Risk factors and medical resource utilization in US adults hospitalized with influenza or respiratory syncytial virus in the Hospitalized Acute Respiratory Tract Infection study

Abstract Background Influenza and respiratory syncytial virus (RSV) are associated with substantial morbidity and mortality in the United States. We assessed risk factors for severe disease and medical resource utilization (MRU) among US adults hospitalized with influenza or RSV in the Hospitalized Acute Respiratory Tract Infection (HARTI) study. Methods HARTI was a prospective global (40 centers, 12 countries) epidemiological study of adults hospitalized with acute respiratory tract infections conducted across the 2017–2019 epidemic seasons. Patients with confirmed influenza or RSV were followed up to 3 months post‐discharge. Baseline characteristics, prevalence of core risk factors (CRFs) for severe disease (age ≥65 years, chronic heart or renal disease, chronic obstructive pulmonary disease, or asthma), and MRU were summarized descriptively. Results The US cohort included 280 influenza‐positive and 120 RSV‐positive patients. RSV patients were older (mean: 63.1 vs. 59.7 years) and a higher proportion had CRFs (87.5% vs. 81.4%). Among those with CRFs (influenza, n = 153; RSV, n = 99), RSV patients required longer hospitalizations (median length of stay: 4.5 days) and a greater proportion (79.8%) required oxygen supplementation during hospitalization compared with influenza patients (4.0 days and 59.5%, respectively). At 3 months post‐discharge, a greater proportion of RSV patients with CRFs reported use of antibiotics, antitussives, bronchodilators, and inhaled and systemic steroids versus those with influenza and CRFs. Many patients with CRFs reported hospital readmission at 3 months post‐discharge (RSV: 13.4%; influenza: 11.9%). Conclusions MRU during and post‐hospitalization due to RSV in adults is similar to or greater than that of influenza. Enhanced RSV surveillance and preventive and therapeutic interventions are needed.


| BACKGROUND
Lower respiratory tract infections (LRTIs) cause substantial morbidity and mortality globally. In 2016, an estimated 2.38 million LRTIassociated deaths occurred across all age groups worldwide. 1 Influenza and respiratory syncytial virus (RSV) are among the most common causes of LRTIs during typical (i.e., non-pandemic) endemic seasons, 2 with influenza causing an estimated 1 billion infections 3 and RSV causing an estimated 64 million acute respiratory infections 4 globally each year. A systematic analysis from the Global Burden of Diseases, Risk Factors, and Injuries study found that influenza caused $500,000 deaths and RSV caused 250,000 deaths annually worldwide. 5 In the United States, there are an estimated 50,000 influenzaassociated and 17,000 RSV-associated deaths each year. 6 The annual disease burden of both influenza and RSV within the United States varies substantially by geographic region 7,8 and endemic season. 9,10 Importantly, RSV-associated burden may be underestimated due to a lack of routine testing for RSV and low provider awareness. 11 Children (<1 year) and older adults (≥65 years) comprise the majority of RSV-associated hospitalizations. 12 A retrospective study analyzing New York City hospitalization data in infants aged <1 year and children aged 1-4 years reported annual average influenza-associated hospitalization rates of 129.0 and 36.4 per 100,000 population and RSV-associated hospitalization rates of 1895.8 and 116.7 per 100,000 population, respectively. 13 Influenza and RSV also cause substantial mortality in infants aged <1 year (2.2 and 5.4 per 100,000 person-years, respectively) and children aged 1-4 years (1.1 and 0.9 per 100,000 person-years, respectively). 6 Older and high-risk adults (i.e., immunocompromised individuals and those with underlying respiratory or cardiovascular comorbidities 14,15 ) also experience high RSV-associated morbidity and mortality. Hospitalization rates for high-risk adults of all ages infected with influenza (242 per 100,000 population) and RSV (91 per 100,000 population) are comparable with those for older adults of all risk levels (256 and 84 per 100,000 population among adults aged 65-74 years, respectively). 16 A prospective study of hospitalized adults in Nashville, TN, found that both influenza (11.8 per 10,000 residents) and RSV (15.0 per 10,000 residents) cause substantial hospitalization rates among adults aged ≥50 years 17 ; the majority of these hospitalizations are concentrated during seasonal surges. The estimated mortality rate among US adults aged ≥65 years is 132.5 and 29.6 per 100,000 person-years for influenza and RSV, respectively. 6 LRTIs also require significant medical resource utilization (MRU).
In the United States, influenza is responsible for an estimated 3.1 million hospitalized days, 31.4 million outpatient visits, and $87.1 billion in total economic burden annually. 18 A recent analysis using data from published studies and public health databases estimated the average cost of influenza-associated hospitalization in the United States ranged from $5211 (in patients <1 year of age) to $12,102 (in patients aged 45-64 years), depending on age group. 19 There are limited data on RSV-specific MRU. In a recent retrospective claims study among hospitalized adults in New York state, the average cost of an RSVassociated hospitalization was $8403, and the total annual cost of RSV-associated hospitalizations in the United States was estimated at $1.2 billion. 20 Additionally, in a different community cohort study in New York City, among RSV-positive hospitalized adults aged ≥65 years, the majority received chest X-rays, antibiotics, and steroids; the mean length of hospital stay in this population was 6.6 days. 12 Seasonal LRTI outbreaks cause significant emergency department utilization, crowding, and potential hospital staff shortages due to infections among staff or their families. 21 Older adults, immunocompromised individuals, and those with underlying respiratory or cardiovascular comorbidities are at risk for severe influenza-or RSV-mediated disease. 14,15 Detailed assessments of the characteristics of adults hospitalized with influenza or RSV and MRU during and post-hospitalization are lacking 17 ; such assessments are important for improving diagnostics, surveillance, prophylaxis, and treatments for both pathogens.
The Hospitalized Acute Respiratory Tract Infection (HARTI) study was a global study during the 2017-2019 epidemic seasons aimed at assessing risk factors for severe disease and MRU in adults hospitalized with acute respiratory tract infections (ARTIs). 15 We used data from the US cohort of HARTI to assess risk factors for severe disease and MRU in adults hospitalized with influenza or RSV.

