Viral infections Respiratory syncytial virus infection following ... - Nature

Bone Marrow Transplantation (2002) 29, 321–327  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Viral infections Respiratory syncytial virus infection following hematopoietic stem cell transplantation TN Small1, A Casson1, SF Malak2, F Boulad1, TE Kiehn3, J Stiles3, HM Ushay4 and KA Sepkowitz2 1

Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medicine, Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 3Department of Clinical Laboratories, Microbiology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; and 4Department of Pediatrics, New York Weill Cornell Medical Center, Cornell University, New York, NY, USA 2

Summary: Respiratory syncytial virus, one of the most common causes of respiratory infections in immunocompetent individuals, is frequently spread to recipients of HSCT by family members, other patients, and health care workers. In immunosuppressed individuals, progression from upper respiratory tract disease to pneumonia is common, and usually fatal if left untreated. We performed a retrospective analysis of RSV infections in recipients of autologous or allogeneic transplants. The incidence of RSV following allogeneic or autologous HSCT was 5.7% and 1.5%, respectively. Of the 58 patients with an RSV infection, 16 of 21 patients identified within the first post-transplant month, developed pneumonia. Seventy-two percent of patients received aerosolized ribavirin and/or RSV-IGIV, including 23 of 25 patients diagnosed with RSV pneumonia. In this aggressively treated patient population, three patients died of RSV disease, each following an unrelated HSCT. Bone Marrow Transplantation (2002) 29, 321–327. DOI: 10.1038/sj/bmt/1703365 Keywords: respiratory syncytial virus (RSV); hematopoietic stem cell transplantation

Respiratory syncytial virus (RSV), a single-stranded RNA virus of the Paramyxoviridae family, is one of the most common causes of respiratory infections during childhood (reviewed in Ref. 1). Although most children are infected with RSV by 2 years of age and produce neutralizing antibodies, life-long immunity is not induced.1–5 Re-infection in immunocompetent adults exposed to an RSV-positive child, manifesting primarily as an upper respiratory tract illness, can be as high as 47%.6 Whereas mortality rates in previously healthy infants with RSV pneumonia and/or bronchiolitis are less than 0.5%, approximately 3 to 5% of Correspondence: Dr TN Small, Department of Pediatrics, Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NYC, NY 10021, USA Received 9 August 2001; accepted 1 November 2001

infants with bronchopulmonary dysplasia or congenital heart disease die from RSV-induced lower respiratory tract disease (reviewed in Ref. 7). Transmission of RSV occurs through contact with large particle droplets and/or fomites.1,2,7,8 Nosocomial spread is common, even among immunocompetent individuals. In immunocompromised patients, large hospital outbreaks have been reported,9–12 resulting in mortality rates of 80– 100% in untreated patients with RSV pneumonia.9–13 Following allogeneic HSCT, progression from upper respiratory tract disease (URTD) to lower tract disease occurs in 40–60% of cases.9–12 Although treatment with aerosolized ribavirin and/or intravenous gammaglobulin (IVIG) can prevent pneumonia in approximately 70% of patients with RSV-associated URTD post HSCT, mortality remains high in patients who develop pneumonia despite prophylaxis.12,13 Due to the variable outcome of RSV-associated respiratory infections post HSCT reported in the literature to date,9–14 we conducted a retrospective observational study to determine the incidence of RSV infection among children and adults following allogeneic (related and unrelated) or autologous HSCT performed at the Memorial SloanKettering Cancer Center between 1 January 1994 and 31 December 1999. We also describe the clinical presentation and outcome of pre-transplant and incident RSV-associated respiratory infections among HSCT recipients. Of the 58 patients identified with an RSV upper (n ⫽ 33) or lower respiratory tract infection (n ⫽ 25), 72% received treatment with aerosolized ribavirin and/or RSV-IGIV. In this highly treated population, the only patients who died of RSV pneumonia (n ⫽ 3) were those infected within the first peritransplant month. Materials and methods From 1 January 1994 to 31 December 1999, 550 consecutive patients received an allogeneic hematopoietic stem cell transplant (HSCT) at the Memorial Sloan-Kettering Cancer Center. Two patients had RSV isolated within 3 weeks prior to their transplant and were excluded from the analysis of incidence yielding an allogeneic population of 548 evaluable patients, of whom 154 (28.1%) were children,

