 Cyclosporine A, 5 46 M 2.5 Cyclosporine A, HTX = heart transplantation; M = male; pneumonia; SOB = shortness of breath. Fever, chills, malaise, SOB, Dyspnea, SOB, Asymptomatic Fever, chills, headache, SOB, cough Low grade fever, SOB Chills, SOB, PCP = Pneumocystis carinii no pathogen was found in those specimens, percutaneous transthoracic needle aspiration of the lung under biplane fluoroscopic control was carried out. The specimen from lung aspiration underwent the same tests as those of the transtracheal aspiration. Definite diagnosis of PCP was confirmed by the demonstration of the organism in the lung tissue by transthoracic needle aspiration or in the material obtained from the respiratory tree by transtracheal aspiration or bronchoalveolar lavage. Results Six episodes in 5 of 153 heart transplant patients had confirmed diagnosis of PCP. One patient took azathioprine and, 1 received cyclosporin A and, and 3 patients were given cyclosporin A,, and azathioprine as immunosuppression. Pneumocystis carinii developed in 4 patients from 2 to 4 months after HTX. Patient 1 was proven to have PCP 1 year after transplantation, and this patient had a recurrent PCP 9 months after the initial infection. The patients had various symptoms including fever, chills, shortness of breath, dyspnea without auscultatory finding, and pleuritic pain. One patient had no symptoms (Table 1). Body temperature greater than 37 C was present in 3 patients with the highest recorded temperature being 39.6"C. Respiratory rate ranged from 16 to 32 per minute (mean, 23 per minute). In the laboratory investigations, leukocytosis was present in 4 of 5 patients. Arterial oxygen tension revealed mild to moderate hypoxia (59 to 81 mm Hg; inspired oxygen fraction, 0.21 to 0.4). Arterial carbon dioxide tension tended to show hypocapnia (30 to 34 mm Hg) in all patients (Table 2). Roentgenographic findings of the lungs revealed bilateral diffuse interstitial and alveolar infiltrates in all patients. In 1 patient, a localized nodular infiltrate in the upper left lung was found on the chest roentgenogram at the time of admission. The infiltrate spread rapidly to both lung fields (see Table 2). A random sputum examination showed Pneumocystis Table 2. Laboratory and Radiographic Findings Patient WBC Count Arterial Blood Gas No. (1091~) PO, (mm Hg) PCO, (mm Hg) SaO, PH Radiographic Findings Severe nodular densities 11.2 (FiO, = 0.21) as well as bilateral diffuse interstitial and alveolar infiltrate Bilateral diffuse Localized infiltrate in left lobe at admission, bilateral diffuse interalveolar infiltrate 2 days after admission Bilateral diffuse (FiO, = 0.4) interstitial and alveolar infiltrate Bilateral diffuse (FiO, = 0.4) Bilateral diffuse (Fi02 = 0.4) FiO, = inspired oxygen fraction; = not done; PO, = oxygen tension; PCO, = carbon dioxide tension; SaO, = oxygen saturation; WBC = white blood cell.

3 Ann Thorac Surg SAIGENJI ET AL 109 PNEUMOCYSTIS CARINII PNEUMONIA Table 3. Diagnostic Procedures and Coexisting Infections Patient No. Sputum TTA TNA BAL Coexisting Organisms Nocardia (TTA), Aspergillus (TTA), Streptococcus viridans (TTA) None Neisseria (TTA), Nonehemolytic streptococci (TTA), Herpes simplex (oral swab) Cytomegalovirus (urine) Enterovirus (TTA), cytomegalovirus (BAL) Cytomegalovirus (urine) BAL = bronchoalveolar lavage; = not done; TNA = transthoradc needle aspiration of the lung; lta = transtracheal aspiration; + = positive Pneumocystis carinii in silver stain; - = negative Pneumocystis carinii in silver stain. carinii in 1 patient, but no Pneurnocystis carinii was obtained from transtracheal aspiration in any patient. Pneumocystis carinii was demonstrated in the lung tissue obtained by percutaneous transthoracic needle aspiration in 4 of 5 patients. No Pneumocystis carinii was found in the bronchoalveolar lavage material in 1 patient in whom it was performed. Coexisting infections in the lung or other organs are presented in Table 3. Other pulmonary infection were found in 3 patients. Viral cultures were positive in 4 of the 5 patients, and cytomegalovirus was found in 3 of these 4 patients. Trimethoprim-sulfamethoxazole (TMP-SMX) was given for the treatment of PCP in all patients with a dosage of 10 to 22 mg - kg-' day-' of TMP (160 mg TMP/800 mg SMX). When a patient could not tolerate TMP-SMX orally due to nausea, vomiting, or endotracheal intubation, TMP-SMX with the dosage of 16 to 18 mg - kg-' day-' of TMP (16 mg/ml TMP/80 mg/ml SMX) was administered intravenously. The serum concentration of SMX 1 to 2 hours after the administration of TMP-SMX was examined in 3 patients. The measured serum level ranged between 97 to 193 pg/ml. The side effects identified with this drug were nausea, vomiting, and anorexia. These were present in 4 patients. Patient 4 required mechanical ventilatory support due to the deterioration of respiratory function after the diagnosis of PCP. He was able to be extubated after 2 days of ventilatory support. Clinical symptoms rapidly improved within 2 to 5 days after the beginning