Diagnostic Microbiology and Infectious Disease 85 (2016) 367–371
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Morbidity and mortality among patients with respiratory syncytial virus infection: a 2-year retrospective review☆,☆☆ Neil W. Anderson a,1, Matthew J. Binnicker a, Dana M. Harris b, Razvan M. Chirila b, Lisa Brumble c, Jay Mandrekar d, D. Jane Hata e,⁎ a
Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology at Mayo Clinic, Rochester, MN, 55905, USA Division of Hospital Internal Medicine at Mayo Clinic, Jacksonville, FL, 32224, USA Division of Infectious Disease at Mayo Clinic, Jacksonville, FL, 32224, USA d Division of Biostatistics at Mayo Clinic, Rochester, MN, 55905, USA e Department of Laboratory Medicine and Pathology at Mayo Clinic, Jacksonville, FL, 32224, USA b c
a r t i c l e
i n f o
Article history: Received 27 January 2016 Received in revised form 12 February 2016 Accepted 17 February 2016 Available online 23 April 2016 Keywords: RSV Transplant Chronic obstructive pulmonary disease
a b s t r a c t Previous studies have demonstrated high morbidity and mortality for adult patients with respiratory syncytial virus (RSV) infection. We performed a retrospective, multicenter, two-year chart review of all patients (n = 334) testing positive for RSV by the ProFlu + ® Influenza A/B and RSV assay (Hologic, Bedford, MA). We analyzed indicators of morbidity and mortality in children b6 years old, immunocompetent and immunosuppressed adults, and transplant patients. Significant morbidity and mortality was observed among hematopoietic stem cell transplant patients (7.3%, 60-day mortality), solid organ transplant patients (13.3%, 60-day mortality), and COPD patients (12.8%, 60-day mortality). Of the patients positive for RSV, 144 (43.1%) of 334 received antibacterials or antifungals following diagnosis. Of these patients, a bacterial or fungal pathogen was not recovered from 60% of cases. Despite advances in RSV treatment, certain populations appear to be inadequately treated, while others appear to be inappropriately treated with unnecessary antimicrobials. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Over the past decade, RSV has been recognized as a pathogen of growing importance in adult populations (Neuzil et al., 2003; Thompson et al., 2003). While the virus typically causes a self-limited infection in an estimated 3% to 10% of adults annually, several high-risk adult populations have been identified (Lee et al., 2013). In the elderly, respiratory viruses in general have been associated with a high rate of complications ranging from pneumonia to respiratory distress (Nicholson et al., 1997). In this population, RSV is a common cause of respiratory disease, second only to influenza in frequency of need for medical attention (Falsey et al., 2005; Sundaram et al., 2014). Patients with chronic obstructive pulmonary disease (COPD) are also at risk for severe disease. A 2013 study by Mehta et al. demonstrated a rate of symptomatic RSV infection among patients with COPD of 11.1%, with almost half of symptomatic patients requiring hospitalization (Mehta et al., 2013). Finally, RSV has been identified as an important pathogen for ☆ Conflicts of Interest: The authors do not have any commercial or other association that pose a conflict of pertaining to the presented work. ☆☆ Funding: None. ⁎ Corresponding author. Tel.: +1-904-953-2906; fax: +1-904-953-2406. E-mail address:
[email protected] (D.J. Hata). 1 Current Affiliation: Department of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO, 63130, USA. http://dx.doi.org/10.1016/j.diagmicrobio.2016.02.025 0732-8893/© 2016 Elsevier Inc. All rights reserved.