RSV infection after HSCT TN Small et al

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defined as patients less than 19 years of age (Table 1). The stem cells for the 548 patients were derived from volunteer unrelated (n ⫽ 153), HLA matched (n ⫽ 338) or HLA mismatched related (n ⫽ 57) donors. The source of stem cells was cord blood (n ⫽ 7), G-CSF-primed T celldepleted peripheral blood stem cells (n ⫽ 46), or bone marrow (n ⫽ 495). Sixty-four percent of the transplants were T cell-depleted (TCD) by soybean agglutination followed by rosetting with sheep red blood cells (SBA⫺ E⫺, n ⫽ 268),15 treatment with the T10B9 monoclonal antibody against the alpha/beta T cell receptor plus complement (n ⫽ 35),16 or CD34-positive selection of G-CSF-mobilized peripheral blood stem cells followed by rosetting with sheep red blood cells (CD34⫹, E⫺ PBSCT, n ⫽ 46).17 Seventy-nine percent of patients received hyperfractionated total body irradiation (1375–1500 cGy) as part of their cytoreduction. Recipients of an unmodified hematopoietic stem cell transplant (HSCT) or a T10B9 TCD unrelated HSCT received cyclosporine A combined with methotrexate or steroids, respectively. Recipients of an SBA⫺ E⫺ HSCT or CD34⫹ E⫺ TCD PBSCT did not receive any post-transplant immunosuppression to prevent GVHD. Eighty-three percent of the patients received an allogeneic stem cell transplant for a hematologic malignancy, while the remainder were transplanted for bone marrow failure, primary immunodeficiency, or hemoglobinopathy (Table 1). One patient received an allogeneic HSCT for the treatment of metastatic rhabdomyosarcoma. During the same time interval (1994–1999), 396 autologous transplants were performed at this center for the treat-

32.0 (16.4)

⭐0.001

373 (94.7) 127 (82.5)

1 3.29 (1.92, 5.64)

196 (92.0) 304 (90.7)

1 1.16 (0.66, 2.04)

Statistical methods

136 234 41 8 58

1.10 1.26 1 1.63 1.16

No. (%) of patients

Age, years: mean (s.d.) 20.3 (16.7) Age Adult 21 (5.3) Pediatric 27 (17.5) Sex Female 17 (8.0) Male 31 (9.3) Underlying disease CML, CLL 11 (7.5) Acute leukemia 22 (8.6) Lymphoma 3 (6.8) Multiple myeloma 1 (11.1) Aplastic anemia, 5 (7.9) MDS, Sickle cell disease, 2 (18.1) Thal SCID, Wiskott Aldrich 3 (20.0) Other 1 (33.3) Underlying disease Hem. malignancy 37 (8.1) Other 11 (12.0) Donor type Matched related 25 (7.4) Mismatched related 7 (12.5) Unrelated 16 (10.4)

Bone Marrow Transplantation

Laboratory methods Nasopharyngeal swabs were placed into the Micro Test M4RT Transport System (Micro Test, Lilburn, GA, USA), and nasopharyngeal washes, bronchial alveolar lavages, sputum, and tissue were placed into sterile containers, and immediately transported to the Microbiology Laboratory. RSV was detected in specimens by direct methods that included the direct fluorescent antibody test (DFA) (Bartels, Issaquah, WA, USA), and the RSV TestPack enzyme immunoassay (EIA) (Abbott Laboratories, Chicago, IL, USA). Nasopharyngeal specimens were deemed adequate for DFA testing if there were 20 or more epithelial cells per slide. Shell vial assays included vials containing MRC5 cells (BioWhittaker, Walkersville, MD, USA) incubated for 2 and 5 days, prior to staining with the DFA reagent. Conventional tube cultures, containing rhesus monkey kidney cells, were observed for 2 weeks for cytopathic effect (CPE). Tubes with positive CPE were confirmed as positive for RSV with the Bartels Viral Respiratory Screening and Identification Kit (Bartels).

