key: cord-292301-h20337ib
authors: Falsey, Ann R; Walsh, Edward E; Esser, Mark T; Shoemaker, Kathryn; Yu, Li; Griffin, M Pam
title: Respiratory syncytial virus–associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure
date: 2018-09-24
journal: J Med Virol
DOI: 10.1002/jmv.25285
sha: 
doc_id: 292301
cord_uid: h20337ib

BACKGROUND: Respiratory syncytial virus (RSV) is recognized as a serious pathogen in people with chronic cardiopulmonary conditions. Immunoprophylaxis might be considered for adults at high‐risk for frequent and severe RSV infection. Thus, we studied the incidence of RSV‐related medically attended acute respiratory illness (MARI) in adults with severe chronic obstructive pulmonary disease (COPD) and/or congestive heart failure (CHF). METHODS: Subjects ≥50 years of age with Gold Class III/IV COPD and/or American Heart Association class III/IV CHF and exposure to children ≥once per month were recruited. Subjects were evaluated over 1.5 to 2.5 years for RSV‐associated MARI, defined as polymerase chain reaction (PCR) and/or seroresponse. RESULTS: Four hundred forty‐five subjects were enrolled between October 2011 and May 2012. Overall, 99 RSV infections were documented by PCR or serology for a cumulative incidence of 22.2%. Of these, 42 (9.4%) subjects had protocol‐specified RSV‐MARI for an incidence of 4.68/100 patient‐seasons. All‐cause MARI was common (63.85/100 patient‐seasons) with rhinovirus most commonly identified. CONCLUSION: RSV infection was common in adults with severe COPD and/or advanced CHF. Given the severity of underlying cardiopulmonary diseases in the study population, most illnesses were surprisingly mild. Thus, active immunization rather than passive immunoprophylaxis with monoclonal antibodies may be a more cost‐effective strategy.

obstructive pulmonary disease (COPD) and congestive heart failure (CHF) affect millions of people worldwide and have been identified as risk factors for severe RSV infection. 2, [6] [7] [8] [9] [10] In addition, these patients may present primarily with symptoms of decompensated heart failure or acute exacerbation of COPD (AECOPD), and the role of viral infection is unappreciated. 11 Although molecular diagnostic testing has markedly improved the recognition of RSV and other respiratory viruses in these settings, adult RSV remains an underrecognized problem.

The most effective means of preventing infectious diseases is vaccination because this approach can be deployed to protect the largest at-risk group possible. Presently, a successful RSV vaccine remains elusive, while passive immunoprophylaxis with a monoclonal antibody, palivizumab, in high-risk infants has been shown to reduce RSV hospitalizations. 12 Although all older adults are at increased risk of more severe RSV infection, certain subgroups such as those with severe COPD or CHF may be at even greater risk and could potentially benefit from passive immunoprophylaxis if infection rates and severity are found to be substantial. There are limited data available on the incidence of RSV infection in adults with Class III or IV COPD and/or CHF. This observational study was designed to collect data in a high-risk population of adults with exposure to children who might exhibit both high rates of infection and severe illness when infected with RSV.

This was a prospective and observational study conducted across multiple consecutive RSV seasons to determine the incidence rate of medically attended acute respiratory illness (MARI) or events leading to worsening cardiorespiratory status in adults with severe COPD and/or advanced CHF associated with RSV and other viral infections.

Fifty-seven sites in nine countries (Bulgaria, Canada, Czech Republic, France, Germany, Italy, Russia, Sweden, and the United States) in the Northern hemisphere participated in the study from fall 2011 through spring 2014. The protocol was approved by independent institutional review boards, and all subjects signed written informed consent at enrollment.

The study population included adults ≥50 years of age with severe COPD (Global Initiative for Chronic Obstructive Lung Disease Stage III/ IV) and/or CHF (New York Heart Association Class III/IV or American College of Cardiology-American Heart Association Stage C/D) and had expected exposure to children (<18 years of age) at least once a month.