immunosuppressed patients. RSV is reported as the cause of severe pneumonia and death in solid organ transplant (SOT) recipients (Billings et al., 2001). In bone marrow transplant (BMT) patients, infection with RSV occurs in an estimated 1% to 12% of patients (Hirsch et al., 2013). Mortality among BMT recipients is reported to be as high as 70% in certain case series (Harrington et al., 1992). Given the high rate of morbidity and mortality in these patients, treatment with antiviral therapy is frequently used in the form of inhaled or systemic ribavirin in conjunction with RSV immunoglobulins or monoclonal antibodies (Empey et al., 2010; Hirsch et al., 2013; Marcelin et al., 2014). Data regarding the extent of morbidity and mortality secondary to RSV in adult populations is often inconsistent. A 2013 Hong Kong study described high rates of lower respiratory (71.9%) and cardiovascular (14.3%) complications among adult patients hospitalized for RSV (Lee et al., 2013). However, a 2010 Swiss study by Uckay et al. involving lung transplant recipients suggested that RSV infections are often mild and resolve without complication (Uckay et al., 2010). An accurate identification of populations at risk for severe disease is important because targeted therapy (ribavirin) is available; however, this therapy may be associated with occasional severe adverse effects, including leukopenia, and its efficacy has not been evaluated in randomized controlled trials. In an effort to better characterize and identify patient populations that are at risk for increased morbidity and mortality following RSV infection, we performed a retrospective, multicenter, two-year review of all
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Table 1 Patient subgroups. Subgroup
Site 1a (n; % of total)
Site 2b (n; % of total)
Total (n; % of total)
Immunocompetent Elderly Immunocompetent Adult Children Transplant Immunosuppressed Non-transplant Total no. of patients
54 (19.4) 22 (7.9) 130 (46.8) 51 (18.3) 21 (7.6)
21 (37.5) 14 (25) NA 18 (32.1) 3 (5.4)
75 (22.5) 36 (10.8) 130 (38.9) 69 (20.7) 24 (7.2)
278 (100)
56 (100)
334 (100)
NA, not applicable; no pediatric practice at this site. a Mayo Clinic in Rochester, MN. b Mayo Clinic in Jacksonville, FL.
patients testing positive for RSV by real-time PCR at our centers. An additional assessment of morbidity and mortality in specific patient subsets such as transplant, immunosuppression, age, and other underlying conditions was performed, with a focus on adult patients. 2. Materials and methods 2.1. Study design We performed a retrospective chart review of patients evaluated for acute respiratory disease at two separate academic medical centers (Mayo Clinic in Rochester, Minnesota and Mayo Clinic in Jacksonville, Florida) over the period from January 1, 2012 to December 31, 2013. All patients positive for RSV by real-time PCR (n = 334) at either institution were included in this review. Both adult and pediatric populations were tested at Mayo Clinic in Rochester (MCR; n = 278), whereas Mayo Clinic in Jacksonville (MCJ; n = 56) only tested adults (pediatric services were not performed). This study was reviewed and approved by the institutional review boards at both centers.
exacerbation. Cardiac complications included clinical documentation of heart failure, atrial fibrillation, acute coronary event, or acute cardiovascular event during patient admission. Patient outcomes were recorded, including duration of hospitalization and 30- and 60-day mortality. We also examined how the level of PCR positivity (inferred from Cp values) related to morbidity and mortality. Finally, we examined how treatment was altered following the diagnosis of RSV. We analyzed the obtained indicators of morbidity and mortality among the following population subsets: children/infants b 6 years old, immunocompetent adults (18 to 65 years old), immunocompetent elderly adults (N65 years old), patients with COPD, immunosuppressed transplant patients, and immunosuppressed nontransplant patients. No cases of RSV in children aged 6–18 years were encountered during the study period. The transplant subgroup consists of patients who received a hematopoietic stem cell transplant (HSCT) or SOT at any point in their life prior to RSV diagnosis. In an effort to identify transplant patients at greatest risk for severe disease, we examined how transplant type and time from transplant to RSV diagnosis related to morbidity and mortality. Patients who were immunosuppressed secondary to chemotherapy, immunomodulator therapy (including steroids N20 mg/day prednisone equivalent), underlying disease, or a formally diagnosed immunodeficiency were classified in the immunosuppressed nontransplant group. The remaining patients were classified as “immunocompetent” and grouped according to age (children b6 years old, adults 18–65 years old, and elderly N65 years old). An additional subgroup of patients with chronic obstructive pulmonary disease (COPD) was analyzed separately as a distinct subset. This consisted of patients with documented COPD also categorized in the “immunocompetent adult” and “immunocompetent elderly” groups. 3. Results 3.1. Patient characteristics
2.2. Microbiological methods All testing by real-time PCR at both locations was performed by the ProFlu + ® Influenza A/B and RSV assay (Hologic, Bedford, MA) using the LightCycler 480 (Roche Diagnostics, Indianapolis, IN) or Cepheid SmartCycler (Cepheid, Sunnyvale, CA). Sample type, crossing point (Cp), and results for other targets on the ProFlu + assay (influenza A/B) were recorded.