Table 1 Characteristics of allogeneic HSCT patients with and without RSV infection

With RSV (n ⫽ 48)

ment of stage IV neuroblastoma, Hodgkin’s disease, multiple myeloma, or a central nervous system tumor. Of these, two patients developed RSV disease during pre-transplant cytoreduction and were excluded from the analysis of incidence, yielding a population of 394 evaluable autologous HSCT recipients. The medical records of the HSCT patients, including all microbiology and pathology reports to 1 April 2001 were reviewed to determine the presence or absence of RSV detected by direct methods, shell vial assay, and/or conventional culture. Fifty recipients of an allogeneic transplant, including two pre-transplant, and eight recipients of an autologous HSCT, including two pre-transplant, were identified. Pertinent clinical information was derived by a systematic chart review of all patients receiving a HSCT who developed RSV. Isolated upper respiratory tract disease secondary to RSV was defined as rhinorrhea, cough, and/or pharyngitis with a normal or stable chest radiograph. RSV pneumonia was defined as an acute respiratory illness with rales, rhonchi, and/or wheezing in the setting of new pulmonary infiltrates on chest radiograph.

P or RR (CI95%)

Without RSV (n ⫽ 500)

(92.5) (91.4) (93.2) (88.9) (92.1)

(0.32, 3.76) (0.39, 4.03) (0.19, 13.94) (0.29, 4.62)

9 (81.8)

2.67 (0.51, 14.06)

12 (80.0) 2 (66.7)

2.93 (0.66, 13.00) 4.89 (0.70, 33.94)

419 (91.9) 81 (88.0)

1 1.47 (0.78, 2.78)

313 (92.6) 49 (87.5) 138 (89.6)

1 1.69 (0.77, 3.72) 1.40 (0.77, 2.55)

Statistical analysis was performed using the SPSS, version 10.0 (SPSS, Chicago, IL, USA). To assess associations between continuous variables and the outcome variable, the t-test and Mann–Whitney U test were used. The chi-square test was used to examine associations between categorical variables. Relative risks were used to evaluate the association between RSV infection and other variables, as were odds ratios to evaluate associations between type of RSV infection (URTD vs LRTD) and other variables. Statistical significance was defined as P ⭐ 0.05. To calculate the incidence of RSV infection over time, the observation period (January 1994 to April 2001) was divided into 4-month intervals, grouping November to February, March to June, and July to September. The population at risk during each time period was determined by


assessing the number of HSCT recipients alive and free from infection during each period. The Kaplan–Meier technique was used to assess the time free from RSV infection between adult and pediatric patients. Follow-up for this analysis began with each patient’s HSCT date, and the endpoint of interest was the development of an RSV infection occurring after the HSCT date. If no RSV infection occurred, the follow-up time was censored at either the date of death or the final day of follow-up (1 April 2001), whichever was sooner. Differences between mean time free from infection in adults and children were assessed using the log-rank test.

The incidence of RSV was similar among males (31/335, 9.3%) and females (17/213, 8.0%), P ⬍ 0.61). RSV infection was less common among patients who had a matched related donor (25/338, 7.4%) compared to those whose donor was mis-matched related (7/56, 12.5%), or unrelated 16/154, 10.4%), yet these differences were not statistically significant, P ⬍ 0.32). RSV was first isolated from the respiratory tract at a median of 4.1 months (range, 0.03–33.33) post transplant. When compared to adults, time free from RSV infection for children was significantly shorter post HSCT (mean 70.7 vs 80.3 months, P ⬍ 0.001; Figure 1).

Results

Clinical presentation and outcome of RSV among HSCT recipients

Incidence of RSV among HSCT recipients

Upper respiratory tract disease: Thirty-three (57%) patients with a positive RSV assay had an isolated upper respiratory infection, of whom 28 had an absolute neutrophil count of ⬎500 cells/␮l. All were incidence cases of RSV (31 allogeneic, two autologous). In none of these patients was an additional respiratory pathogen isolated. In 11 patients, the DFA, shell vial assay, and culture were all positive. The remaining patients were diagnosed by DFA alone (n ⫽ 3), DFA plus shell vial assay (n ⫽ 7), DFA and culture (n ⫽ 4), shell vial assay plus culture (n ⫽ 2), culture (n ⫽ 4) or EIA alone (n ⫽ 1). Thirteen afebrile patients with mild upper respiratory symptoms were not given anti-viral therapy (Table 2). Ninety-two percent of these patients received stem cells from an HLA matched sibling. Patients who received a matched related transplant were significantly less likely to receive treatment than those patients whose transplant was from a mismatched related (RR ⫽ 3.40, 95% CI, 1.63– 7.10) or unrelated donor (RR ⫽ 3.02, 95% CI, 1.4–6.54). In untreated patients, RSV was initially identified a median of 5.0 months (range 0.1–33.3 months) post transplant, with 12 (92%) of 13 patients diagnosed longer than 1.5 months post transplant. In nine untreated patients with follow-up cultures, RSV shedding resolved by a median of 7 days