An acute respiratory illness (ARI) was defined as new onset or worsening of at least two of the following respiratory symptoms (sore throat, nasal congestion or discharge, hoarseness, cough, sputum, wheezing, dyspnea, and pleuritic chest pain) or one respiratory symptom and ≥1 systemic symptoms (feverishness, fatigue, headache, and myalgia). Worsening cardiorespiratory events were defined as follows: AECOPD: worsening of ≥2 major symptoms (dyspnea, sputum volume, and sputum purulence) for ≥2 consecutive days; or worsening of any one major symptom together with anyone minor symptom (sore throat, cold, fever without other cause, or increased cough or wheeze) for ≥2 consecutive days. Worsening of CHF was defined as a change in ≥1 symptom or sign (pulmonary edema, dyspnea, weight gain ≥5 pounds, pedal edema, jugular venous distension, and tachycardia and tachypnea) beyond normal day-to-day variation and warranting medication changes. MARI was considered any illness where a subject sought outpatient, inpatient, or over-the-phone medical consultation for ARI or worsening cardiorespiratory status. Subjects were considered to have per protocol RSV-MARI if they had a positive reverse transcriptase polymerase chain reaction (RT-PCR) during the acute phase of illness and/or a ≥4-fold increase in RSV-specific serum antibody in the period surrounding the health care visit. 

Three different PCR assays were used to test for RSV in nasal and sputum samples. These included the GenMark respiratory viral panel (www.genmarkdx.com) 13 that tests for 14 common respiratory viruses and subtypes, an M gene-based PCR assay 14 and an assay that detects RSV F and N genes. 15 Serology: RSV-specific antibodies were measured at enrollment, at the time of MARI (acute), approximately 30 days after illness (convalescent) and each October and May. Serum antibodies were measured using an RSV neutralizing antibody assay and a 4-plex RSV F, Ga, Gb, and N-specific IgG electrochemiluminescent (ECL) assay on the MesoScale Discovery platform. 16 An RSV seroresponse was defined as >4-fold rise in neutralizing antibody titer or to any RSV antigen in the ECL assay over seasonal baseline or between samples.

Continuous variables were summarized by descriptive statistics, including mean, standard deviation, median, and range. Confidence intervals were two-sided unless otherwise stated. The primary endpoint objective of the study was to determine the incidence rate of inpatient and outpatient RSV-MARI across multiple consecutive RSV seasons. Primary endpoint analysis and secondary outcomes (allcause MARI and death) were performed with adjustment for individual subject follow-up time.

Four hundred fifty-three subjects were enrolled in the study between An inverse relationship between serum RSV antibody levels and incidence of RSV-MARI was observed ( Figure 2 ). Higher antibody levels to each of the RSV antigens were associated with a lower incidence of RSV-MARI, and the relationship was most clearly seen in season 2 possibly due to more subjects with RSV-MARI and available serology in season 2 versus season 3 (20 vs 8, respectively). Season 1 was not included because subjects were being enrolled throughout the year, and preseason blood was not available for many subjects.

In addition to the 42 subjects with per protocol RSV-MARI, an additional 57 RSV infections were also identified. Of these, 55 had For all viruses, the addition of sputum testing resulted in (11.8%-50.0%) increased viral detections during illness (Table 3) . for severe illness and hospitalizations in prior studies. 6, 7, [18] [19] [20] However, in our population of adults with Class III/IV COPD and CHF, it was surprising that illnesses were not as severe as expected.

In a previous study of high-risk adults with COPD and CHF of varying stages including mild or moderate disease, the rate of RSV-MARI was 4.40/100 person-seasons, similar to the rate of 4.68 observed in this study. 2 In that study, 16% of high-risk patients were hospitalized and 4% died when infected with RSV. When all RSV infections, including serologic diagnoses in this study, were considered, 17% of RSV-infected subjects were hospitalized and there were no deaths.

Notably, 35% of infected patients either were asymptomatic or had a mild illness that did not require any medical intervention.

