Article, Respiratory Medicine

RSV in adult ED patients: Do emergency providers consider RSV as an admission diagnosis?

a b s t r a c t

Background: respiratory syncytial virus has been recognized for over half a century as a cause of morbidity in infants and children. Over the past 20 years, data has emerged linking RSV as a cause of illness in adults resulting in 177,000 annual hospitalizations and up to 14,000 deaths among older adults.

Objective: Characterize clinical variables in a cohort of adult RSV patients. We hypothesize that emergency phy- sicians do not routinely consider RSV in the differential diagnosis (DDx) of influenza like illness.

Methods: Observational study of all adult inpatients, age >= 19, with a positive RSV swab ordered within 48 h of

their hospital visit, including their emergency department (ED) visit, and who initially presented to a university affiliated urban 100,000 annual visit emergency department from 2007 to 2014. A data collection form was cre- ated, and a single trained clinical research assistant abstracted demographic, clinical variables. ED providers were given credit for RSV DDx if an RSV swab was ordered as part of the diagnostic ED workup. Results: 295 consec- utive inpatients (mean age = 66.5 years, range, 19-97, 53% male) were RSV positive during the 7-year study pe- riod. 207 cases (70%) were age >= 60. 76 (26%) had fever, 86 (29%) had O2sat b 92% and 145 (49%) had wheezing. 279 patients required admission, 30 needed ICU stay and overall mortality was 12 patients (4%). Age >= 60 was associated with overall mortality (p = 0.09). There were 106 (36%) Immunocompromised patients (23% trans- plant, 40% cancer, 33% steroid use) in the cohort. A diagnosis of RSV was considered in the ED in 105 (36%) of pa- tients. Being immunocompromised, having COPD/asthma, O2sat b 92, or wheezing did not alert the ED provider to order an RSV test.

Conclusion: Adults can harbor RSV as this can lead to significant mobility and mortality, especially in individuals who are over the age of 60. RSV is not being considered in the DDx diagnosis, and this was especially surprising in the transplant/immunocompromised subgroups. Given antiviral treatment options, educational efforts should be undertaken to raise awareness of RSV in adults.

(C) 2017

Introduction

Respiratory Syncytial Virus (RSV), a single-stranded, negative sense, enveloped RNA virus belonging to the Paramyxoviridae fami- ly, is a well-known cause of lower respiratory tract illness in infants and children. Estimates suggest that RSV is responsible for 1%-2% of hospitalizations of infants during the winter months in the US, ap- proximately 57,500 hospitalizations annually in children younger than 5 years old, and 500,000 emergency department visits in

* Corresponding author.

E-mail address: [email protected] (W. Binder).

children under 5 years old yearly [1,2,3]. Worldwide RSV is estimat- ed to cause 66,000-199,000 deaths from pneumonia in children under 5 years of age [4,5].

Older adults are also subject to infection with RSV, presumably due to diminished immunologic response to the virus [6]. Immunosenescence has been demonstrated in an animal model exam- ining immunologic response to an experimental live attenuated recom- binant RSV vaccine. This has also been noted in the limited response to vaccines for pneumococcus and influenza in the elderly [7]. Conse- quently, older adults suffer an appreciable burden of illness from RSV. RSV infects 3%-9% of older adults yearly, and may be responsible for 6%-10% of seasonal hospital admissions [8,9]. The virus is responsible for 2%-5% of community acquired pneumonia among elderly patients annually, and peaks at 5%-15% during winter months [10].

http://dx.doi.org/10.1016/j.ajem.2017.06.022

0735-6757/(C) 2017

W. Binder et al. / American Journal of Emergency Medicine 35 (2017) 11621165 1163

Retrospective studies suggest that during epidemics, RSV associated hospitalizations in the older adult are similar to that seen in Influenza infections [11]. Estimates suggest that annual rates of hospitalization in patients without identifiable high risk conditions are 0.2/10,000 pa- tients 18-49 years of age and 10.6/10,000 patients >= 65 years of age [12]. To date, there has been limited data examining the burden of RSV on the ED adult population. The goal of the present investigation is to char- acterize adult patients admitted through the ED with RSV, and to assess whether ED providers consider RSV in the differential diagnosis of patient’s with respiratory symptoms requiring an inpatient admission.

Methods

Study design

We performed a retrospective, observational study in which we col- lected data through chart review of adult patients presenting to the ED. The setting was a university-affiliated, urban hospital with approxi- mately 100,000 visits annually.

Study setting and population

The dataset consisted of all hospitalized adult (>= 19 years) patients admitted through the emergency department between 2007 and 2014, and who had a positive nasopharyngeal RSV swab within 48 h of their hospital admission. A dataset that included all inpatients with a positive RSV swab was obtained from the hospital’s virology laboratory.