From 1 January 1994 to 1 April 2001, 54 recipients of an HSCT had a positive RSV assay following transplant, an incidence of 5.7% (95% confidence interval (CI), 4.2% to 7.3%). Forty-eight cases of RSV infection were identified following an allogeneic HSCT, representing an incidence of 8.8% (95% CI, 6.3% to 11.2%). RSV infection occurred in six of 394 patients following an autologous transplant, 1.5% (95% CI, 0.3% to 2.8%). RSV was isolated from the nasopharynx (NP) alone (n ⫽ 36), bronchial alveolar lavage ⫾ NP (n ⫽ 13), sputum (n ⫽ 4) or lung at autopsy (n ⫽ 1). Only one patient had an additional respiratory pathogen (influenza A) isolated at the time of initial RSV positive assay. In the four cases of RSV infection identified pretransplant, RSV was isolated from the BAL and NP (n ⫽ 3) or nasopharynx alone (n ⫽ 1). RSV among allogeneic HSCT recipients Among the 48 patients who had an RSV infection following an allogeneic transplant, the grafts were derived from an unrelated (n ⫽ 16), HLA-matched (n ⫽ 25) or HLA mismatched related (n ⫽ 7) donor. From one to eight patients with an RSV-positive respiratory sample were identified in each of the years of study, except 1997, during which time 15 RSV-positive patients were identified. Since the winter of 1997, a nasal culture to identify respiratory viral pathogens has been performed on all transplant patients with any symptoms of coryza, sneezing, sore throat, or other upper respiratory complaints. Thirty-eight (79%) of RSV cases occurred during the winter months, November to February, with an average incidence of 2.9%, ranging from a high of 6.6% and a low of 0.0%. The mean age of patients who developed an RSV infection following allogeneic HSCT was significantly less than those without RSV (20.3 vs 32.0, P ⬍ 0.001). Children were more likely to develop RSV than adults (17.5% vs 5.3%) (relative risk (RR) ⫽ 3.29, 95% CI, 1.92–5.64). The association between RSV infection and whether or not a patient was a child persists among patients with or without severe combined immunodeficiency disease (SCID). There were no significant age differences between children with and without RSV disease (mean age 7.7 vs 9.8, P ⬍ 0.13), or adults with or without RSV infection (mean age, 36.5 vs 39.5, P ⬍ 0.21).

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Figure 1 Kaplan–Meier plot of RSV infection in children and adults following hematopoietic stem cell transplantation. Graph depicts proportion of patients without RSV infection. Bone Marrow Transplantation


324

Table 2

Treatment of RSV infection among allogeneic HSCT patients Upper Respiratory Tract Disease No. (%) of patients Treated (n ⫽ 18)

Median onset of RSV post HSCT, months Donor type Matched related Mismatched related Unrelated Mortality Treatment Ribavirin, RespiGam Ribavirin, IV gammaglobulin IV gammaglobulin RespiGam Ribavirin, RespiGam, IV gammaglobulin

4.1 5 (29.4) 5 (100.0) 8 (88.9)

P ⬍ 0.18

12 (70.6) 0 (0.0) 1 (11.1)

1 3.40 (1.63, 7.10) 3.02 (1.40, 6.54)

0 (0)

