Infections post transplant Respiratory syncytial virus infections ... - Nature

Bone Marrow Transplantation (2001) 28, 271–275  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt

Infections post transplant Respiratory syncytial virus infections in autologous blood and marrow transplant recipients with breast cancer: combination therapy with aerosolized ribavirin and parenteral immunoglobulins S Ghosh1, RE Champlin2, NT Ueno2, P Anderlini2, K Rolston1, I Raad1, D Kontoyiannis1, K Jacobson1, M Luna3, J Tarrand4 and E Whimbey1 1

Division of Internal Medicine, and Departments of 2Blood and Marrow Transplantation, 3Pathology and 4Microbiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Summary: Scant data are available concerning the impact and response to therapy of respiratory syncytial virus (RSV) infections in patients undergoing autologous blood and marrow transplantation (BMT) for breast cancer. During eight winter seasons from 1992–1993 to 1999–2000, nine (4%) of 249 such patients were hospitalized with RSV infections. Six patients, including all five patients who were early post transplant in the pre-engraftment period, developed pneumonia and were treated with a combination of aerosolized ribavirin and IVIG. Among five patients with pneumonia in whom therapy was initiated prior to respiratory failure, one (20%) died. The sixth patient, in whom therapy was initiated after respiratory failure developed, also died. In total, two (1%) patients, both of whom were in the preengraftment period, died of progressive pneumonia. In conclusion, RSV is a significant cause of life-threatening pneumonia in autologous BMT recipients with breast cancer during the early post-transplant period, and accounted for a substantial portion of the overall transplant-related mortality, which in recent years has been minimal. Bone Marrow Transplantation (2001) 28, 271– 275. Keywords: respiratory syncytial virus; autologous BMT; breast cancer

Respiratory syncytial virus (RSV) is a significant cause of life-threatening pneumonia in some subsets of immunocompromised patients, most notably transplant recipients and patients with hematological malignancies.1–19 Although it is well established that RSV may cause severe pneumonias in autologous as well as allogeneic bone marrow transplantation (BMT) recipients with underlying hematological malignancies, scant data are available concerning Correspondence: Dr E Whimbey, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 02, Houston, Texas 77030, USA Received 30 October 2000; accepted 29 January 2001

the impact of RSV and response to therapy in patients undergoing autologous BMT for breast cancer. This is of particular interest in the light of ongoing discussions concerning the risk–benefit ratio of high-dose chemotherapy followed by autologous BMT compared with standard chemotherapy in the management of breast cancer.20,21 Minimizing transplant-related morbidity and mortality remains imperative. Between November 1992 and April 2000, adult BMT recipients with RSV pneumonia hospitalized at The University of Texas MD Anderson Cancer Center (MDACC) were treated with the combination of aerosolized ribavirin and intravenous immunoglobulin (IVIG).6 The efficacy of combination therapy was initially investigated in an open trial conducted at MDACC during the winter of 1992–1993 for several reasons: monotherapy with aerosolized ribavirin had been reported to be associated with a mortality rate of greater than 70% in BMT recipients with radiographically confirmed RSV pneumonia; the therapeutic options were limited; and studies in vitro, in animal models and in humans had suggested that parenteral immunoglobulins might be of benefit therapeutically as well as prophylactically in RSV infections, and might also be synergistic with ribavirin.22–35 Because of the favorable response rate demonstrated in this initial study and subsequent studies reported from other centers, combination therapy has continued to be the standard of care in our institution.6,9,14,17 To assess the frequency of RSV infections and the associated morbidity and mortality and response to therapy of RSV pneumonia with combination aerosolized ribavirin and IVIG in autologous BMT recipients with breast cancer, we reviewed our experience with 249 such patients hospitalized at MDACC during eight winter seasons from 1992–1993 to 1999–2000. Methods Between 1 November 1992 and 1 November 2000, active surveillance for community respiratory viruses was conducted among adult BMT recipients hospitalized at MDACC.8 Patients with an acute respiratory illness had samples of respiratory secretions obtained for viral culture and rapid