| Study design
HARTI was a prospective cohort study in adults (≥18 years old) hospitalized with ARTIs during the influenza/RSV/human metapneumovirus Patients with confirmed influenza, RSV, or hMPV (latter not included in this analysis due to small sample size) were invited to enroll in the substudy comprising a hospitalization phase (two visits: 48 h postenrollment, and within 2 days prior to discharge) and a follow-up phase with phone interviews at 1, 2, and 3 months post-discharge.

| Statistical analysis
Data collected from study questionnaires were summarized descriptively by pathogen and risk group. Patients were considered to have core risk factors (CRFs) for progression to severe disease if they were aged ≥65 years or had chronic heart disease, chronic renal disease, chronic obstructive pulmonary disease (COPD), or asthma.
Clinical symptom severity was assessed at screening (within 24 h of hospitalization) using the National Early Warning Score (NEWS), a validated tool used to detect clinical deterioration in adults, which is calculated using seven graded vital sign measurements (respiratory rate, oxygen saturation, oxygen supplementation, temperature, blood pressure, heart rate, and level of consciousness). [22][23][24][25] Each vital sign was scored from 0 to 3; NEWS scores were calculated by summing vital sign scores, with higher scores representing more severe illness (low severity: 0-4; moderate: 5-6 or an individual parameter scoring of 3; high: ≥7). Since all patients signed the informed consent form for study participation, level of consciousness was assumed to be "Alert" (i.e., a score of 0) for all patients at enrollment.
Symptom severity was also assessed using a total clinical symptom score comprising general symptom (cough, sputum production, shortness of breath, and malaise), lower respiratory symptom (dyspnea; rales, rhonchi, or other abnormal breath sounds; and wheezing), and upper respiratory symptom (nasal discharge, pharyngitis, and sinus tenderness) scores, with higher scores representing more severe disease (see Table S1). Hospital length of stay (LoS) was summarized and reported categorically by ≤3 or >3 days.