of treatment with TMP-SMX; however, radiographic clearing was prolonged an average of 1 month after treatment was initiated. The duration of hospitalization ranged from 5 to 13 days (mean, 10.3 days). All patients prophylactically received TMP-SMX with doses of 4.2 to 5.5 mg - kg-' * day-' of TMP (160 mg TMP/800 mg SMX) for 2 to 20 months after resolution of clinical disease. The only recurrence was in a patient who received only 2 months of postinfection therapy. One patient died 4% years after Pneumocystis carinii infection because of acute myocardial infarction. The remaining 4 patients are doing well from 4 months to 6.5 years after initial Pneumocystis carinii infection (Table 4). Comment Protozoal infection after heart transplantation is infrequent [6, 71, but poses high mortality [8]. The usual organism of protozoal infection is Pneumocystis carinii, and the site of infection is in the lung [9]. From March 1979 to March 1988, 153 patients underwent heart transplantation and 142 of 153 survived at least 1 month after heart transplantation. Pneumocystis carinii pneumonia developed in 5 of the 142 patients (3.5%) surviving more than 1 month, demonstrating the low incidence of PCP. Pneumocystis carinii pneumonia developed in 4 of 5 patients in the early postoperative period (2 to 4 months). Oyer and associates [lo] reported that 87% of all Pneumocystis carinii infections have been diagnosed after the first 3 postoperative months. Most likely, Pneurnocystis carinii infection is opportunistic. All transplanted patients are maintained on immunosuppressive regimens and their resistance to Table 4. Treatment and Prognosis Dose of TMP Dose of SMX Serum Concentration day-') day-') of SMX 1-2 h (mg * kg-'. (mg kg-'. Prophylaxis Patieht After Intake Side Duration Dose No. PO IV PO IV (clg/ml) Effects (mo) (mg. kg-'. day-') Result Abd pain Alive Abd pain, Alive N, V N, V Died" N, V Alive N, V Alive None Alive a Died due to acute myocardial infarction. Abd = abdominal; IV = intravenous administration; N = nausea; = not done; PO = oral intake; SMX = sulfamethoxazole; TMP = trimethoprim; V = vomiting.

4 110 SAIGENJI ET AL PNEUMOCYSTZS CARZNIZ PNEUMONIA Ann Thorac Surg Table 5. Relationship Between lmmunosuppressive Regimen and lncidence of Pneumocystis carinii Pneumonia AZ CsA CsA + Variable + Pred + Pred Pred + AZ Total (1)" 101 (5)" transplantations Survival >1 mo Pneurnocystis carinii 1(3.6%) 1(3.9%) 3 (3.2%) infection a Numbers in parentheses are retransplantations. AZ = azathioprine; CsA = cyclosporin A; Pred =. infection is always reduced in this immunocompromised state. The most aggressive immunosuppression is provided in the early postoperative period and corresponds to the period of the onset of PCP. We have used three different immunosuppressive protocols, but there was no demonstrable difference (x2 analysis) in frequency of PCP among them (Table 5). Definite diagnosis for PCP is confirmed if Pneurnocystis carinii is found in the lung tissue or in the materials from the respiratory tree. Our approach to all transplant patients with fever and any chest roentgenographic abnormality, which might be secondary to infection, is to perform an immediate transtracheal aspiration and to then treat the patient if pathogens are found on stains, cultures, or cytology [ll-131. With transtracheal aspiration, we have had 96% specificity, 70% sensitivity, and 78% accuracy in the diagnosis of pulmonary infections. Although none of these were Pneumocystis, we did reach a diagnosis for 1 patient in our series with a posttranstracheal aspirate sputum (ie, sputum produced immediately after transtracheal aspirate). If early studies (Gram stain, KOH preparation, cytology, Legionella fluorescent antibody) are negative and our patient is toxic or septic or deteriorating clinically or persistently febrile, we proceed immediately to percutaneous transthoracic needle aspiration under fluoroscopic or computed tomographic control. Using this technique, we diagnosed 5 of 6 Pneurnocystis infections and have had 100% specificity, 89% sensitivity, and 91% accuracy with our total series of pulmonary infections. The combination of transtracheal aspiration and transthoracic needle aspiration yielded a sensitivity of 90%, a specificity of loo%, and an accuracy of 91%. In general, we have avoided bronchoscopy in the heart transplant population. Our feeling is that it adds a level of complexity to patient care that is, in most cases, unnecessary and that it may be associated with contaminated cultures by virtue of the transoral approach. Similarly, we have avoided open lung biopsy, an unnecessary and morbid procedure, for cardiac recipients. The diagnostic value of sputum examination is low in our series, but Pitchenik and associates [15] reported that this method was effective in 55% of patients with PCP. Other invasive diagnostic maneuvers such as bronchial brushing, transbronchial lung biopsy, bronchoalveolar lavage, and open lung biopsy have had diagnostic values ranging from 69% to 90% [ Recently, noninvasive