Overall, 334 patients tested positive for RSV during the study period. A total of 278 patients were positive at MCR, and 56 patients were positive at MCJ. Among the total 334 patients, 69 (20.7%) were transplant recipients, 24 (7.2%) were immunosuppressed patients, 130 (38.9%) were immunocompetent children, 36 (10.8%) were adults, and 75 (22.5%) were immunocompetent elderly adults (Table 1). No patients were simultaneously positive for both influenza and RSV during the study period.
2.3. Definitions 3.2. Clinical presentation Clinical information from patients positive for RSV was retrospectively obtained from the medical record. These data included patient demographics (i.e. age and gender), comorbidities, and history of hematopoietic or solid organ transplantation. Symptoms and duration of symptoms at presentation, length of hospital stay, treatment, and the presence of health complications (e.g. respiratory, cardiac, renal, neurologic) during admission were also obtained. Respiratory complications included any diagnosis of pneumonia, COPD exacerbation, or asthma
Symptoms at presentation were determined by either a subjective history reported by the patient or during physical examination. For nearly all subgroups, cough was the most commonly observed symptom at admission (92%). The exception was patients with COPD, who more commonly reported shortness of breath as the primary complaint. With the exception of immunocompetent children, fever was observed in less than half of all patients (Table 2).
Table 2 Clinical presentation among population subgroups diagnosed with RSV infection. Patient Subgroup
Cough (%) SOB (%) Sputum (%) Rhinorrhea (%) Fever (%) Length of symptoms prior to admission (days)
Transplant (n = 69)
Immunocompromised nontransplant (n = 24)
Immunocompetent adult (n = 36)
Immunocompetent elderly (n = 75)
COPD (n = 39)
Immunocompetent children (n = 130)
89.9 60.9 66.7 50.7 47.8 4.58
83.3 66.7 58.3 25 50 6.13
86.1 77.8 36.1 50 44.4 5.39
89.3 74.7 68 37.3 41.3 4.64
84.6 92.3 71.8 28.2 35.9 4.13
97.7 93.8 82.3 80 70 3.25
COPD, chronic obstructive pulmonary disease; SOB, shortness of breath.
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Table 3 Morbidity and mortality among patient subgroups. PCR Cpa
Patient Subgroup
Any Respiratory Complications (%) Pneumonia (%) Cardiovascular Complications (%) Other Complications (%) Inhaled Oxygen (%) Mechanical Ventilation (%) Required Admission (%) Average Hospital Stay (days) 30 Day Mortality (%) 60 Day Mortality (%)
Transplant (n = 69)
Immunocompromised Nontransplant (n = 24)
Immunocompetent Adult (n = 36)
Immunocompetent Elderly (n = 75)
COPD (n = 39)
Immunocompetent Children (n = 130)
Cp b25 (n = 89)
Cp ≥25 (n = 167)
43.5 36.2 4.3 27.5 37.7 13 71 8.2 5.8 7.2
62.5 58.3 16.7 50 45.8 4.2 91.7 6.9 4.2 8.3
50 33.3 19.4 16.7 44.4 13.9 72.2 3.8 0 0
54.7 34.7 21.3 50.7 57.3 10.7 88 5.1 4.0 5.3
87.1 38.5 25.6 38.5 79.5 17.9 100 5.8 10.3 12.8
24.6 23.1 1.5 19.2 39.8 3.8 65.4 3.6 0 0
50.6 46.1 6.7 24.7 47.2 9.0 77.5 5.4 1.1 2.2
41.9 29.3 10.8 26.9 44.3 6.6 76 4.1 3.6 3.6
COPD, chronic obstructive pulmonary disease; Cp, PCR crossing point. a Nasopharyngeal swab samples only.