Study protocol

A standardized data collection form was created, and a single, trained clinical research assistant abstracted demographic and clinical variables. Before data collection began, the research assistant reviewed cases with the Principal Investigator (PI) to train in data abstraction. The research assistant was blinded to study hypotheses, and the PI peri- odically monitored the data collection. Data obtained included: demographics–age and sex, past medical history, physical exam find- ings, radiology findings, clinical course, and final disposition. Any rele- vant comorbidities (CHF, COPD, other respiratory illnesses) in the patient’s past medical history were noted. Physical exam findings that were found in the patient’s chart, such as fever, wheeze and respiratory distress (defined as oxygen saturation b 92% on room air) were also accounted for in the data collection form. chest X-ray findings were also reviewed for congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and pneumonia. Cases were considered to be definitively diagnosed in the ED if the RSV swab was in the ED provider’s order set. Swabs that were sent after admission or while the patient was boarding under a medical team were considered to be diagnosed by the medical or surgical admitting team. Any complications during the patient’s hospitalization were also noted, such as intubation, myocardial infarction, sepsis or death. Finally, patients’ dispositions (ICU, medical/observation floor, home) were examined.

Data analysis

RSV testing utilized a Copan/Quidel dipstick immunoassay flocked swab with a manufacturer’s reported sensitivity of 92% and occurred in the hospital virology laboratory. Data analysis included chi square/ fisher exact tests/t-test (not shown) and odds ratio calculations.

Results

There were 295 inpatients with a positive RSV swab who were en- rolled over the 7 year study period. Descriptive demographic and clini- cal variables are summarized in Table 1. An RSV swab was ordered by

Table 1

Demographics and clinical characteristics of RSV+ patients

Variable Value

Age (mean, range) 66.5 (19-97)

Male 155 (53%)

Symptoms

Fever (T N 100.4 F) 76

Wheezing 145

respiratory compromise 86

Co-morbidities

CHF 73

COPD 87

pulmonary fibrosis 11

Immune compromised 106 (35.9%)

Cancer 42

Steroid treatment 35

HIV 5

Organ transplant 24

Chest X-ray

Air space disease 89

COPD 6

Interstitial abnormality 39

Pleural effusion 9

Normal 133

Not performed/Other 19

Disposition

24 h observation 16

Floor admission 249

ICU admission 30

the emergency department team in 105 (35.6%) cases. The remaining swabs were ordered by the admitting service (174 or 59%) or in the emergency department observation unit (16 or 5.4% of cases).

We investigated whether ED practitioners were more likely to con- sider the diagnosis of RSV based upon a patient’s past medical history and comorbidities. The study institution has an active transplant and cancer service, and ED evaluation of these patients is commonplace. However, patients who were immunocompromised or had comorbidi- ties were no more likely to have an RSV swab ordered in the ED than as an inpatient (see Table 2).

When an older cohort (>= 60 years) was compared with those b 60 years, there was a significantly greater proportion of HIV and trans- plant patients in the younger group. Mortality, however, was signifi- cantly more common in the >= 60 year old patients. Table 3 summarizes these clinical variables.

Of the 295 RSV positive patients, 11% (30/279) required an intensive care unit bed, and 9.8% (29/279) required intubation. Overall mortality in the cohort was 4.1%.

Table 2

Likelihood of being diagnosed with RSV in the ED based on clinical characteristics

Variable

RSV diagnosed in ED

RSV diagnosed as inpatient

OR

95% CI

Immunocompromised

42

64

0.76

0.47-1.25

Cancer

12

30

Steroids

15

20

0.66

0.32-1.4

HIV

3

2

0.33

0.05-2.0

Organ transplant

12

12

0.5

0.21-1.2

History of

27

56

1.2

0.71-2.1

COPD/Asthma

No history Of

78

134

COPD/Asthma

Age >= 60

67

139

1.5

0.92-2.6

Age b 60

38

51

Male

59

96

0.8

0.49-1.3

Female

46

94

1164 W. Binder et al. / American Journal of Emergency Medicine 35 (2017) 11621165

Table 3

Comparisons of older versus younger cohorts with RSV.