RSV infections in BMT recipients with breast cancer S Ghosh et al

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RSV antigen assay by means of ELISA and/or indirect immunofluorescence. In most cases, specimens consisted of combined nasopharyngeal washes (NPW) and throat swabs. When available, endotracheal (ET) aspirates from intubated patients and bronchoalveolar lavage (BAL) fluids were also sampled. At MDACC, a BAL sample is obtained from most adult BMT recipients with undiagnosed pneumonia suspected to be of non-bacterial or non-fungal etiology or with undiagnosed pneumonia that does not promptly respond to broad-spectrum empirical antibiotic therapy. In the Houston community, RSV infections typically occur during the cooler months extending from November to March. Because all cases of RSV infection in this study occurred during this time period, the denominator for the number of patients at risk was tabulated for these 5 months rather than the entire year. A minimum of 3 ml of fluid was inoculated into 1–3 ml of viral transport media. Specimens were transported on ice and inoculated within 4 h of collection on to tissue cultures (Madin–Darby canine kidney cells, rhesus monkey kidney continuous cell line (LLC-MK2), human laryngeal tumor cells (Hep-2) and human embryonic lung fibroblasts (WI38)). RSV was identified by characteristic cytopathic effect in cell cultures and confirmed by staining with a fluorescein-conjugated polyclonal antibody.36 Therapy consisted of a daily dose of 6 g of ribavirin administered as an aerosol via a SPAG-2 generator at a concentration of 20 mg/ml for 18 h a day via a face mask. This was combined with IVIG (500 mg/kg every other day) for the duration of therapy. In two cases, ‘hot lots’ of IVIG containing an RSV microneutralization Ab titer of 1:2048 to 1:8192 were administered. In all other cases, standard commercially available lots of IVIG were administered. To avoid possible drug-related bronchospasm, inhalational bronchodilator therapy was administered every 4 h. The length of therapy was individualized according to the underlying immunologic status of the patient, the clinical response, and viral shedding. An acute URI was defined as the recent onset of rhinorrhea, nasal or sinus congestion, otitis media, pharyngitis, and/or cough with a clear chest radiograph. Pneumonia was defined as an acute respiratory illness occurring in association with signs and/or symptoms of lower respiratory tract disease and a new radiographic infiltrate. Neutropenia was defined as ⭐500 neutrophils/ml of blood. Engraftment was defined as the resolution of neutropenia for 3 days following conditioning therapy and transplantation. Lymphopenia was defined as less than 200 lymphocytes/ml of blood. As a conservative estimate, an infection was considered to be nosocomial if symptoms developed ⭓7 days after hospital admission. Results During the eight winter seasons extending from November through March during the years 1992–1993 to 1999–2000, 249 patients with breast cancer underwent an autologous BMT at MDACC. RSV infections were diagnosed in nine (4%) hospitalized patients. The frequency was similar among patients who received a peripheral blood stem cell

Bone Marrow Transplantation

and a bone marrow transplant (0.5% vs 2%, respectively). Two cases occurred during each of the 1992–1993, 1997– 1998, 1999–2000 seasons, and one case occurred during each of the 1993–1994, 1995–1996, 1998–1999 seasons. Although active surveillance took place year round, no cases were detected during the warmer months between April and October. Patient characteristics and frequency of progression to pneumonia and death are listed in Table 1. All nine patients presented with signs and symptoms of a URI at a mean of 65 days (range ⫺3 days to ⫹370 days) after receiving the transplant. Four of five patients who had sinus films obtained were documented radiographically to have acute sinusitis. Six patients developed pneumonia a mean of 4 days (range 0 to 6 days) after the onset of symptoms. Four patients initially presented with unilateral infiltrates; however, all six patients eventually developed bilateral pulmonary infiltrates. No patients were documented to have concurrent serious infections pre- or post mortem. Five of the six pneumonias occurred in patients who were early post transplant in the pre-engraftment period. The sixth pneumonia occurred in a patient who was 75 days post transplant and receiving high doses of steroids for presumptive pulmonary BCNU toxicity. In spite of aggressive therapy with aerosolized ribavirin and IVIG, this patient developed respiratory failure necessitating mechanical venTable 1 RSV infections among autologous BMT recipients with breast cancer hospitalized during eight winter seasons from 1992–1993 to 1999–2000 Patients 9

Pneumonia 6 (66%)

Stage of breast cancer Stage III Stage IV

3 6

3 3

0 2 (66%)

