Viral infections Cytomegalovirus pneumonia in adult autologous blood and marrow transplant recipients

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1 (2001) 27, Nature Publishing Group All rights reserved /01 $ Viral infections Cytomegalovirus pneumonia in adult autologous blood and marrow transplant recipients S Konoplev 1, RE Champlin 1, S Giralt 1, NT Ueno 1, I Khouri 1, I Raad 2, K Rolston 2, K Jacobson 2, J Tarrand 3, M Luna 4, Q Nguyen 2 and E Whimbey 2 1 Department of Blood and Marrow Transplantation, 2 Division of Internal Medicine, and Departments of 3 Laboratory Medicine and 4 Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Summary: CMV pneumonia is a major cause of morbidity and mortality among allogeneic BMT recipients. To assess the frequency, timing, risk factors and response to therapy of CMV pneumonia among autologous BMT recipients, we reviewed our experience with 795 patients. Sixteen (2%) patients were diagnosed with CMV pneumonia. The frequency was higher among patients who were seropositive than those who were seronegative (3.3% vs 0%, P = 0.008). Among seropositive patients, the frequency was higher among patients with hematological malignancies than patients with solid tumors (5.0 % vs 1.0%, P = 0.019). Eleven cases occurred 30 days, and five cases occurred 100 days post transplant. The overall CMV pneumonia-related mortality rate was 31%. Seven (78%) of nine patients treated with ganciclovir and IVIG prior to respiratory failure survived; neither of two patients treated after respiratory failure survived. Four of five (80%) untreated patients survived. In conclusion, CMV is a not infrequent cause of pneumonia among autologous BMT recipients. Risk factors include CMV seropositivity and an underlying hematological malignancy. A favorable response hinges on the prompt initiation of therapy. The survival of 25% of the patients without antiviral therapy suggests that the isolation of CMV from a BAL specimen occasionally reflects oropharyngeal contamination or that CMV pneumonia may sometimes be self-limited in more immunocompetent autologous BMT recipients. (2001) 27, Keywords: autologous bone marrow transplantation; cytomegalovirus; pneumonia CMV is a major cause of morbidity and mortality among blood and marrow transplant (BMT) recipients, especially allogeneic BMT recipients. Among autologous BMT Correspondence: Dr E Whimbey, Director of Clinical Virology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 47, Houston, Texas 77030, USA Received 1 April 2000; accepted 3 January 2001 recipients, the frequency of CMV infection has been reported to be comparable to that in allogeneic BMT recipients (approximately 40 50%). However, the frequency of serious CMV disease has been reported to be considerably lower, generally ranging from 1% to 9% To evaluate the frequency, timing, risk factors and response to therapy of CMV pneumonia among adult autologous BMT recipients during the first year post transplant, we reviewed the experience of 795 patients cared for at The University of Texas MD Anderson Cancer Center (MDACC). Patients and methods The virology records and autopsy reports of all patients 17 years old who underwent an autologous BMT at MDACC between May 1992 and May 1996 were reviewed until 1 year post transplant. The medical records of all patients identified to have CMV pneumonia were reviewed. Viral cultures of blood and respiratory samples were performed at the discretion of the primary physician for symptomatic disease. Blood and BAL samples were assayed for CMV by shell vial centrifugation and conventional viral cultures. CMV shell vials consisted of two MRC5 vials, inoculated with 0.2 ml of cellular specimen, centrifuged at 1000 g for 15 min, incubated at 35 C overnight, and developed with antibody to HCMV immediate early antigen (Intracel, Issaquah, WA, USA). Conventional cultures used human diploid foreskin fibroblasts inoculated with 0.3 ml of specimen and observed for characteristic cytopathic effects for 21 days (Viromed, Minneapolis, MN, USA). CMV pneumonia was defined as the presence of clinical and radiographic evidence of pneumonia and either the isolation of CMV in cultures of BAL fluid or lung tissue or the detection of characteristic histopathologic changes in lung tissue confirmed by immunofluorescence. Death was attributed to CMV if the pneumonia progressed and the patient died of respiratory failure. Therapy for CMV pneumonia consisted of ganciclovir 5 mg/kg i.v. twice daily and IVIG 500 mg/kg i.v. every other day for a minimum of 3 weeks or until the pneumonia resolved. Foscarnet 60 mg/kg i.v. three times a day was substituted for ganciclovir in patients with neutropenia.