3.3. Morbidity and mortality Morbidity and mortality among patient groups were examined (Table 3). Compared to other subgroups, patients with COPD had more respiratory complications overall (54.7% [CI 43.43–65.97%]), requirements for inhaled oxygen (57.3% [CI 46.11–68.49%]), and admission rates (100%). The highest rates of 60-day mortality were observed among COPD, immunocompromised nontransplant, and transplant patients (12.8%, 8.3%, and 7.2%, respectively), though due to limited sample sizes, the differences between these groups were not statistically significant. Morbidity and mortality were also compared to the level of PCR positivity (i.e. Cp value). When comparing patients with low Cp values to patients with high Cp values, several differences were observed, though none reached statistical significance. Patients with a low Cp value (b25) demonstrated a higher average risk of respiratory complications, including pneumonia, COPD exacerbation, or asthma exacerbation. Patients with low Cp values also showed a greater association with cardiovascular complications. Morbidity and mortality among specific adult transplant patient subgroups were analyzed. Patients were classified as having received an allogeneic HSCT, autologous HSCT, or SOT. These patients were further grouped by recent HSCT (b2 months prior to diagnosis), remote HSCT (N2 months prior to diagnosis), recent SOT (b1 year prior to diagnosis), and remote SOT (N1 year prior to diagnosis). At least two-thirds of each transplant subgroup required hospital admission resulting in an average length of stay greater than five days total (Table 4). 3.4. Antimicrobial or antifungal therapy The proportion of patients who received antibacterial or antifungal therapy following the diagnosis of RSV was also determined. Among 69 transplant patients, 36 (52.2%) received antibacterial or antifungal therapy following their RSV diagnosis. Of these 36 patients, only 15 (41.7%) had culture-proven infections other than RSV. Among all
positive patients, 144 (43.1%) received antibacterial and/or antifungal therapy following their diagnosis of RSV. Antibiotics were administered to treat a culture-proven infection, COPD exacerbation, or otitis media in 40% of these patients (Table 5). The remaining 87 patients (60%) were treated with an antimicrobial without a microbiologic result to support the therapeutic choice. 4. Discussion The presenting symptoms (e.g. cough, shortness of breath) in the populations analyzed in our retrospective review were consistent with those previously reported in the literature (Falsey et al., 2005; Lee et al., 2013; Mehta et al., 2013; Sundaram et al., 2014; Tang and Crowe, 2011). In all adult groups, classic RSV symptoms were less frequent overall when compared to children. In adult groups, cough was the most common symptom at presentation (88.2%), with the exception of shortness of breath being most common (92.3%) among patients with COPD. Symptomatic days before presentation ranged from four to five among immunocompetent elderly (4.64 days), patients with COPD (4.13 days) and transplant patients (4.58 days). Symptomatic days until presentation were higher amongst immunocompetent adults (5.39 days) and immunocompromised nontransplant patients (6.13 days). These findings may be due to the fact that adults are more hesitant to seek medical care until symptoms became more severe. Immunocompetent adults exhibited low rates of mortality (0% [CI 0–2.8%] 60-day mortality) and respiratory complications (50.6% [CI 39.8–61.3%]); however, nearly 19.4% (CI 8.2–36.0%) exhibited cardiovascular complications. While cardiovascular complications have been recognized in healthy adults with RSV, the incidence of these complications may be underestimated. RSV infection appeared to be most severe among the other groups of adults. Immunocompetent elderly, transplant patients, and immunocompromised nontransplant patients had 60-day mortality rates of 5.3% (CI 1.5–13.1%), 7.3% (CI 2.4–16.1%), and 8.3% (CI 1.0–27.0%), respectively. All patients with COPD required hospital admission; 87.21%
Table 4 Morbidity and mortality among transplant subgroups.