methods of diagnosis in PCP have shown promise. Kovacs and co-workers [20] report that 90% of PCP can be diagnosed with indirect immunofluorescence. The characteristic findings on chest radiogram in PCP are bilateral perihilar and basilar infiltrates seen as a diffuse alveolar consolidation without pleural change [4]. All patients in our series have shown these typical changes; however, the initial chest radiographic change in 1 patient was a focal nodular infiltrate. Various atypical radiographic changes in PCP have been reported [21]. These changes include lobular involvement, unilateral predominance, atelectatic-appearing infiltrate, and a pseudonodular pattern. Furthermore, some patients have no abnormalities [22]. Because of the numerous atypical radiographic presentations with PCP, close follow-up and a high level of suspicion are necessary to make diagnosis early. All patients received TMP-SMX (160 mg TMP/800 mg SMX) for the treatment of PCP with the dosage of 10 to 20 mg * kg-' * day-' of TMP. We administer this drug as the initial choice in the treatment of PCP because of fewer reported side effects than pentamidine [23]. Intravenous administration of TMP-SMX with the dosage of 16 to 18 mg * kg-' - day-' of TMP was introduced in those patients who could not tolerate oral administration. The serum concentration of SMX 1 to 2 hours after administration ranged from 97 to 193 pg/ml. Winston and associates [23] reported that the serum levels of SMX were parallel to those of TMP but were about 20 times greater, and a 1.5-hour serum SMX level of at least 100 pg/ml might be used to guide therapy whenever TMP level could not be measured. In 3 patients we were only able to measure the SMX level 1 to 2 hours after TMP-SMX administration. Although 1 patient had a serum level of SMX of 97 pg/ml, the other 2 had levels in excess of 100 pg/ml with our dose regimen. These doses of TMP-SMX were considered high enough to be therapeutic for treatment of PCP. The interaction between TMP-SMX and immunosuppressive regimens is not clear. Though Schafers and colleagues [7] reported that they discontinued use of and azathioprine for the treatment of PCP with TMP-SMX, we found no reason to change the dosages of and azathioprine. Patients receiving azathioprine should be given sulfa with caution as there may be synergistic myelosuppression with these two agents [ll]; however, no one to date has reported pancytopenia, leukopenia, or thrombocytopenia. In all of our heart transplant patients, the dose of cyclosporin A is adjusted daily to keep a serum concentration of 200 to 250 ng/ml for the first postoperative month and 100 to 150 ng/ml after the first month measured by radioimmunoassay. Although it is well known that some kinds of antibiotics affect the serum concentration of cyclosporin A [5], we have not found any adverse interaction between TMP-SMX and cyclosporin A. In all 5 of our patients, the clinical symptoms improved within 2 to 5 days after the beginning of treatment with TMP-SMX; however, radiographic improvement was not

5 Ann Thorac Surg 1991; SAICENJI ET AL 111 DNEUMOCYSTIS CARIN11 PNEUMONIA complete until about 1 month after the beginning of TMP-SMX. Prophylactic continuation of TMP-SMX was given at 4 to 5 mg - kg-' * day-' for 2 to 20 months. Recurrent PCP developed in 1 patient 9 months after initial infection. Although we havqnot determined how long patients must take TMP-SMX prophylactically, we currently recommend continuous therapy for 3 to 6 months after the initial infection with monthly follow-up, because our only recurrence was in a patient treated for 2 months. We do not use this drug permanently, because PCP is considered to be treatable if a recurrence develops. Our retrospective study includes many patients from before the contemporary use of prophylactic TMP-SMX. Although we have been treating cardiac recipients with prophylactic TMP-SMX for 1 year, we have serious reservations and are considering the discontinuation of such therapy. Most important are the toxicities of this therapy: nausea, vomiting, inability to take adequate nutrition or oral medications, and the aforementioned myelotoxicity, especially in the face of ongoing azathioprine treatment. Finally, the low number of Pneumocystis cases in our series (3.5%) and the absence of related mortality may not justify prophylaxis. In summary, Pneumocystis carinii pneumonia developed in 5 of 142 patients who have survived at least 1 month after heart transplantation. All patients recovered from this infection. Trimethoprim-sulfamethoxazole is an effective treatment of this infection in the patients who undergo heart transplantation. References 1. Kaye MP. The registry report. Eighth Annual Meeting of the International Society for Heart Transplantation, Los Angeles, Copeland JG, Mammana RB, Fuller JK, et al. Heart transplantation: four years' experience with conventional immunosuppression. JAMA 1984;251:156%6. 3. Copeland JG, Emery RW, Levinson MM, et al. 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