Clinical variable Number of patients

b 60 years

Number with RSV

88

207

Number diagnosed by ED

team

38

67

0.07

Deaths

0

12

0.01*

Intubations

5

24

0.12

ICU admission

7

23

0.41

Immunocompromised

38

68

0.09

Transplant

13

11

0.006

HIV

5

0

0.002*

Steroids

7

28

0.18

Cancer

13

29

0.86

COPD/Asthma

4

20

0.14

Discussion

Number of patients

N 60 years

P

value

regarding the enormous morbidity and mortality of the disease is limit- ed. This may have a deleterious effect on Infection control within the hospital, as well as early therapeutic interventions for an increasingly aging population. RSV outbreaks among hospitalized patients increase length of stay and has an impact on morbidity and mortality [20]. Data from a systematic review of infection control measures enacted to pre- vent the spread of RSV can lead to at least a 50% reduction in nosocomial transmission [20]. Furthermore, pharmacologic interventions such as the use of ribavirin, RSV-specific immunoglobulin, and palivizumab for transplant patients may be delayed [21,22,23]. Future studies should ex- amine the impact of a Delay in diagnosis on RSV transmission in the hospital.

Limitations of this study are significant and plentiful, and include both its retrospective design, as well as the lack of an ED protocol for testing of patients. We did not track the number of negative RSV swabs sent by emergency providers during the study period but recog- nize that future studies of emergency department providers should in- clude this data. Furthermore, a selection bias was incurred as many patients with RSV were diagnosed in private offices and community

RSV has been increasingly recognized as a significant illness in the adult population, and in particular, in the elderly, those with comorbid- ities and in Immunocompromised patients. Residents of nursing homes and long term care facilities may have higher attack rates, ranging from 12%-89% [13].. Pneumonia is estimated to occur in up to 20% of these patients [9]. In our study about 70% of patients were N 60 years of age and over 2/3 had a primary pulmonary comorbidity (pulmonary fibro- sis, copd) or were immunocompromised. Conversely and surprisingly, our study also demonstrated a relatively high number of patients under the age of 60 who were diagnosed and admitted with RSV (88/ 295, 30%) and who were admitted but had neither a comorbidity nor were immunocompromised (73/295 or 24.7%).

RSV is recognized as contributing to increased utilization of intensive care and ventilator support. In one retrospective study of hospitalized adults with laboratory confirmed RSV, patients requiring ventilator sup- port exceeded 10% [14]. Mortality is significant in RSV and ranges from 2%-10%, with even greater numbers in high risk patients [8,14]. In a pro- spective study of RSV positive patients admitted from long term care fa- cilities, mortality was 38% as opposed to 3% of patients admitted from the community [8]. Modeled estimates of mortality attributed to RSV in the US suggest approximately 10,000-14,000 deaths annually [5,6, 15,16,17]. In our study almost 30% of admitted patients had respiratory compromise, defined as oxygen saturation b 92%. Additionally, our study agrees with previous findings, as we demonstrated an 11% ICU ad- mission rate and 4% mortality (12 deaths). Twenty percent of patients admitted to the ICU had neither comorbidities nor were immunocom- promised and all were N 60 years. Of the 12 deaths, all patients were N 60 years (although 3 were <= 65 years of age) and all but one had co- morbidities or were immunocompromised.

Very little information has been published examining RSV in the adult emergency department. In one of the few studies investigating RSV in the ED, Widmer prospectively enrolled patients with respiratory symptoms presenting to the ED or who were hospitalized over a 1 year period in 4 different hospitals. This group identified 32 patients with RSV, of which 14 were enrolled in the emergency department [18]. No information regarding emergency physician awareness of the disease in the adult population was noted. Camargo examined RSV in the emer- gency department and its relationship to acute Exacerbations of COPD and identified 6 patients with RSV subtype A and B, but physician awareness was not examined [19]. In our study, using the initial ED order set as a proxy, the diagnosis of RSV was entertained by the EM provider in only 35.6% of patients subsequently identified as RSV posi- tive. Neither the presence nor absence of comorbidities or an immuno- compromised state appeared to have any influence on whether emergency physicians tested for RSV.

While data suggests that RSV has a significant impact on the health of adults and especially older adults, emergency physician awareness

clinics associated with the hospital. Many RSV positive patients were treated as outpatients during the study period, and consequently highly symptomatic patients were seen in the emergency department. Addi- tionally, we did not specify whether RSV was the leading diagnosis or an associated diagnosis. Finally, using the order set to define whether RSV was considered by the emergency department team may not be an accurate depiction of the team’s decision process.

Conclusions

In spite of the limitations, this study confirms that RSV contributes to inpatient admission among adults and suggests that emergency physi- cians infrequently consider RSV in their differential diagnosis of influen- za like illnesses. Given the high incidence of RSV and its associated mortality, as well as the potential for increasing use of therapeutic and pharmacologic intervention, emergency physicians will require an in- creasing awareness of this underappreciated and highly morbid disease.