2 878 Table 1 Frequency of CMV pneumonia and associated mortality in 795 adult autologous BMT recipients Total No. (%) CMV No. (%) pneumonia penumoniaassociated deaths Underlying disease (2.0) 5 (31) Hematological (3.1)* 5 (36) malignancies ALL 7 1 (14.3) 1 (100) Multiple myeloma 65 5 (7.7) 1 (20) AML 14 1 (7.1) 1 (100) NHL (2.8) 2 (33) CLL 36 1 (2.8) 0 Hodgkin s disease CML 14 0 Solid tumors (0.6)* 0 Breast cancer (0.7) 0 Others 51 0 Prior radiotherapy involving 62 1 (1.6) 0 chest *P = Patients in whom the pneumonia had already resolved when the culture results became available were not treated. HSV prophylaxis with acyclovir was administered to all patients from the time of conditioning therapy until engraftment. IVIG prophylaxis was not used routinely. All patients received CMV seronegative or filtered leukocyte-depleted blood products. The 2 test was used to compare differences in proportions between groups, and the results were confirmed by Fisher s exact test where appropriate. Differences were considered significant when the P value was All results of tests of significance are reported as two-tailed. Results From May 1992 to May 1996, 795 adults with underlying malignancies received an autologous BMT at MDACC. The type of transplant, underlying diseases, and conditioning regimens are outlined in Tables 1, 2 and 3. Forty-seven Table 3 Characteristics and outcome of 16 adult autologous blood and marrow transplant recipients with CMV pneumonia No. (%) patients No. (%) deaths n = 16 n = 5 (31%) Onset of symptoms Pre-engraftment 6 (38) 3 (50) Post engraftment 10 (62) 2 (20) Before day (69) 4 (36) After day (31) 1 (20) Conditioning regimen TBI/Cytoxan 1 (6) 0 TBI/Cytoxan/Etoposide 2 (13) 0 Thiotepa/Busulfan/Cytoxan 7 (44) 4 (57) BCNU/Cytoxan/Ara-C/Etoposide 2 (13) 1 (50) BCNU/Cytoxan/Etoposide 4 (25) 0 Concurrent infections 6 (38) 2 (33) 30 days s/p BMT (n = 11) 2 (18) 1 (50) 100 days s/p BMT (n = 5) 4 (80) 1 (25) patients received a total body irradiation (TBI) containing regimen (mainly cytoxan or cytoxan/etoposide); and 748 patients received a non-tbi containing conditioning regimen (mainly cytoxan/busulfan/thiotepa or cytoxan/ carmustine/thiotepa). Sixty-two patients had received prior radiotherapy involving the chest. Forty-four patients received CD34 + cell-selected transplants (underlying disease: hematological malignancy (n = 27), solid tumor (n = 17); source of stem cells: marrow (n = 22), PBSC (n = 17), combined marrow and PBSC (n = 5)). Sixteen patients (2%) were diagnosed to have CMV pneumonia during the first year post transplant. All 16 patients were CMV seropositive pretransplant. Fourteen patients had hematological malignancies, and two patients had breast cancer. The frequency of CMV pneumonia among patients with different types of transplants and underlying diseases is shown in Tables 1 and 2. The CMV serostatus was known in 686 (86%) of the 795 patients (87% patients with hematological malignancies and 85% of patients with solid tumors) (Table 2). Seventy percent of these patients were seropositive (71% of patients with hematological malignancies and 69% of patients with solid tumors). The frequency of CMV pneumonia was sig- Table 2 All patients Frequency of CMV pneumonia related to CMV serostatus pretransplant Pretransplant CMV serostatus Seropositive cases/total (%) Seronegative cases/total (%) Unknown cases/total (%) 16/480 (3.3)* 0/206 (0)* 0/109 (0) Source of stem cells Bone marrow 9/283 (3.2) 0/15 (0) 0/85 (0) PBSC 5/186 (2.7) 0/191(0) 0/24 (0) BM + PBSC 2/11 (18.2) 0/0 (0) 0/0 (0) Hematological malignancies 14/282 (5.0) 0/115(0) 0/67 (0) Solid tumors 2/198 (1.0) 0/91 (0) 0/42 (0) TBI 3/39 (7.7) 0/7 (0) 0/1 (0) No TBI 13/441 (3.0) 0/199(0) 0/108(0) CD34 selected 0/26 (0) 0/9 (0) 0/9 (0) Non-CD34 selected 16/454 (3.5) 0/197(0) 0/100 *P = 0.008; P = 0.058; P = 0.051; P = 0.019; P = 0.136; P =