Any Respiratory Complications (%) Pneumonia (%) Cardiovascular Complications (%) Other Complications (%) Inhaled Oxygen (%) Mechanical Ventilation (%) Required Admission (%) Average Hospital Stay (days) 30 Day Mortality (%) 60 Day Mortality (%)
Allogeneic HSCT (n = 24)
Autologous HSCT (n = 15)
SOT (n = 30)
Recent HSCT (n = 10)
Remote HSCT (n = 29)
Recent SOT (n = 12)
Remote SOT (n = 18)
37.5 37.5 4.2 20.8 33.3 16.7 66.7 7.7 8.3 8.3
38.2 29.3 10.2 33.3 26.7 13.3 80 12.7 0 6.7
40 26.7 6.7 30 43.3 10 83.3 6.0 13.3 13.3
60 60 0 30 30 20 80 12.0 0 0
41.4 37.6 3.4 24.1 31.0 13.8 69 9.1 6.9 10.3
25 8.3 0 8.3 33.3 0 91.7 5.1 0 0
50 38.9 11.1 44.4 50 16.7 72.8 6.9 22.2 22.2
HSCT, Hematopoietic stem cell transplant; SOT, Solid organ transplant.
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Table 5 Distribution of patients who received antibiotics after diagnosis of RSV. Patients who Received Antibiotics After Diagnosis (n = 144) Culture Proven Infection COPD Exacerbation Otitis Media No Clear Indication
20% 15% 5% 60%
(CI 72.6–95.7%) had respiratory complications, 79.5% (CI 63.5–90.7%) required inhaled oxygen, and 18% (CI 7.5–33.5%) required mechanical ventilation. The 60-day mortality among this population was 12.8% (CI 4.3–27.4%). These findings are somewhat similar to those of Lee et al. who reported a crude, all-cause 60-day mortality of 11.9% among adults in Hong Kong with RSV (Lee et al., 2013). While the findings of Lee et al. were generalized for all adults with RSV, our study identified this high mortality rate specifically in adult patients with COPD. Another indicator of disease severity was the level of PCR positivity, as inferred by the Cp value associated with the real-time PCR result. Patients with a PCR Cp value b25 cycles (i.e. strong positive) were associated with more respiratory complications, pneumonia, and need for mechanical ventilation. These patients also had an average length of stay one day greater than other patients (5.4 days versus 4.1 days). Though these differences failed to reach statistical significance due to overlapping confidence intervals (Table 3), they suggest that the level of PCR positivity may have some utility as a predictor of disease severity. Among transplant patients, the overall 60-day mortality was 7.3% (CI 2.4–16.1%). While high, this mortality rate is actually lower than reported in previous studies (70% reported by Harrington et al.) (Harrington et al., 1992). There are several possible explanations related to institutional practices, which may account for this relatively low overall mortality rate among transplant patients in our study. First, of the 69 transplant patients in this study who were diagnosed with RSV, 54 (78.3%) received oral or inhaled ribavirin. Of the 54 ribavirin treated patients, 21 (38.9%) also received intravenous immunoglobulin (IVIG). The effectiveness of this treatment has been documented in several independent studies (Boeckh et al., 2007; Gueller et al., 2013; Hynicka and Ensor, 2012; Lee and Barton, 2007; Marcelin et al., 2014; Shah et al., 2013). Although not the focus of this study, some authors suggest there is no difference in oral versus aerosolized ribavirin on patient outcome, whereas other studies suggest oral ribavirin is equally effective as the aerosolized route of administration with reduced cost and risk of teratogenicity (Li et al., 2012; Marcelin et al., 2014). Interestingly, when the data were analyzed by transplant type, it was found that patients with bone marrow transplant had a mortality rate at 7.7% (CI 0–16.07%) whereas solid organ transplant patients had a mortality rate at 13.3% (CI 3.8–30.7%). The use of IVIG may have partially accounted for these differences since 49% (19/30) of bone marrow transplant patients received IVIG and only 7% of SOT patients received IVIG. Mortality rates did not appear to be higher in patients with recent solid organ transplants, since all 12 patients who were transplanted within a year of RSV diagnosis survived. A final parameter that we examined in this study was the use of antibacterial and antifungal therapies following the diagnosis of RSV. We found that 36/69 (52.2%) transplant patients in this study received antifungal or antibacterial therapies following the diagnosis of RSV. Of these 36 patients, only 15 (41.7%) had a culture-proven diagnoses of bacterial or fungal infection. When antibiotic use was examined among all RSVpositive populations, there were similar findings (Table 5). A total of 144 patients received antifungal or antibacterial therapies following RSV diagnosis. Of these patients, 20% had culture-proven infection, 15% had a diagnosis of COPD exacerbation without culture, and 5% had a diagnosis of otitis media without culture. The remaining 60% (CI 51.2–67.8%) of patients were treated for lower respiratory infections without clear indication for a cause other than RSV. While it can be argued that some of these patients may have had bacterial or fungal co-