Type of transplant PBSC Bone marrow

6 3

4 2

1 (25%) 1 (50%)

Conditioning chemotherapy CVP C/CBT CVP/CBT

1 1 7

1 1 4

0 1 (100%) 1 (25%)

Steroids

1

1

Time s/p BMT: onset of symptoms ⭐30 days ⬎30–100 days ⭓100 days

6 1 2

5 1 0

2 (40%) 0 0

5 4

5 1

2 (40%) 0

Lymphocytes ⭐200 cells/ml ⬎200 cells/ml

6 3

6 0

2 0

Underlying lung disease BCNU toxicity

1

1

0

Nosocomial infection

5

4

Pre-engraftment Post-engraftment

Deaths 2 (33%)

0

2 (50%)

CVP ⫽ cyclophosphamide, etoposide, cisplatin; CBT ⫽ cyclophosphamide, carmustine, thiotepa. No patient received total body irradiation.


tilation. The patient ultimately recovered, and is alive at 2. years of follow-up. Two patients, both of whom were in the pre-engraftment period, died of progressive respiratory failure 20 days and 32 days, respectively, after the onset of respiratory symptoms. An autopsy examination performed on the latter patient, who had received 14 days of antiviral therapy, revealed severe acute and organizing diffuse alveolar lung damage. Immunohistochemical staining for RSV was negative. No other microorganisms were identified pre- or post mortem. All nine patients were treated with the combination of aerosolized ribavirin and IVIG (Table 2). In four patients (one of whom was in the pre-engraftment period, and three of whom were in the post-engraftment period), therapy was initiated at the URI stage and was continued for a mean of 10 days (range 8 to 11 days). The one patient who was in the pre-engraftment period developed pneumonia. All four patients survived. In the other five patients, therapy was initiated at the pneumonia stage and was continued for a mean of 12 days (range 7 to 17 days). Among four patients with pneumonia in whom therapy was initiated at least 24 h before the onset of respiratory failure requiring mechanical ventilation, one died. The fifth patient, who was treated after the onset of respiratory failure, died. Five (63%) infections were acquired nosocomially, two of which were fatal. Four of these nosocomial cases and both fatal cases occurred during the first four winter seasons from 1992–1993 to 1995–1996. There were no nosocomial or fatal cases during the latter four seasons. The diagnostic specimens were: (BAL) and NPW (n ⫽ 4); BAL (n ⫽ 2); BAL and ET aspirate (n ⫽ 1) and NPW (n ⫽ 2). The method of diagnosis was: rapid antigen and culture (n ⫽ 6); rapid RSV antigen only (n ⫽ 2); and culture only (n ⫽ 1). Discussion This study demonstrates that RSV may cause significant morbidity and mortality among patients with breast cancer

undergoing autologous BMT, particularly those who are early post transplant in the pre-engraftment period. In this study, five (2%) of 249 patients who were in the preengraftment period developed RSV infections. All five infections were complicated by pneumonia and two were fatal. The significance of an RSV-associated mortality of 1% can best be appreciated in the light that the overall transplant-related mortality in patients with breast cancer has been reduced to less than 2% in recent years due to advances in the supportive care and the technology of hematopoietic transplantation.20,21 These advances have included minimization of the morbidity and mortality attributable to preventable and treatable infections such as RSV. The results of this study further suggest that patients who are later post transplant with underlying regimen-related pulmonary disease receiving steroids may also be at risk for serious RSV-associated pneumonia. The magnitude of the risk during the later post-transplant period remains to be defined as these patients are cared for primarily by their community-based physicians during the later post-transplant period. In BMT recipients in general, the overall mortality rate associated with RSV pneumonia developing early post transplant before leukocyte engraftment, has been reported to be over 70%.5,6 In this study, the mortality rate among high risk, early post-transplant patients with pneumonia treated aggressively with combination therapy before the onset of respiratory failure was substantially less, namely 25%. The extent to which this favorable outcome reflected the impact of the therapeutic intervention awaits further elucidation in controlled trials. The role of innate immunity and prior myelosuppressive and immunosuppressive therapies in rendering patients with underlying breast cancer more immunologically capable of resolving these infections than patients with underlying hematologic malignancies remains to be clarified. The benefit of combining aerosolized ribavirin with IVIG also remains to be elucidated in controlled trials, as does the benefit of using standard IVIG preparations as compared with antibody preparations containing high titers of RSV Ab (RSV-IVIG (Respigam;