6 (33.3) 3 (16.7) 3 (16.7) 6 (33.3) —

— — — — —

Lower tract disease: Twenty-five patients (43.1%) had evidence of lower respiratory tract disease which by our definition required new pulmonary infiltrates (4 pre-transplant cases – 2 autologous, 2 allogeneic; 21 incident cases – 4 autologous, 17 allogeneic). Only half of the patients who developed RSV pneumonia had a neutrophil count of ⬎500 cells/␮l. In one of the 25 patients with RSV pneumonia, a co-pathogen, influenza A, was also isolated. In 20 (83%) of 24 patients diagnosed with RSV pneumonia antemortem, the DFA, shell vial assay, and culture were all positive for RSV. In the remaining four patients, RSV was diagnosed by positive shell vial assay and culture (n ⫽ 2) or positive DFA and shell vial assay (n ⫽ 2). RSV pneumonia was diagnosed in 16 (76%) of the 21 patients whose initial RSV positive assay occurred less than 1 month post transplant. Twelve (75%) of these 16 patients

No. (%) of patients Treated (n ⫽ 16)

5.0

(range 3–16 days). None of the untreated patients developed subsequent lower tract disease. Twenty of 33 patients with URTD and a positive RSV assay received treatment, including five patients diagnosed within the first month of transplant. RSV was first isolated from treated patients a median of 4.5 months (range 0.2– 12.2 months) post transplant. Of those treated, 11 (55%) received aerosolized ribavirin, alone (n ⫽ 2), or with intravenous gammaglobulin (n ⫽ 9) (conventional IVIG, n ⫽ 3 or RSV-IVIG (RespiGam, Medimmune, Gaithersburg, MD, USA, n ⫽ 6). The nine remaining treated patients received gammaglobulin alone. In 17 (85%) of the 20 patients who received treatment, sequential follow-up cultures were performed. In those 17 patients, RSV shedding resolved at a median of 10 days (range 3–30 days). The most prolonged shedding was observed in three patients with SCID who developed RSV URTD following a T cell-depleted haploidentical parental BMT. None of the treated patients progressed to RSV pneumonia.


P or RR (CI95%)

Untreated (n ⫽ 13)

0 (0)

Lower Respiratory Tract Disease P or RR (CI95%)

Untreated (n ⫽ 1) 0.43

P ⬍ 0.36

8 (100.0) 2 (100.0) 6 (85.7)

0 (0) 0 (0) 1 (14.3)

1 — 0.86 (0.63, 1.16)

2 (12.5)

1 (100.0)

P ⬍ 0.16

1.35

11 (68.8) 3 (18.8) 1 (6.3) — 1 (6.3)

— — — —

developed RSV pneumonia prior to engraftment, when their neutrophil count was less than 500 cells/␮l. In sharp contrast, only nine (24%) of 37 patients who developed RSV infection longer than 1 month post transplant developed pneumonia (RR ⫽ 2.21, 95% CI 1.11–4.42, P ⬍ 0.05). Six of the latter nine patients received a transplant from an unrelated (n ⫽ 5) or mismatched related (n ⫽ 1) donor. All but one patient with RSV pneumonia diagnosed antemortem received therapy with aerosolized ribavirin. This was a patient diagnosed 15 months following an unmodified HLA matched sibling BMT who received treatment with alternate day intravenous gammaglobulin (400 mg/kg/dose) for seven doses. Of the remaining 23 patients, all received aerosolized ribavirin (6 g over 18 h), combined with RSV-IGIV (n ⫽ 19) or conventional IVIG (n ⫽ 4). Conventional IVIG was given due to lack of availability of RSV-IGIV. A median of nine doses (range 2–27) of aerosolized ribavirin and two doses (range 1–5) of RespiGam were given to patients with RSV pneumonia transplanted for malignancy. Six patients received less than 7 days of aerosolized ribavirin due to early death (n ⫽ 1), or intolerance (n ⫽ 5). Three children with SCID who developed RSV pneumonia following a TCD HLA mismatched parental HSCT received prolonged therapy with aerosolized ribavirin, consisting of 27, 34 and 80 doses, respectively, in addition to monthly RespiGam. Of note, only 50% of patients who developed RSV pneumonia reported or were diagnosed with an antecedent URI. Twenty-one (84%) of 25 patients with RSV pneumonia required supplemental oxygen and six required mechanical ventilation. Of these, two were subsequently extubated. Features of both groups (Table 3) The differences in symptoms associated with upper respiratory tract or lower respiratory tract involvement are illustrated in Figure 2. Rhinorrhea (94%) and cough (66%) were common in patients with an RSV-associated URTD. Fever