3 nificantly higher among patients who were seropositive than among patients who were seronegative (3.3% vs 0%, P = 0.008). Among seropositive patients, the frequency of CMV pneumonia was also significantly higher among patients with hematological malignancies than among patients with solid tumors (5.0% vs 1.0%, P = 0.019). Neither a TBI-based conditioning regimen nor a pretransplant history of radiotherapy involving the chest, nor the source of the stem cells were found to be significant risk factors for CMV pneumonia among seropositive patients. There were no cases of CMV pneumonia among the 44 patients who received a CD34 + cell-selected transplant. Detailed characteristics of patients with CMV pneumonia are shown in Table 3. The median age was 45 years (range, years). The median time to engraftment was 13 days (range 8 17 days): 10 days after PBSC vs 15 days after marrow transplant (P = 0.075). The time of onset of symptoms of CMV pneumonia had a bimodal distribution: 11 cases occurred early post transplant (median, 17 days; range, 5 26 days) and five cases occurred late post transplant (median, 209 days; range, days). Six of the 11 early onset pneumonias occurred prior to engraftment. The underlying disease and disease status of the five patients with late onset pneumonias were breast cancer in PR not receiving chemotherapy, NHL in CR not receiving chemotherapy, NHL in relapse receiving etoposide, multiple myeloma in relapse receiving cytoxan and dexamethasome, and AML in relapse receiving fludarabine. Among the 16 patients with CMV pneumonia, the most common presenting signs and symptoms were fever (94%), cough (63%), hypoxia (63%) and dyspnea (50%). By definition, all patients had radiographic infiltrates, which were bilateral and diffuse in eight (50%) cases. Seven (44%) patients also had pleural effusions. None of the patients had other unexplained major organ dysfunction such as gastrointestinal disease, hepatitis, retinitis or encephalitis. Although there were two cases of graft failure among the early onset pneumonias, the contributing role of CMV was not clear. Six (38%) patients had potentially serious concurrent pulmonary infections (Table 3). Four of these patients had community respiratory virus infections, including parainfluenza virus, respiratory syncytial virus (RSV), influenza B virus and adenovirus infections. 18 The incidence of concurrent infections was significantly higher in patients with late onset CMV pneumonia ( 100 days post BMT) than with early onset CMV pneumonia ( 30 days post BMT) (80% vs 18%, P = 0.036). The two patients with early onset CMV pneumonia had Pseudomonas aeruginosa isolated from the diagnostic BAL (n = 1) and parainfluenza virus isolated from nasopharyngeal washes obtained 4 and 10 days prior to the diagnostic BAL (n = 1). The four patients with late onset CMV pneumonia had the following organisms isolated concurrently from the diagnostic BAL: adenovirus and Pneumocystis carinii (n = 1); P. aeruginosa (with bacteremia, n = 1), RSV (n = 1) and influenza B virus (n = 1). Two of the six patients with concurrent infections died: one patient with early onset CMV pneumonia with concurrent parainfluenza virus infection and one patient with late onset CMV pneumonia with concurrent mixed adenovirus and Pneumocystis carinii infection. Overall, the mortality rate was similar among patients with and without concurrent infections (33% vs 30%). Among the 16 patients with CMV pneumonia, the CMVassociated mortality rate was 31%. All five patients who died had hematological malignancies. Four of the five patients who died had early-onset CMV pneumonia ( 30 days post BMT); the fifth patient had late-onset CMV pneumonia ( 100 days post BMT). This patient had AML in relapse, was receiving chemotherapy with fludarabine, and died with concurrent Pneumocystis carinii and adenovirus pneumonia. The outcome of CMV pneumonia related to therapy is shown in Table 4. The 11 patients treated with a combination of ganciclovir and IVIG had a mortality rate of 36%. The mortality tended to be higher when therapy was initiated less than 24 h compared to more than 24 h before respiratory failure requiring mechanical ventilation (100% vs 22% respectively; P = 0.11). Among the five patients who did not receive antiviral therapy, only one patient died. This patient, who had relapsed NHL and who died of early-onset CMV pneumonia was not treated because the diagnosis only became known post mortem. The other four surviving patients were not treated because the diagnosis became known after the pneumonia had resolved. One patient with stage IV breast cancer had early-onset CMV pneumonia. The other three patients had late-onset CMV pneumonia: two patients (one with NHL in CR and the other with breast cancer in PR) were not