| Patients
The US cohort of the international HARTI study included 280 patients with influenza and 120 patients with RSV in the main study (Table 1)  RiiQ™, Respiratory Intensity and Impact Questionnaire; RSB, Respiratory Symptoms Bother and Change in Health Status Questionnaire; RSV, respiratory syncytial virus; SoC, standard-of-care. † When a nasal swab was collected as part of SoC, a mid-turbinate swab was collected from the opposite nostril and then used for the SoC test. Rapid PCR analysis was used to identify respiratory pathogens from the SoC nasal and midturbinate swabs. ‡ Leftover nasal swab or blood samples were stored for potential future exploratory research. § For patients discharged within 48 h of screening, only one visit was conducted (at discharge). ¶ Patient-reported questionnaires included the Barthel ADL, Lawton IADL, RiiQ™, RSB, EQ-5D-5L, and MRU questionnaires.
(33.3%, 22.7%, and 34.7%, respectively) compared with patients with influenza (24.4%, 16.5%, and 25.0%, respectively; Figure 2B). Oxygen supplementation prior to hospitalization was only collected for patients with COPD; among these, a higher proportion of those with RSV had at-home supplemental oxygen use at baseline compared with those with influenza (Table S2).  F I G U R E 3 Key MRU parameters during hospitalization. CRF, core risk factor; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; LoS, length of stay; LTCF, long-term care facility; RSV, respiratory syncytial virus. † CRFs included any one or a combination of the following: age ≥65 years, chronic heart disease, COPD, chronic renal disease, and asthma. ‡ The one patient with influenza discharged to a LTCF was in an LTCF prior to hospitalization. Of the eight patients with RSV who were discharged to LTCFs, four patients reported LTCF residence prior to hospitalization.

| MRU
F I G U R E 4 Medication use post-discharge (substudy). Percentage of patients reporting use of (A) antibiotics, (B) antitussives, (C) bronchodilators, (D) inhaled steroids, (E) systemic steroids, or (F) oxygen at 1, 2, and 3 months post-discharge. CRF, core risk factor; COPD, chronic obstructive pulmonary disease; RSV, respiratory syncytial virus. † CRFs included any one or a combination of the following: age ≥65 years, chronic heart disease, COPD, chronic renal disease, and asthma.
supplemental oxygen compared with those with influenza  Figure 3). Patients with RSV also experienced more complications during hospitalization, including lower respiratory complications, cardiovascular complications, and bacterial superinfections, compared with patients with influenza ( Figure S1).
In general, patients with CRFs (regardless of pathogen) reported more medication use at 1, 2, and 3 months post-discharge compared with patients without CRFs; those with RSV and CRFs generally reported more medication use post-discharge than those with influenza and CRFs (Figure 4) 11.0%) at 3 months post-discharge ( Figure 5).

| DISCUSSION
In the US cohort of HARTI, RSV was associated with MRU comparable with or greater than influenza. Observations in the US cohort reflect those in the global HARTI population; patients with RSV were older and a greater proportion had CRFs compared with patients with influenza. 15 An analysis using data from the global HARTI study also found that patients with RSV reported more severe lower respiratory tract symptoms up to 3 months post-discharge compared with patients with influenza, in agreement with results in this study showing that patients with RSV reported greater MRU at 3 months postdischarge compared with those with influenza. 26 Additionally, results from the US cohort of HARTI are also consistent with other studies comparing the disease burden of RSV and influenza. In a F I G U R E 5 MRU post-discharge (substudy). Percentage of patients reporting (A) hospital readmission, (B) use of medical consultations, † and (C) professional home care ‡ at 1, 2, and 3 months post-discharge. CRF, core risk factor; COPD, chronic obstructive pulmonary disease; MRU, medical resource utilization; RSV, respiratory syncytial virus. † Medical consultations included utilization of a pulmonologist or respiratory physiotherapist. ‡ Professional home care included utilization of a general practitioner, nurse, or respiratory physiotherapist. § CRFs included any one or a combination of the following: age ≥65 years, chronic heart disease, COPD, chronic renal disease, and asthma.
retrospective claims study among hospitalized adults aged ≥60 years, Ackerson et al found that patients with RSV were older, more likely to have CHF and COPD at baseline, and had greater odds of requiring a hospital stay ≥7 days and ICU admission. 27 Another retrospective claims study found that, among hospitalized adults in New York City, patients with RSV required a longer hospital LoS than patients with influenza (median: 4.4 vs. 3.9 days, respectively). 28 Patients with RSV also more frequently experienced acute exacerbation of asthma or COPD, exacerbation of CHF, and hypoxemia; this may parallel the association between RSV infections early in life and development of bronchospastic diseases such as asthma and recurrent wheezing in childhood. 29,30 Collectively, these results suggest that the severity of RSVassociated illness in adults rivals that of influenza. However, there is currently no licensed RSV vaccine, and there are only two US Food and Drug Administration-approved antiviral drugs for either RSV prophylaxis (palivizumab) or treatment (ribavirin). 31