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Table 2 Outcome of RSV infections in nine autologous BMT recipients with breast cancer treated with the combination of aerosolized ribavirin and intravenous immunoglobulin (IVIG)a Stage of respiratory illness when therapy initiated

Patients 9

Pneumonias 6

Upper respiratory illness (URI) Before engraftment After engraftment

4 1 3

1 1 0

Pneumonia Before engraftment After engraftment

5 4 1

5 4 1

2 (40%) 2 (50%) 0

4 1

4 1

1 (25%) 1 (100%)

Earlyb Lateb

Associated deaths 2 (33%) 0 0 0

a Therapy consisted of 6 g of ribavirin aerosolized at a concentration of 20 mg/ml for 18 h a day via a face mask combined with standard IVIG (500 mg/kg every other day) for the duration of therapy. The exception was that two patients received ‘hot lots’ containing an RSV microneutralization Ab titer of 1:2048 to 1:8192 (one patient was treated for a URI during the post-engraftment period; the other patient was treated for pneumonia during the pre-engraftment period; both patients survived). b Early vs late: ⬍ or ⭓ 24 h prior to respiratory failure requiring mechanical ventilation.



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MedImmune Inc, Gaithersburg, MD, USA) or monoclonal RSV Ab (Synagis; MedImmune Inc)). The favorable response rates (ranging from 69% to 81%) reported from several centers in open trials of combination therapy for RSV pneumonia over the last decade are promising, but may in part reflect a growing appreciation of the potential lethality of these infections and a more aggressive approach to identifying and initiating therapy at a less advanced stage of the respiratory illness.6,9,14,17 In conclusion, RSV is a significant cause of life-threatening pneumonia in patients with breast cancer who have received high-dose chemotherapy and who are early post transplant. Infections due to RSV accounted for a significant proportion of the overall transplant-related mortality in these patients, which in recent years has been minimal. As this is a potentially preventable and treatable infection, it is our policy, based on the currently available data, to postpone transplants in patients with RSV-URIs; rigorously enforce hospital infection control measures;37,38 actively pursue the diagnosis; promptly initiate antiviral therapy at the URI stage in high risk patients; and aggressively treat RSV-associated pneumonias with a combination of aerosolized ribavirin and parenteral immunoglobulins. References 1 Englund JA, Sullivan CJ, Jordan C et al. Respiratory syncytial virus infections in immunocompromised adults. Ann Intern Med 1988; 109: 203–208. 2 Ljungman P, Gleaves CA, Meyers JD. Respiratory virus infections in immunocompromised patients. Bone Marrow Transplant 1989; 4: 35–40. 3 Hertz MI, Englund JA, Snover D et al. Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine 1989; 68: 269–281. 4 Whimbey E, Bodey GP. Viral pneumonia in the immunocompromised adult with neoplastic disease: the role of common community respiratory viruses. Semin Respir Infect 1992; 7: 122–131. 5 Harrington RD, Hooton RD, Hackman RC et al. An outbreak of respiratory syncytial virus in a bone marrow transplant center. J Infect Dis 1992; 165: 987–993. 6 Whimbey E, Champlin R, Englund JA et al. Combination therapy with aerosolized ribavirin and intravenous immunoglobulin for respiratory syncytial virus disease in adult bone marrow transplants. Bone Marrow Transplant 1995; 16: 393–399. 7 Whimbey E, Couch R, Englund J et al. Respiratory syncytial virus pneumonia among hospitalized adult patients with leukemia. Clin Infect Dis 1995; 21: 376–379. 8 Whimbey E, Champlin R, Couch R et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22: 778–782. 9 DeVincenzo JP, Leombruno D, Soiffer RJ, Siber GR. Immunotherapy of respiratory syncytial virus pneumonia following bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1051–1056. 10 Whimbey E, Englund JA, Couch RB. Community respiratory virus infections in immunocompromised patients with cancer. Am J Med 1997; 102: 10–18. 11 Bowden RA. Respiratory virus infections after marrow transplant: The Fred Hutchinson Cancer Research Center Experience. Am J Med 1997; 102: 27–30.


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