Regular exposure to children required for participation in this study may have led to higher infection rates (7%-14.6%) compared with those observed in previous surveillance and vaccine studies (2%-3%). 21, 22 One explanation for lack of severe illness in this very frail population might be that regular exposure to children resulted in recent RSV infections before the study leading to increased protective baseline immunity. 23 attention. Influenza with abrupt illness onset and fever tends to drive patients to seek medical attention within several days. 5 The typical RSV illness begins with a cold and progresses over several days to dyspnea and wheezing. The average time to seek medical attention is 5-6 days by which time virus may no longer be detectable in the upper airways. 33, 34 In addition, because RSV infection in adults represents reinfection, a rapid amnestic antibody response may obscure a rise in antibody if acute sera collection is delayed. Finally, because the analysis of acute and convalescent sera is not possible in patients that die, results may have been biased toward milder illness.

In summary, RSV, as well as other respiratory viruses, led to significant morbidity in high-risk persons with cardiopulmonary disease. The finding that RSV can result in relatively mild disease in patients with very advanced COPD and CHF highlights the incomplete understanding of disease pathogenesis in adults. Given our results, immunoprophylaxis with an RSV monoclonal antibody of a select high-risk adult population may not be practical.

However, given the overall burden of RSV in older adults, programs to develop vaccines for active immunization may be a feasible approach.

We would like to thank the study participants and the site investigators listed as follows: Marc Afilalo/Canada, Andreea

A R Falsey served as an advisor for Sanofi Pasteur, Pfizer, Novavax, and Gilead Sciences. E E Walsh provides consultative advice to

Clinical and epidemiologic features of respiratory syncytial virus

Respiratory syncytial virus infection in elderly and high-risk adults

Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults

Mortality associated with influenza and respiratory syncytial virus in the United States

Medically attended respiratory syncytial virus infections in adults aged >/=50 years: clinical characteristics and outcomes

Risk factors for severe respiratory syncytial virus infection in elderly persons

High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections

Respiratory viral infections in adults with and without chronic obstructive pulmonary disease

Global and regional estimates of COPD prevalence: systematic review and meta-analysis

Epidemiology and risk profile of heart failure

Can analysis of routine viral testing provide accurate estimates of respiratory syncytial virus disease burden in adults?

The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants

Comparison of the GenMark Diagnostics eSensor respiratory viral panel to real-time PCR for detection of respiratory viruses in children

The burden of hospitalized lower respiratory tract infection due to respiratory syncytial virus in rural Thailand

Development and pilot study of a dualtarget RSV assay to detect and subtype respiratory syncytial virus in nasal swab samples

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Influenza-and RSVassociated hospitalizations among adults

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Winter viruses: influenza-and respiratory syncytial virus-related morbidity in chronic lung disease

Comparison of the safety and immunogenicity of 2 respiratory syncytial virus (RSV) vaccinesnonadjuvanted vaccine or vaccine adjuvanted with alum-given concomitantly with influenza vaccine to high-risk elderly individuals

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Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults

Diagnosis of respiratory syncytial virus infection: comparison of reverse transcription-PCR to viral culture and serology in adults with respiratory illness

The diagnosis of viral respiratory disease in older adults

Detection of respiratory viruses in sputum from adults by use of automated multiplex PCR

Update on human rhinovirus and coronavirus infections

Virus-induced exacerbations in asthma and COPD

Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease

A prospective, observational cohort study of the seasonal dynamics of airway pathogens in the aetiology of exacerbations in COPD

Clinical impact of human coronaviruses 229E and OC43 infection in diverse adult populations

Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease

Viral shedding and immune responses to respiratory syncytial virus infection in older adults

Yield of sputum for viral detection by reverse transcriptase PCR in adults hospitalized with respiratory illness

Respiratory syncytial virus-associated illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure

AR Falsey, MP Griffin, and MT Esser participated in the study design, collection, analysis and interpretation of data and the writing of this report. EE Walsh participated in collection and analysis of data and reviewed the manuscript. K Shoemaker and L Yu provided statistical analysis. AR Falsey and MP Griffin are the guarantors of the paper and take responsibility for the integrity of the work as a whole, from inception to published article.

http://orcid.org/0000-0002-7141-9701