325

Table 3 Comparison of patients with URTD and LRTD due to RSV infection among HSCT recipients No. (%) of patients

P or OR (CI95%)

LRTD URTD (n ⫽ 25) (n ⫽ 33) Age, years: mean (s.d.) Age Adult Pediatric Sex Female Male Underlying disease Chronic leukemia Acute leukemia Lymphoma Multiple myeloma Aplastic anemia/ Myelodysplastic syndrome Sickle cell disease, thalassemia SCID, WAS BT NB Other Donor type Matched related Mismatched related Unrelated Autologous Median onset of RSV post HSCT, months Resolution of RSV shedding, days Outcome of RSV infection Mortality Resolution Treated Yes No Treatment Ribavirin Ribavirin, RespiGam Ribavirin, IV gammaglobulin Ribavirin, RespiGam, IV gammaglobulin RespiGam IV Gammaglobulin

15.4 ⬍0.05 (16.3)

26.2 (16.5)

14 (56.0) 11 (44.0) 2.55 (0.77, 8.60) 11 (33.3) 22 (66.7) 1 10 (55.6) 8 (44.4) 2.08 (0.59, 7.51) 15 (37.5) 25 (62.5) 1 3 9 2 2 2

(25.0) 9 (75.0) 1 (40.9) 13 (59.1) 2.08 (0.36, 14.97) (66.7) 1 (33.3) 6.0 (0.20, 392.24) (66.7) 1 (33.3) 6.0 (0.20, 392.24) (40.0) 3 (60.0) 2.0 (0.11, 28.38)

1 (50.0)

1 (50.0)

3 2 1 0

2 1 1 1

(60.0) (66.7) (50.0) (0.00)

0.33 (0.00, 34.82)

(40.0) 4.5 (0.31, (33.3) 6.0 (0.20, (50.0) 0.33 (0.00, (100.0) 0.0 (0.00,

73.21) 392.24) 34.82) 130.0)

8 (33.3) 16 (66.7) 1 4 (40.0) 6 (60.0) 1.33 (0.21, 7.67) 7 (43.8) 9 (56.3) 1.56 (0.35, 6.89) 6 (75.0) 2 (25.0) 6.0 (0.78, 69.63) 0.6 4.8 ⬍0.01 13.5

8.5

3 (12.0) 0. (0.0) 22 (88.0) 33 (100.0)

0.06 0.07

24 (96.0) 20 (60.6) ⬍0.01 1 (4.0) 13 (39.4) 0 (0.0) 17 (70.8) 5 (20.8)

2 (10.0) 6 (30.0) 3 (15.0)

1 (4.2)

0 (0.0)

0 (0.0) 1 (4.2)

6 (30.0) 3 (15.0)

was seen in only 15% of patients with an URTD compared to 69% of those with RSV pneumonia. Aerosolized ribavirin was initiated a median of 1 day (range 0–17) following initial isolation of RSV from the respiratory tract. Twenty-three (77%) of 30 patients who received ribavirin started therapy within 2 days of isolation of RSV. Overall, a median of 2 (range 1–8) doses of RespiGam were infused at a dose of 750–1500 mg/kg. Despite this therapy, persistent viral shedding was observed in the majority of patients for ⬎1 week, and in 14 patients for ⬎2 weeks. Despite prolonged viral shedding (⬎2 months), full recovery without sequelae was observed in all five patients with SCID. In three (12%) of 25 patients who developed RSV pneu-

Figure 2 Comparison of signs and symptoms in patients with isolated RSV upper respiratory tract infection (open square) vs lower respiratory tract disease (closed squares).