receiving myelosuppressive or immunosuppressive therapy; the third patient had multiple myeloma in relapse and was receiving cytoxan and dexamethasone. In all 16 patients, the diagnosis was based on the isolation of CMV from a BAL specimen. In one patient, CMV was also isolated from lung tissue. Shell vial and conventional viral blood cultures were obtained from six patients during the 10 days preceding the detection of CMV in the BAL. CMV viremia was detected in two cases: 8 days prior to the BAL in one and concurrently in the other. Two patients underwent autopsy evaluation. These two patients died 5 days and 30 days, respectively, after the isolation of CMV from BAL specimens. Both autopsies revealed death due to diffuse alveolar lung damage consistent with viral pneumonitis. Characteristic histologic features of CMV infection were not seen in lung tissue and immunohistochemistry staining for CMV was negative. Table 4 Outcome of CMV pneumonia related to therapy a in 16 adult autologous blood and marrow transplant recipients No. patients No. (%) deaths Treatment 11 4 (36) Initiated early b 9 2 (22) Initiated late b 2 2 (100) No treatment 5 1 (20) a Therapy consisted of ganciclovir 5 mg/kg i.v. twice a day and IVIG 500 mg/kg every other day. Foscarnet was substituted for ganciclovir in patients with neutropenia. b Early vs late: Initiated 24 h or 24 h prior to respiratory failure requiring mechanical ventilation. 879

4 880 Discussion CMV pneumonia is a not infrequent cause of serious and sometimes fatal pneumonia in autologous BMT recipients, and has in general been reported to occur in 1% to 9% of patients In our population of patients, the overall incidence of CMV pneumonia was relatively low (2%). This is a minimal estimate of the frequency as autologous BMT recipients transplanted in tertiary care referral centers frequently return to their home towns to be cared for by their primary physicians during the later post-transplant period. The most significant risk factor for CMV pneumonia was the CMV serostatus prior to transplant. The incidence was significantly higher among patients who were seropositive than among patients who were seronegative (3.3% vs 0%). All cases of CMV pneumonia occurred in patients who were seropositive suggesting that these pneumonias reflected reactivation of latent infections rather than primary infections. The lack of cases attributable to primary infections is consistent with previous studies demonstrating the prophylactic efficacy of administering only CMV seronegative or filtered leukocyte-depleted blood products to seronegative BMT recipients The frequency of CMV pneumonia also varied according to the underlying disease and was significantly higher among patients with hematological malignancies than among patients with solid tumors (primarily patients with breast cancer). Among patients who were seropositive the frequency was 5% and 1%, respectively. The extent to which this reflected differences in specific underlying diseases or disease stages or differences in the type and intensity of pretransplant chemotherapeutic regimens and transplant conditioning regimens remains to be elucidated. In contrast to the findings in a recently published report of a high incidence (23%) of CMV pneumonia in 31 seropositive patients undergoing CD34-selected autologous PBSC transplant, 11 there were no cases of CMV pneumonia among the 26 seropositive patients who received CD34- selected cells in this study. The overall mortality rate with CMV pneumonia was high (31%), although somewhat lower than previously reported (56 100%) The majority of patients in this study were treated at an early stage of pneumonia. This may in part have contributed to the lower mortality rate compared to previous studies, which did not specify the proportion of patients who were treated before the development of respiratory failure. That both patients in this study who began therapy at an advanced stage of respiratory dysfunction died highlights the need to initiate therapy promptly. The low overall mortality may also reflect the inclusion of patients in whom the isolation of CMV in the BAL specimen merely reflected shedding of CMV in the respiratory tract rather than the occurrence of invasive viral pneumonia. The diagnostic value of the detection of CMV in BAL, which is high in allogeneic BMT recipients with pneumonia and low in patients with acquired immunodeficiency syndrome, has not been determined in autologous BMT recipients. 