References

  1. Meng J, Stobart CC, Hotard AL, Moore ML. An overview of respiratory syncytial virus. PLoS Pathog 2014:e1004016. http://dx.doi.org/10.1371/journal.ppat.100.
  2. Haynes AK, Prill MM, Iwane MK, Gerber SI. Respiratory syncytial virus–United States, July 2012-June 2014. MMWR 2014;63:1133-6.
  3. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus in- fection in young children. NEJM 2009;360:588-98.
  4. Byington CL, Wilkes J, Korgenski K, Xiaoming S. Respiratory syncytial virus-associat- ed mortality in hospitalized infants in young children. Pediatrics 2015;135:e24-31.
  5. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, et al. Global burden of acute lower Respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375:1545-55.
  6. Wong TM, Boyapalle S, Sampayo V, Nguyen HD, Bedi R, et al. Respiratory syncytial virus (RSV) infection in elderly mice results in altered antiviral gene expression and enhanced pathology. PLoS One 2014;9:e88764.
  7. Guichelaar T, Hoeboer J, Widjojoatmodjo MN, Reemers SSN, van Els CACM, Otten R, et al. Impaired immune response to vaccination against infection with human respi- ratory syncytial virus at advanced age. J Virol 2014;88:9744-50.
  8. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. NEJM 2005;352:1749-59.
  9. Falsey ARCC, Barker WH, et al. Respiratory syncytial virus and influenza A infections in the hospitalized elderly. J Infect Dis 1995;172:389-94.
  10. Murata Y. respiratory syncytial virus infection in adults. Curr Opin Pulm Med 2008; 14:235-40.
  11. Sundaram ME, Meece JK, Sifakis F, Gasser RA, Belongia EA. Medically attended respi- ratory syncytial virus infections in adults aged greater than 50 years. Clin Infect Dis 2014;58:342-9.
  12. Mullooly JP, Bridges CB, Thompson WW, et al. Influenza and RSV associated hospi- talizations among adults. Vaccine 2007;25:846-55.
  13. Falsey AR, Walsh EE. Respiratory syncytial virus infection in elderly adults. Drugs Aging 2005;22:577-87.
  14. Lee N, Lui GCY, Wong KT, Li TCM, et al. High morbidity and mortality in adults hos- pitalized for respiratory syncytial virus infections. Clin Infect Dis 2013;57:1069-77.
  15. Johnstone J, Majumdar SR, Fox JD, Marrie TJ. Viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens, and presentation. Chest 2008;134:1141-8.

    W. Binder et al. / American Journal of Emergency Medicine 35 (2017) 11621165 1165

    Van Asten L, van den Wijngaard C, van Pelt W, et al. Mortality attributable to 9 com- mon infections: significant effect of influenza a, respiratory syncytial virus, influenza B, norovirus and parainfluenza in elderly persons. J Infect Dis 2012;206:628-39.

  16. Matias G, Taylor R, Haguinet F, Schuck Paim C, Lustig R, Shinde V. Estimates of Mor- tality Attributable to Influenza and RSV in the United States during 1997-2009 by Influenza Type or Subtype, Age, Cause of Death, and Risk Status. Influenza and Other Respiratory Viruses, 8; 2014 507-15.
  17. Widmer K, Griffin MR, Zhu Y, Williams JV, Talbot HK. Respiratory syncytial virus-and human metapneumovirus-associated emergency department and hospital burden in adults. Influenza Other Respi Viruses 2014;8:347-52.
  18. Camargo CA, Ginde AA, Clark S, Cartwright CP, Falsey AR, Niewoehner DE. Viral path- ogens in acute exacerbations of chronic obstructive pulmonary disease. Intern Emerg Med 2008;3:355-9.
  19. French CE, McKenzie BC, Coope C, Rajanaidu S, Paranthaman K, et al. Risk of nosoco- mial respiratory syncytial virus infection and effectiveness of control measures to prevent transmission events: a systematic review. Influenza Other Respi Viruses 2016;10:268-90.
  20. Waghmare A, Campbell AP, Hu X, Seo S, et al. Respiratory syncytial virus lower respi- ratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. Clin Infect Dis 2013;57:1731-41.
  21. Marcelin JR, Wilson JW, Razonable RR. Oral ribavirin therapy for respiratory syncy- tial virus infections in moderately to severely immunocompromised patients. Transpl Infect Dis 2014;16:242-50.
  22. Simoes EAF, DeVincenzo JP, Boeckh M, Bont L, et al. Challenges and opportunities in developing respiratory syncytial virus therapeutics. J Infect Dis 2015;211(S1):S1-20.