monia, the primary cause of death was RSV disease, confirmed by autopsy in two. Deaths from RSV occurred in three unrelated transplant recipients at 0, 9 and 28 days after its initial isolation. Among the three fatal RSV cases, one patient was diagnosed at autopsy, precluding therapy. The other two patients with fatal RSV pneumonia received aerosolized ribavirin for 2 or 7 days, respectively prior to their deaths, with (n ⫽ 1) or without (n ⫽ 1) concomitant RSV-IGIV. Of the remaining 22 patients diagnosed with RSV pneumonia, nine are alive and well a median of 56.7 months (range 14.7–82.5) post infection. Six patients died of a subsequent infection associated with Aspergillus (n ⫽ 2), CMV (n ⫽ 1), EBV (n ⫽ 1) or bacterial sepsis (n ⫽ 2). The remaining patients died of graft failure (n ⫽ 2), recurrent malignancy (n ⫽ 2), multi-organ failure of unknown etiology despite autopsy (n ⫽ 1), or renal failure (n ⫽ 1). None of the five recipients of a mismatched parental transplant for SCID, three of whom had RSV pneumonia, died of respiratory complications. Discussion This paper examines the outcome of a large number of patients with RSV-associated respiratory tract disease following HSCT. Initial studies describing the outcome of RSV disease reported an 80–100% mortality rate in untreated patients with RSV pneumonia or those who received treatment after the onset of respiratory failure,9–13 compared to 22% in patients treated early with aerosolized ribavirin and intravenous gammaglobulin selected for high titers of neutralizing antibodies against RSV.10 In contrast, systemic therapy with intravenous ribavirin has not been efficacious.12,18 Although treatment of patients with URTD has been associated with improved outcome, mortality rates as high as 50% have been observed in those who progress to pneumonia despite treatment with aerosolized ribavirin and gammaglobulin.12,13 In this study, three of 25 patients diagnosed with RSV pneumonia died of RSV disease, one in the absence of therBone Marrow Transplantation


326

apy. Of the 16 patients in our study treated with aerosolized ribavirin and RespiGam, only one patient died of RSV pneumonia. This patient died on the second day of ribavirin therapy. Similar results were reported by DeVincenzo et al19 who treated 10 children with RSV pneumonia with RSV-IG (750–1500 mg/kg/dose) and aerosolized ribavirin. The one death in this latter series occurred in a patient with SCID who died 41 days following a mismatched parental transplant. Of 11 children with SCID and RSV pneumonia including three from this study, five reported by DeVincenzo et al,19 and three by Crooks et al,20 each of whom received aerosolized ribavirin and RespiGam, nine children survive, despite having been transplanted from a mismatched parental donor and having received myeloablative cytoreduction. The highest mortality rate in our series, like those of others, remains in patients infected with RSV within the first month of transplant, generally prior to engraftment.9–13 Unlike the outcome in the autologous transplant patients14 reported by Anaissie and colleagues, five of the six autologous transplant recipients in our series diagnosed with an RSV URI in the early transplant period, developed pneumonia, which required mechanical ventilation in three. Although all five patients ultimately cleared the virus, two patients died of respiratory failure 29 and 45 days, respectively, post transplant. A limitation due to the retrospective nature of this study is that patients with RSV infection may have gone undetected resulting in an underestimation of the true incidence. Nevertheless, the 5.7% incidence found in this series is strikingly similar to the 6.3% incidence reported by McCarthy et al18 in 336 allogeneic BMT recipients, and of those RSV patients identified, the clinical presentation, treatment, and outcome are known. We found a substantially lower mortality rate for RSV pneumonia in this population than that previously described from other centers, possibly due to our aggressive treatment approach which has been publicized due to the disturbingly high mortality rates at other centers. In the 11 patients with RSV pneumonia which developed prior to engraftment, early treatment with aerosolized ribavirin and RSV-IG was associated with a 9% mortality rate, compared to 25–60% in other studies which employed different therapy. In addition, we found that RSV developing more than 1 month post transplant, in the absence of fever or lower respiratory tract symptoms, is associated with an extremely low morbidity and mortality (0%) even among those who receive no therapy. Our data demonstrate that recipients of unrelated or mismatched related transplants who develop RSV pneumonia more than 1 month post HSCT can be successfully treated, despite the presence of hypoxemia. Khushalani and colleagues21 have also reported the successful treatment of three adult patients with hypoxia and extensive pulmonary disease due to RSV, with aerosolized ribavirin and conventional intravenous gammaglobulin. The optimal therapy for this transplant group will require prospective randomized trials. Randomized trials designed to prevent pneumonia in patients who develop an RSV URI less than 1 month post transplant remain difficult due to the rapidity of progression to lower respiratory tract disease and the high mortality rate still observed in this population.


Acknowledgements This work was supported by PO1 CA23766 from the National Cancer Institute, National Institute of Health.

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