infections, we believe that a large proportion of these patients may have received unnecessary antimicrobial therapy. A major strength of this study is its large scale. By analyzing a significant number of RSV-positive patients (n = 334), we were able to assess morbidity and mortality among different groups of patients. Furthermore, data were analyzed from two distinct centers using identical molecular testing methods, creating a more geographically diverse study population. However, both centers are large, tertiary care academic hospitals, so severely ill patients may be overrepresented. Also, treatment practices at these institutions likely affected results, limiting the applicability of these data to institutions that do not commonly follow similar practices. In the absence of specific treatment guidelines for RSV, it is difficult to correlate effects of treatment on morbidity and mortality in affected populations. An additional limitation of this study is that despite the overall large number of RSV-positive patients included, certain underrepresented population subgroups did not have sufficient differences in observed findings to prove statistical significance. A final limitation of the study is that retrospective information obtained was from medical records, which are restricted to episodes of care received at the treating institution. 5. Conclusions In summary, this retrospective multicenter review identified several important findings. First, our data suggests that adults with RSV have less characteristic symptoms and generally take a longer time to present for treatment following the onset of symptoms as compared to children. This is particularly true of immunocompetent adults and immunosuppressed nontransplant patients, two populations in which the index of suspicion for RSV may be low. While our study demonstrated a high degree of morbidity and mortality among HSCT transplant patients, these levels did not appear to be as high as those previously reported in adult populations, a finding that may be secondary to treatment with ribavirin. The highest levels of morbidity and mortality were seen among SOT and COPD patients (12.8% and 13.3% 60-day mortality, respectively). These high levels suggest the need for early recognition and management of RSV infection particularly among patients with COPD. Another observation from our study was that the strength of positivity by RSV real-time PCR may provide a useful metric to assess severity of disease, especially among patients presenting with pneumonia. Finally, while the diagnosis of RSV should allow for the de-escalation of antibiotics in certain populations, this appears to be inconsistent in practice. Despite advances in diagnosis and treatment of RSV infection, certain populations appear to be inadequately treated, while others may be inappropriately treated with antimicrobial therapy. Further studies are needed to identify these populations and refine the management of patients with RSV. Acknowledgements We would like to acknowledge laboratory staff within the division of microbiology at both Mayo Clinic Jacksonville and Mayo Clinic Rochester for their work and contribution to this project. References Billings JL, Hertz MI, Wendt CH. Community respiratory virus infections following lung transplantation. Transpl Infect Dis 2001;3:138–48. Boeckh M, Englund J, Li Y, Miller C, Cross A, Fernandez H, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007; 44:245–9. Empey KM, Peebles Jr RS, Kolls JK. Pharmacologic advances in the treatment and prevention of respiratory syncytial virus. Clin Infect Dis 2010;50:1258–67. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749–59. Gueller S, Duenzinger U, Wolf T, Ajib S, Mousset S, Berger A, et al. Successful systemic high-dose ribavirin treatment of respiratory syncytial virus-induced infections
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