OBJECTIVE. We sought to determine the epidemiologic features of respiratory syncytial virus infection in immunocompromised pediatric patients and to identify the risk factors for severe disease.
METHODS. We designed a retrospective study examining the experience with respiratory syncytial virus infection in pediatric patients with underlying malignancies and hematopoietic stem cell transplant recipients seen between 1997 and 2005. Clinical and laboratory data were extracted from patient records, and independent predictors of disease severity were investigated.
RESULTS. Fifty-eight patients met the study criteria. Twenty-three patients (40%) had underlying diagnoses of acute lymphoblastic leukemia, 11 (19%) had solid tumors, and 24 (41%) were hematopoietic stem cell transplant recipients, had acute myeloid leukemia, or had severe combined immunodeficiency syndrome. Seventeen patients (29%) were <2 years of age. Overall, 16 patients (28%) developed lower respiratory tract infections. The frequency of lower respiratory tract infections was highest in patients with hematopoietic stem cell transplants, acute myeloid leukemia, or severe combined immunodeficiency syndrome (42%). Independent predictors of lower respiratory tract infections were profound lymphopenia, with absolute lymphocyte counts of <100 cells per mm3, and age of ≤2 years. Of all patients with lower respiratory tract infections, 31% died as a result of respiratory syncytial virus infection. The overall mortality rate was low (5 of 58 patients; 8.6%). All deaths occurred in patients with lower respiratory tract infections who were before or after hematopoietic stem cell transplants or were <2 years of age and receiving treatment for acute myeloid leukemia. Neutropenia was not a predictor of respiratory syncytial virus lower respiratory tract infection or death.
CONCLUSIONS. This study identified profound lymphopenia and young age as independent predictors of respiratory syncytial virus-related lower respiratory tract infections in immunocompromised children. No association between neutropenia and respiratory syncytial virus-related morbidity or death was found. These findings can guide interventions for respiratory syncytial virus infection in high risk hosts.
Respiratory syncytial virus (RSV) is a common cause of respiratory infections in children. RSV is a significant cause of morbidity in previously healthy infants, but disease generally is more severe and often is fatal in immunosuppressed patients.1–4 In immunocompetent and immunocompromised patient populations, upper respiratory tract infections (URTIs) frequently progress to involve the lungs, causing pneumonia. Progression to lower respiratory tract infections (LRTIs) is more common during periods of severe immunosuppression, in children receiving chemotherapy, and in recipients of stem cell transplants.5–7 Although there is some literature that describes the natural history of RSV infection in adults with cancer, with up to 60% of subjects developing LRTIs and with mortality rates associated with RSV LRTIs being between 50% and 100%,5,7–9 the epidemiologic features and clinical course of RSV disease in immunocompromised children are less well characterized. Given this paucity of literature reports, the aggressive course of RSV disease in immunocompromised hosts, and the absence of an ongoing, prospective, clinical study addressing this topic, we designed a retrospective analysis of the course of RSV infection in pediatric oncology patients, to identify the predictors of RSV-related morbidity and death.
Patients were identified by reviewing records maintained by the virology laboratory at St Jude Children's Research Hospital. Patients <21 years of age with neoplasias, hematologic disorders, immunodeficiency syndromes, or hematopoietic stem cell transplants (HSCTs) who had positive RSV test results (culture and/or direct fluorescent antibody [DFA]) for ≥1 respiratory specimen between January 1997 and April 2005 (8 successive RSV winter seasons) were evaluated. Viral diagnostic tests were not performed routinely for asymptomatic patients. One investigator (Dr El Saleeby) reviewed all patients' charts and extracted the patient information. Data collected included patients' demographic features and clinical, laboratory, and radiologic information near the time of diagnosis of RSV infection. Completed data collection sheets were then reviewed with the senior author (Dr Gaur), to ensure that study-related definitions were being applied. The study was conducted with the approval of the St Jude Children's Research Hospital institutional review board.
RSV disease location was classified as either URTI only or LRTI. This classification was mutually exclusive (ie, patients with both URTI and LRTI were analyzed only in the LRTI group). LRTI was defined as crackles, hypoxia, tachypnea, or apnea and/or radiographic evidence of pneumonia (infiltrates or consolidation). All other patients were defined as having URTI only. For the purposes of this study, clinical signs such as wheezing or cough or radiologic signs such as peribronchial thickening, atelectasis, or pleural effusion alone did not fulfill the criteria for LRTI.
Patients were dichotomized according to age as younger or older than 2 years. Because of differences in degrees of immunosuppression, patients were grouped a priori, according to diagnosis, into 3 mutually exclusive categories, namely, patients with acute lymphoblastic leukemia (ALL), patients with solid tumors, and patients with HSCT/acute myeloid leukemia (AML)/severe combined immunodeficiency syndrome (SCIDS). The latter category included patients who were diagnosed as having RSV during conditioning for HSCT and up to 24 months after HSCT, regardless of their underlying diagnosis. Although dissimilar in pathophysiologic features and primary treatments, patients with HSCT, AML, or SCIDS were combined in 1 subgroup. This categorization was performed before analyses were conducted, on the basis of the significant degree of lymphocyte immunosuppression associated with HSCT and the highly cytotoxic agents used for AML treatment.10–12
Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) at the time of RSV diagnosis were documented. Neutropenia was defined as ANC of ≤500 cells per mm3 and profound neutropenia as ANC of ≤100 cells per mm3. Lymphopenia was defined as ALC of ≤300 cells per mm3 and profound lymphopenia as ALC of ≤100 cells per mm3. An infection was considered nosocomially acquired if the onset of respiratory tract symptoms occurred ≥8 days after hospitalization.
Descriptive statistics were used to characterize the study population. To identify the predictors of RSV-related morbidity and death, 2 disease severity measures were identified as outcome variables, namely, LRTI and death. These variables were chosen for their pathophysiologic and clinical relevance, as well as ease of characterization.
The independent variables tested in the predictive models were selected on the basis of previous association with disease severity and biological plausibility. First, univariate analyses and simple association studies were used to test the associations of the independent variables with both disease severity markers. Univariate analyses included χ2 tests and Fisher's exact tests for dichotomous variables, t tests for continuous variables, and correlation studies to test for collinearity. Second, statistical models were built by using multivariate logistic regression analysis, including all independent variables found to be associated (P < .1) with the outcome variables in the univariate analyses. Odds ratios (ORs) were calculated by using univariate and multivariate analyses. Predictor variables were considered significant when their respective multivariate OR 95% confidence intervals (CIs) did not include 1. Goodness-of-fit diagnostics were applied to the final 2 models to demonstrate that these models adequately fit the data and that no significant predictor of outcomes had been left untested. Statistical analyses were performed by using the SAS 9 software package (SAS Institute, Cary, NC). Significance tests were all 2-tailed (P < .05).
A total of 58 patients met the inclusion criteria during the study period (1997–2005). Twenty-one (36.2%) of 58 patients had positive DFA test results and negative culture results, and 6 (10.3%) of 58 patients had positive culture results and negative DFA test results.
Epidemiologic Features and Clinical Presentation
As expected, most cases (54 of 58 cases) were diagnosed between October and March of each year (Fig 1). A few sporadic cases were documented during the rest of the year. Nosocomially acquired infections were not clustered over time (Fig 1), inpatient location, or primary care team (data not shown). Twenty-three patients (39.7%) had an underlying diagnosis of ALL, 11 (19%) solid tumors, and 24 (41.4%) HSCT/AML/SCIDS (Fig 2). Other characteristics of the study population are shown in Table 1. The youngest subject had SCIDS and was diagnosed as having RSV at 30 days of age. There were more male patients than female patients, and the study population was predominantly white, reflecting the ethnic distribution of patients treated at this institution.
Cough and rhinitis were the most common symptoms present at the onset of respiratory disease (86% and 78% of cases, respectively). Congestion (33%), fever (29%), and wheezing (7%) were less common. At the time of laboratory diagnosis of RSV, cough (93%) and rhinitis (84%) remained the most common symptoms, followed by fever, which was noted in 60% of cases. Overall, the mean time between symptom onset and laboratory diagnosis was 3.0 days (median: 2.0 days; range: 0–17 days). Most cases were diagnosed promptly (93% within 1 week after onset of symptoms).
Laboratory and Radiologic Data
At the time of laboratory diagnosis of RSV, the median ANC was 1428 cells per mm3 (range: 0–5000 cells per mm3) and the median ALC was 529 cells per mm3 (range: 0–5040 cells per mm3); 27.6% of patients had neutropenia (ANC of ≤500 cells per mm3), and 17.2% had profound lymphopenia (ALC of ≤100 cells per mm3). Chest imaging was performed for 82.7% patients; abnormalities were seen in approximately one half of those studies. Peribronchial thickening was noted in 13 cases (27%), interstitial infiltrates in 11 (23%), hyperaeration in 6 (13%), and atelectasis and consolidation in 5 (10%).
Clinical Courses and Outcomes
Patients were grouped under URTI only or LRTI by following the clinical and radiologic definitions outlined. At some point during their clinical course, 16 patients (27.6%) met the study criteria for LRTI. All of the patients with LRTI had some preceding symptoms of URTI except for 4 subjects who presented with concurrent symptoms of URTI and LRTI. None of the patients had LRTI only.
Thirty-six percent of the patients were hospitalized (median length of RSV-related hospital stay: 7 days; range: 3–51 days); 13 (22%) required oxygen therapy and 5 (9%) mechanical ventilation. Overall, 25 patients (43%) received some form of antiviral treatment. Ten patients received intravenously administered immunoglobulin, 13 received RSV immunoglobulin, 9 received ribavirin, and 14 received therapeutic palivizumab (25–30 mg/kg per dose, administered intravenously). Three patients received RSV immunoglobulin, ribavirin, and palivizumab; 3 received ribavirin plus palivizumab; 2 received RSV immunoglobulin plus palivizumab; 6 received palivizumab alone (including 2 who also received intravenously administered immunoglobulin); 3 received ribavirin alone (including 1 who also received intravenously administered immunoglobulin); and 8 received RSV immunoglobulin alone. Overall, patients who were severely ill and more immunocompromised received more-aggressive treatment. Because of the heterogeneity of these therapies and the variations in their timing, in relation to the onset of LRTI, the impact of treatment on outcomes could not be statistically ascertained.
Copathogens were identified for only 4 (6.9%) of 58 patients. These included Aspergillus spp (1 patient), parainfluenza virus (2 patients), and both Aspergillus spp and parainfluenza virus (1 patient). Of the mechanically ventilated patients, 80% (4 of 5 patients) died. Overall, 5 patients died (8.6% of all patients and 31% of patients with LRTIs). All deaths involved patients with disease of the lower respiratory tract clinically consistent with RSV. Information on these patients is provided in Table 2.
Predictors of RSV LRTI
Forty-two percent of patients with HSCT/AML/SCIDS, 36.4% with solid tumors, and only 2 (8.7%) of 23 with ALL developed LRTIs (P = .03) (Fig 2 and Table 3). Disease severity also varied according to age group. Although only 6 (14.6%) of 41 subjects >2 years of age had LRTIs, a significantly larger proportion of patients ≤2 years of age (58.8%) had LRTIs (P < .001). In addition, profound lymphopenia (ALC of <100 cells per mm3) at the time of RSV diagnosis was a significant predictor of LRTI, with 60% of lymphopenic patients developing LRTIs, in contrast to 20.8% of those who were not lymphopenic (P = .01). In this univariate analysis, factors found to be significantly associated with RSV LRTI were age of ≤2 years, underlying diagnosis, nosocomial infection, and profound lymphopenia (Table 3). There was no association between neutropenia and RSV LRTI.
In the multivariate analyses, the dichotomous variables of age and profound lymphopenia at RSV diagnosis were found to be independent predictors of the development of LRTI, with ORs of 9.84 (95% CI: 1.95–49.8) and 7.17 (95% CI: 1.17–44.03), respectively (Table 3). Although it was significant in the univariate analysis and trended toward significance in the multivariate analysis, underlying diagnosis was not found to be a significant predictor of LRTI in the final model. Because of the lack of biological plausibility and the likelihood of nosocomial acquisition being a marker of acquiring RSV infection during a more-vulnerable period (ie, hospitalization for some other illness), nosocomial acquisition was not included in the final multivariate model.
Predictors of Death
Factors associated with death were also analyzed. In the univariate analysis, younger age (≤2 years) and profound lymphopenia at the time of RSV diagnosis showed a significant association with death (Table 4). Only 1 patient >2 years of age died. In addition, deaths were seen only in the group of patients with LRTIs who had an underlying diagnosis of HSCT/AML/SCIDS (Fig 2). Such a skewed distribution of deaths precluded the calculation of ORs for these variables. Details of the subjects who did not survive the infection are outlined in Table 2. Small sample size and uncommon occurrence of this outcome variable precluded further examination of the factors associated with death by using a multivariate approach.
This study was designed to describe the epidemiologic features and clinical course of RSV disease in children with cancer and to identify predictors of severe RSV-related morbidity and death in this population. Describing the largest cohort of pediatric patients with cancer with RSV infection, we found that patients <2 years of age and those with profound lymphopenia were at increased risk of developing RSV LRTI. Interestingly, no association between neutropenia and LRTI was found. Although the overall mortality rate was low (8%), deaths occurred exclusively in the HSCT/AML/SCIDS patient group, specifically those who were before or after HSCT or were young and receiving treatment for AML. These patients were all severely immunocompromised as a result of their underlying disease, intensive chemotherapy, or HSCT.
The majority of cases in this study followed the RSV seasonality for immunocompetent hosts described for temperate regions of the Northern Hemisphere, with infections occurring between October and March. The few cases identified between April and September (all culture positive) highlight the importance of considering RSV as a possible cause of respiratory infections in immunodeficient hosts at any time of the year. Because of the relatively greater chance of a false-positive DFA result when the test is performed outside the usual RSV season, culture confirmation is desirable.
Cough and rhinitis were the most common initial clinical symptoms. Although these symptoms remained common at the time of laboratory diagnosis of RSV infection, more patients were febrile at that point (60% febrile), compared with the time of onset of clinical symptoms (30% febrile). Although wheezing is a very common finding for children hospitalized with RSV, only 7% of patients in our study had documented wheezing at the onset of their respiratory disease and 17% at any time during their illness. It is unlikely that lack of elicitation or incomplete documentation accounted for this low value. It is possible that the immunosuppressive effects of the patients' cancer therapies altered the natural RSV-induced inflammation, which normally contributes to wheezing. Clinicians caring for pediatric patients with cancer should be aware of the frequency with which RSV presents without wheezing or fever. In this vulnerable population, symptoms of URTI should prompt appropriate diagnostic tests for respiratory viruses despite the absence of wheezing or fever.
In this study, less than one third of the patients diagnosed as having RSV disease developed symptoms of LRTI during the course of their illness. Consistent with previous reports on adults,13–15 the majority of these patients presented solely with URTI symptoms (75%) before the symptoms progressed to involve the lower respiratory tract. This highlights a window of opportunity for early diagnosis and possibly intervention, especially for high-risk hosts.
There is limited literature on risk factors predicting disease progression from URTI to LRTI for adult immunocompromised patients and none for pediatric patients with cancer. This study places HSCT recipients and patients receiving treatment for AML at high risk for developing RSV LRTIs. Almost one half (42%) of patients with an underlying diagnosis of HSCT/AML/SCIDS developed LRTIs, as opposed to only 9% of those with ALL. In adults receiving HSCTs, RSV infection results in high rates of LRTIs (between 50% and 80%).3,6,13,16,17 In this adult population, patients in the peritransplant period are at highest risk.3,5 Similar rates were reported for adult patients with leukemia, with up to 67% of RSV infections being complicated by pneumonia.18 In contrast, only 9% of children with ALL in this study developed LRTIs. Although the association between the underlying cancer diagnosis and development of LRTI did not remain significant in the multivariate analysis, a trend toward significance was noted and should be further evaluated in studies with larger sample sizes. One reason for patients with solid tumors being more prone to have RSV LRTIs, compared with patients with ALL, may involve the ages of the patients. More patients with RSV who had an underlying diagnosis of a solid tumor were ≤2 years of age (6 of 11 patients; 55%), compared with patients with ALL (2 of 23 patients; 9%). Indeed, young age and profound lymphopenia significantly and independently predicted LRTI.
Young age is a well-described risk factor for severe RSV disease in immunocompetent pediatric patients.19–21 Not surprisingly, this study found age of ≤2 years to be an independent risk factor for RSV LRTI (OR: 9.8; 95% CI: 1.9–49.8) in immunocompromised pediatric patients as well.
Lymphopenia has been identified as a risk factor for progression of RSV disease in immunocompromised adults. In the multivariate analysis, lymphopenia (ALC of <100 cells per mm3) was the only independent predictor (OR: 14; P < .001) of development of RSV LRTI after URTI among adult HSCT recipients.22 The Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation also identified lymphopenia as the sole predictor of development of RSV LRTI (OR: 3.04; 95% CI: 1.26–7.35) in HSCT recipients.23 We did not find an age-based cutoff value for profound lymphopenia as a risk factor for severe RSV disease (data not shown). These efforts were certainly limited by the small size of the patient population, and future studies should attempt identification of age-based cutoff values for lymphopenia, for better risk group characterization.
Neutropenia7,24 and defects in neutrophil function25 have been reported in association with severe RSV disease. Defects in neutrophil number or function as independent risk factors for development of severe RSV disease remain unproven. We and others22,23 found neutropenia not to be predictive of RSV LRTI. This finding is important for cancer specialists, who traditionally have assessed risk and made clinical decisions for oncology patients on the basis of neutrophil counts.
In this study, although the overall RSV-related mortality rate was relatively low (8.6%), 31% of patients with RSV LRTIs died. Descriptions of mortality rates associated with RSV disease are quite variable. Early reports placed mortality rates for LRTI in adult patients with leukemia and HSCT recipients as high as 60% to 100%.5,13,16,18 However, other studies and more-recent studies with adult and pediatric patients with cancer reported lower mortality rates, in many cases similar to ours.17,23–31 This declining mortality rate6,15 may reflect the increasing awareness of RSV as a significant pathogen in immunocompromised patients and the early institution of appropriate diagnostic, preventive, and even therapeutic measures. Other possible factors explaining the discrepancy in mortality rates among these various studies include diversity in the degree of immunosuppression in the described populations, criteria differences for ordering RSV diagnostic tests, especially between adult and pediatric care providers, differences in the diagnostic tests that were used to make a diagnosis, differences in RSV-related interventions, and lack of standardization of death attributed to RSV illness.
In the current study, all deaths involved patients with LRTIs, and factors associated with death were age of <2 years (OR: 12.3; 95% CI: 1.26–120) and profound lymphopenia (OR: 9.9; 95% CI: 1.39–69.8). Because 69% of infants experience ≥1 RSV infection by 1 year of age and 98.9% by 2 years of age,32 our category of >2 years represents patients who are likely immunologically RSV experienced. The 2 significant independent risk factors for RSV severity found in our study were profound lymphopenia and age. This finding implies that both the specific RSV functionality of existing lymphocytes and their number substantially dictate RSV disease severity in this population. Indeed, RSV clearance was shown to occur at the time of reconstitution of presumed RSV-specific CD8+ cells in a patient with SCIDS.33 Lack of pulmonary CD8+ effector cells was observed recently in cases of fatal RSV pneumonia among immunocompetent infants.34 Some reports of very low HSCT-associated RSV case fatality ratios may be explained by differences in the numbers and functionalities of lymphocytes caused by different stem cell transplantation techniques.24,27
Because large, well-designed, prospective studies examining outcomes with specific therapies after RSV disease in immunocompromised hosts have not been conducted, treatments for RSV infection in patients with cancer remain unproven. Mostly anecdotal and often conflicting evidence from small uncontrolled trials is available in the literature. However, studies using historical control subjects suggested that prompt institution of therapy might lead to improved outcomes,3,15 especially when dual therapy with ribavirin and immunotherapy is used.8,14,28,29 One randomized, double-blind, treatment study with HSCT recipients examined the preemptive use of aerosolized ribavirin to prevent progression to pneumonia in patients with RSV URTIs.9 Although a trend toward significance was documented, that study had a small number of patients and was terminated because of slow accrual. For our study patients, the application of treatment was heterogeneous with respect to type, route, duration, and timing of administration. Also, all patients who succumbed to their infections received some form of therapy. Therefore, comparative analyses to evaluate the impact of treatment could not be made. We were, however, able to identify a subset of patients with cancer who were at increased risk of developing RSV LRTI and at increased risk of death. Until randomized, controlled studies that examine the role of antiviral interventions in the management of RSV infections in patients with cancer are performed, considerations for treating RSV LRTIs in high-risk patients, as identified in this study, should be made. Currently available interventions include aerosolized ribavirin and immunologically based therapies.35
The limitations of this study are a retrospective design, a small number of study subjects, and even smaller numbers of patients with the outcomes of interest (ie, LRTI and death). In addition, although this study has clear definitions of RSV LRTI, there is a lack of consensus in the existing RSV literature with regard to these definitions, which makes it difficult to conduct cross-study comparisons. Finally, the definition of RSV infection allowed cases with only positive DFA test results to be included as cases of RSV infection. There were 21 such cases. On the basis of the time of the year when these cases were diagnosed (all between October and March), the clinical symptoms (all patients had symptoms of viral URTIs), and the findings of positive DFA test results for >1 specimen in some cases (7 patients had repeat positive DFA test results), we think that the majority of test results were true-positive results. Careful specimen collection and timely processing are critical to a laboratory's ability to culture RSV, and we think that at least some of the results for the DFA test-positive, culture-negative specimens (false-negative results) might have been related to problems in these areas. Despite these limitations, this study takes the first step toward improving our understanding of RSV disease in children with cancer.
This study identifies patients with cancer who are young or have profound lymphopenia as being at highest risk of RSV LRTI and death. These findings not only require confirmation in larger studies in similar patient populations but also should prompt examination of the role of lymphopenia as a risk factor for severe viral illnesses in immunocompromised hosts. There is significant focus on the ANC and its association with the risk of bacterial infections. This study draws attention to the ALC; such results are often available but are less commonly used in clinical decision-making for pediatric patients with cancer. In addition, this study sets the stage for prospective, controlled trials to evaluate the efficacy of therapeutic interventions for pediatric patients with cancer at highest risk for RSV-related morbidity and death.
This work was supported by National Institutes of Health grant CA21765 and the American Lebanese Syrian Associated Charities. The funding sources had no role or input in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
- Accepted July 13, 2007.
- Address correspondence to Aditya H. Gaur, MD, Department of Infectious Diseases, Mail Stop 600, St Jude Children's Research Hospital, 332 N. Lauderdale St, Memphis, TN 38105. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
All listed authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Dr El Saleeby's current affiliation is Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital for Children, Boston, MA.
- Couch RB, Englund JA, Whimbey E. Respiratory viral infections in immunocompetent and immunocompromised persons. Am J Med.1997;102(3A) :2– 9
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