19,20 In the two patients in this study who died and underwent autopsy examination, the diagnosis of invasive CMV disease was not confirmed, although the findings of diffuse alveolar lung damage were consistent with viral induced inflammatory damage. Similarly, in four (25%) of the 16 patients in this study in whom pneumonia was defined by the isolation of CMV from a BAL specimen in a compatible clinical and radiographic setting, the pneumonia resolved without specific antiviral therapy. Three of these four patients were more than 100 days post transplant. Of interest, the only two patients with breast cancer who developed CMV pneumonia were among those who survived without antiviral therapy. These findings suggest that the isolation of CMV from a BAL specimen in autologous BMT recipients may occasionally reflect oropharyngeal contamination or that CMV pneumonia may sometimes be self-limited in more immunologically intact subsets of autologous BMT recipients, such as those with underlying solid tumors or those who are late post transplant. In conclusion, CMV is a not infrequent, life-threatening cause of pneumonia in some subsets of autologous BMT recipients. Risk factors for pneumonia include CMV seropositivity prior to transplant and an underlying hematological malignancy. A favorable response appears to hinge on the prompt initiation of therapy. As one quarter of the pneumonias resolved without antiviral therapy, the clinical significance of isolating CMV from a BAL specimen in autologous BMT recipients awaits further clarification. References 1 Pecego R, Hill R, Appelbaum FR et al. Interstitial pneumonitis following autologous bone marrow transplantation. Transplantation 1986; 42: Valteau D, Hartmann O, Benhamou E et al. Nonbacterial nonfungal interstitial pneumonitis following autologous bone marrow transplantation in children treated with high-dose chemotherapy without total-body irradiation. Transplantation 1988; 45: Wingard JR, Chen DY, Burns WH et al. Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation. Blood 1988; 71: Wingard JR, Sostrin MB, Vriesendorp HM et al. Interstitial pneumonitis following autologous bone marrow transplantation. Transplantation 1988; 46: Reusser P, Fisher LD, Buckner CD et al. 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5 10 Singhal, R Powles, J Treleaven et al. Cytomegaloviremia after autografting for leukemia: clinical significance and lack of effect on engraftment. Leukemia 1997; 11: Holmberg LA, Boeckh M, Hooper H et al. Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood 1999; 94: Bilgrami S, Aslanzadeh J, Feingold JM et al. Cytomegalovirus viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no need for surveillance. Bone Marrow Transplant 1999; 24: Offidani M, Corvatta L, Olivieri A et al. Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF. Bone Marrow Transplant 1999; 24: Bowden RA, Sayers M, Flournoy N et al. Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation. New Engl J Med 1986; 314: Verdonck LF, de Graan-Hentze YCE, Dekker AW et al. Cytomegalovirus seronegative platelets and leukocyte-poor red blood cells from random donors can prevent primary cyto- megalovirus infection after bone marrow transplantation. Bone Marrow Transplant 1987; 2: DeWitte T, Schattenberg A, Van Dijk BA et al. Prevention of primary cytomegalovirus infection after allogeneic bone marrow transplantation by using leukocyte-poor random blood products from cytomegalovirus unscreened blood-bank donors. Transplantation 1990; 50: Bowden RA, Slichter SJ, Sayers MH et al. Use of leukocytedepleted platelets and cytomegalovirus-seronegative red blood cells for prevention of primary cytomegalovirus infection after marrow transplant. Blood 1991; 78: Whimbey E, Champlin RE, Couch RB et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22: Crawford SW, Bowden RA, Hackman RC et al. Rapid detection of cytomegalovirus pulmonary infection by bronchoalveolar lavage and centrifugation culture. Ann Intern Med 1988; 108: Mann M, Shelhamer JH, Masur H et al. Lack of clinical utility of bronchoalveolar lavage cultures for cytomegalovirus in HIV infection. Am J Respir Crit Care Med 1997; 155: