Background
Respiratory syncytial virus (RSV) is a major pathogen causing acute respiratory infections (ARIs), particularly in infants and older adults. In individuals aged 60 years and above, RSV is associated with considerable morbidity, mortality and healthcare burden [1–3]. Clinical presentation ranges from mild upper respiratory symptoms to severe lower respiratory tract infections [4].
Older adults often have chronic comorbidities, increasing the risk of complications and RSV infection can precipitate exacerbations of underlying pulmonary conditions [5–7].
Due to limited testing and the often nonspecific symptoms the true burden of RSV infections within the outpatient setting remains difficult to estimate. Only a few studies have investigated the epidemiology and clinical characteristics of RSV infections in adults in the outpatient setting. The incidence of PCR-confirmed RSV infections varies substantially across age groups.
Data from the USA revealed an incidence of 136 to 255/100,000 over three seasons in patients older than 65 years compared to 7.7 to 11.9/100,000 in adults under 50 in the inpatient setting [8]. Results over several seasons reported an overall RSV incidence of 139/10,000 cases, whereas incidence in patients with pre-existing cardiopulmonary disease (196/10,000) was nearly twice as high as in those without (103/10,000) [9]. Similar results were also observed in a large observational study including patients 50 years and older (154/10,000) with increasing incidence in adults ≥ 70 years compared to age groups 50 to 59 and 60 to 69 years [10].
In adults, RSV infection is more often associated with respiratory manifestations such as cough, wheezing, and dyspnea, whereas influenza typically presents with systemic manifestations including fever and myalgia [11–13].
Thus, more in-depth knowledge about RSV infections in the outpatient setting among older adults is needed. This study aimed to elucidate the prevalence, incidence and disease burden of PCR-confirmed RSV infections in nasopharyngeal swabs in a cohort of patients aged ≥ 60 years attending pneumologists or general practitioners in Germany for ARI over three consecutive infection seasons.
Methods
Study design
“BUrden of Disease and COst of illneSS for RSV and other pathogens in patients 60 years and older within the outpatient setting” (BUCOSS RSV 60+) was a prospective, multicenter, active surveillance, observational study. The study period covered three consecutive infection seasons between 1st October and 30th April from 2022 to 2025. Primary endpoint was the prevalence of RSV confirmed by PCR-positive nasopharyngeal swabs.
Secondary endpoints included the incidence of RT-PCR–confirmed RSV-ARI, the distribution of RSV-positive and RSV-negative ARI cases as well as the detection of non-RSV respiratory pathogens from nasopharyngeal samples at day 0 (baseline visit). Secondary endpoints further included the duration of RSV-associated ARI and associated symptoms, frequency of complications, occurrence and duration of hospitalizations (stratified by main and secondary diagnoses) and HRQoL using the EQ-5D-3L at baseline (Day 0) at Day 14 and, if applicable, Day 28 post-onset of infection. Co-detection of more than one pathogen was documented without separate analysis or exclusion.
Patients with a positive RSV result were assigned to the RSV group irrespective of additional pathogen detection.
Study population
Adults aged ≥ 60 years presenting with ARI were recruited from 21 general practices and eight pulmonary specialist practices across Germany. Case definitions for ARI and LRTI were prespecified and adapted from the phase 3 efficacy trial of the RSVPreF3 OA vaccine in adults aged ≥ 60 years [14], with modifications to reflect the symptoms and signs assessable in routine outpatient care. ARI was defined as the presence of at least two respiratory symptoms/signs (cough, purulent or changed sputum, sore throat, rhinorrhea, rales/wheezing, acute or progressive dyspnea [MRC dyspnea scale > 0], or acute or progressive hypoxemia [oxygen saturation < 95%]) or at least one respiratory symptom/sign combined with one systemic symptom/sign (myalgia, feverishness or chills, fatigue), with onset within 10 days prior to presentation.
LRTI was defined as at least two lower respiratory symptoms/signs including at least one lower respiratory sign (wheezing or crackles on auscultation, oxygen saturation < 95%, or requirement for supplemental oxygen), or at least three lower respiratory symptoms (new or increased sputum, cough, or dyspnea [MRC > 0]). Symptoms and signs were recorded as new or worsened relative to the patient’s usual state rather than as absolute presence. Patients were excluded if they were unable to comply with study procedures, had previously received an RSV vaccine or were participating in or had been enrolled in another investigational study within the preceding 28 days.
Data collection
At the initial visit (Day 0, Visit 1), nasopharyngeal swabs were collected from all eligible participants, processed according to manufacturer’s instructions and analyzed by the Institute of Virology at the University Hospital Freiburg using the Qiagen® QIAStat-Dx Respiratory SARS-CoV-2 Panel. The pathogens included are listed in Table S1 (left column), along with the grouping used for subsequent analysis (right column).
Data were collected from medical records including date of birth, gender, height, weight, symptoms, date of symptom onset, temperature, oxygen saturation, heart rate, MRC dyspnea scale, vaccination status (SARS-CoV-2, Influenza, Pneumococcus). Information about comorbidities was subclassified into chronic pulmonary conditions (COPD, asthma bronchiale, bronchiectasis, pulmonary fibrosis, sarcoidosis, sleep apnea), cardiac disorders (ischemic heart disease, congestive heart failure, arrhythmia and other), malignant diseases, hypertension and other vascular/cerebrovascular diseases, hepatitis B/C, renal failure, diabetes type 1 and 2, dyslipidemia, immunosuppression due to chronic condition or medication including chronic systemic steroids use (≥ 20 mg prednisolone-equivalent ≥ 14 days), chemotherapy within the past 3 months and other reasons. Multimorbidity was defined as the presence of two or more comorbidities.
Complications after RSV infection included bronchitis, pneumonia, asthma or COPD exacerbation and cardiovascular complications (myocardial infarction, pulmonary embolism, thrombosis and others). For further analysis, comorbidities were summarized as shown in Table S2. HRQoL was self-reported using the EQ-5D-3L and the EQ-5D-5 L during the first season with conversion of results into the EQ-5D-3L.
Analyses of HRQoL were descriptive with no statistical testing between groups. High-Risk status was defined as the presence of COPD, asthma, any other chronic respiratory/pulmonary disease, diabetes mellitus, chronic heart failure, chronic liver or renal disease.
RSV-positive patients were contacted by telephone at Day 14 to assess disease course, including patient status, persistent respiratory and systemic symptoms, time since symptom resolution, complications, and HRQoL. Patients who had not fully recovered — defined as the absence of ARI-attributable symptoms and complications as documented at inclusion — were followed up again at Day 28, with identical data collected. Hospitalization data were provided by the responsible physician following discharge and recorded within the 28-day observation period (Fig.
1).
Fig. 1Study procedure. This study enrolled patients with ARI in the outpatient setting with nasopharyngeal swab for virology testing and baseline characteristics with two follow-up timepoints for RSV positive patients.
For each stage, the number of patients is indicated (n). ICD = International Statistical Classification of Diseases and Related Health ProblemsOf 3,268 patients enrolled, 3,261 had a valid PCR result. For 3,069 patients, no pathogen was detected, or a pathogen other than RSV was identified.; 192 were RSV positive and continued to follow-up.Baseline assessment covered eligibility, characteristics, symptoms, examination, medical history, comorbidities, diagnosis, quality of life, and costs.
All 192 RSV-positive patients were followed up on day 14; 98 who had not fully recovered were followed up on day 28. Both follow-ups assessed patient status, symptoms, treatment, complications, quality of life, and costs. Hospitalization was reported for four RSV-positive patients.
All study participants provided written informed consent. It was conducted following the ethical principles in the Declaration of Helsinki and all applicable national laws, regulations and guidelines. The study was approved by the local ethic committee of Goethe University Frankfurt/Main (Project approval number: 2022 − 907).
Statistical analysis
Baseline characteristics were summarized separately for RSV-associated ARI and for other respiratory pathogens (other ARI). Continuous variables are presented as mean (standard deviation), categorical variables as counts (percentages). Group comparisons (RSV vs. other ARI) used two-sample t tests for continuous variables and chi-square tests or Fisher’s exact tests for categorical variables.
Baseline comorbidities were treated as binary indicators (present/absent), summarized as counts (percentages), and compared between groups using chi-square or Fisher’s exact tests. Age was dichotomized at a predefined cut-off of 70 years.
Pathogen-specific prevalence was estimated for each German federal state as the proportion of participants with a positive RT-PCR result among all participants with a valid RT-PCR result. Overall prevalence was estimated as a weighted aggregation of state-specific prevalence, using the reported number of ARI patients during the observation period to account for differences in underlying ARI counts; 95% CIs were calculated according to Korn and Graubard (1998).
Incidence was estimated analogously. For each state, the number of pathogen-positive cases among all ARI patients was obtained by scaling observed RT-PCR positives to the total number of ARI patients represented. State-specific incidence was then calculated relative to the number of treatment certificates for patients aged ≥ 60 years (averaged over the two quarters covering the observation period), corresponding to the number of individuals of that age attending the respective practices during that period.
A treatment certificate documents the treatment of one insured person by one practice within a calendar quarter, irrespective of the number of consultations. As German ambulatory care involves neither patient registration nor gatekeeping, no enumerated practice population exists. Therefore, treatment certificates provide the only complete routine record of the population attended, and national survey data indicate that approximately 90% of individuals aged ≥ 60 years consult a general practitioner within a given year [15].
Comparable catchment-population approaches have been used in German primary care sentinel surveillance [16]. Because only patients presenting to a physician were captured, this measure represents medically attended RSV incidence among individuals attending ambulatory care. Overall incidence was derived from weighted aggregation across states, with weights reflecting site participation time (proportion of weeks contributing during the observation period).
Further details about the calculation including formulas are available in the supplement.
To compare baseline symptoms and comorbidities (present/absent) across pathogens separate logistic regression models for each symptom, with pathogen as the independent variable were used. Model-based symptom risks were used to derive risk ratios for pathogen comparisons.
Symptom duration up to 28 days was analyzed using Kaplan–Meier methods, estimating symptom-specific time-to-resolution curves; symptoms persisting at day 28 were censored. Complications during the 28-day follow-up were summarized descriptively. For the endpoint “any complication”, logistic regression was used to assess predictors: age, sex and baseline comorbidities were evaluated in univariable models, followed by a multivariable model including age, sex, comorbidity groupings (chronic pulmonary disease, chronic heart disease, vascular/cerebrovascular disease, chronic liver disease, chronic renal diseases, renal insufficiency, diabetes mellitus type II, dyslipidemia) and infection type (URTI vs.
LRTI). For ease of clinical interpretation, associations of the variables of interest derived from logistic regression models are presented as Risk Ratios (RRs) rather than Odds Ratios. Following model fitting, estimated marginal probabilities for the respective groups were obtained on the response scale using the emmeans package in R.
These model-based probabilities were then reparameterized on the log scale, and contrasts between groups were exponentiated to obtain RRs and corresponding 95% confidence intervals. All tests were two-sided.
Results
Incidence and prevalence
Incidence and prevalence for RSV were 1,030.63/100,000 (95% CI: 824.48; 1,287.66) and 5.49% (95%CI: 2.96–8.03), respectively. The overall estimated prevalence and incidence over three seasons was highest for Rhino-/Enterovirus with 12.57% (95%CI: 9.1; 16.04) and 2,300.61/100,000 (95% CI: 1982.79; 2668) followed by SARS-CoV-2 with 11.34% (95% CI: 7.3; 15.38) and 1,935.68/100,000 (95% CI: 1,645.64; 2275.66) (Table 1). The number of confirmed viral detections and ARI cases without pathogen detection is shown in Table 1.
Table 1Overall incidence and prevalence of respiratory pathogens over three seasons by sitePathogenPatients positive(% of all ARI patients)Incidence1(95% CI)Prevalence2RSV192 (6%)1030.63824.48; 1287.665.49 2.96; 8.03Influenza265 (8%)1676.061407.5; 1994.838.445.9; 10.97SARS-CoV-2365 (11%)1935.681645.64; 2275.6611.347.3; 15.38Human Coronavirus203 (6%)1141.58923.5; 1410.416.313.84; 8.79Rhino/Enterovirus451 (14%)2300.611982.79; 266812.579.1; 16.04Others145 (4%)1094.99881.85; 1358.957.425; 9.841: Per 100.000 patients 2: Korn & GraubardAbbreviations: ARI, acute respiratory infection; RSV, respiratory syncytial virus; CI, confidence interval. RSV, respiratory syncytial virus
Study population
Over three seasons (2022/23–2024/25) a total of 3261 patients with ARI were included of whom 192 tested positive for RSV. Detailed patient characteristics are depicted in Table 2. The mean age among RSV-infected patients was 71.6 years and 42.2% were male.
In the RSV cohort, 90.6% of patients had at least one comorbidity, compared with 90.2% in the other-ARI cohort, most commonly arterial hypertension (62.0% and 63.4%) and chronic pulmonary disease (44.3% and 44%). Multimorbidity was present in 134 (69.8%) RSV-infected patients and in 2201 (71.7%) with other ARI, increasing from 59.8% to 62%, respectively, in those aged < 70 years to 79% and 82.6% in those aged ≥ 70 years. Influenza vaccination was less frequent in patients with influenza than in those without (47.2% vs.
64.7%), whereas SARS-CoV-2 vaccination exceeded 95% irrespective of SARS-CoV-2 detection (Table S3). An additional pathogen was detected in 17 RSV-positive patients (8.9%) (Table S4). The prevalence of individual comorbidities stratified by pathogen, along with pairwise comparisons to RSV, is presented in Table S5a + b.
Table 2Patient characteristics of patients with ARI due to RSV and ARI due to other respiratory pathogensOther ARI (N = 3069)RSV-ARI (N = 192)p-valueAge (years), mean (SD)71.0 (8.3)71.6 (8.5)nsAge (50%), n (%)ns < 701622 (52.9%)92 (47.9%) ≥ 701447 (47.1%)100 (52.1%)Sex (male), n (%)1278 (41.6%)81 (42.2%)nsComorbidities (any), n (%)2942 (90.2%)174 (90.6%)nsMultimorbidity1, n (%)2201 (71.7%)134 (69.8%)ns Age < 701005 (62%)55 (59.8%)ns Age ≥ 701196 (82.6%)79 (79%)nsHigh-risk status, n (%)2070 (63.5%)116 (60.4%)nsChronic pulmonary diseases, n (%)1353 (44%)85 (44.3%)ns COPD686 (22.3%)30 (15.6%)ns Asthma743 (24.2%)51 (26.6%)ns Bronchiectasis110 (3.6%)5 (2.6%)ns Pulmonary fibrosis28 (0.9%)1 (0.5%)ns Sarcoidosis19 (0.6%)2 (1%)0.045 Sleep apnea165 (5.4%)7 (3.7%)ns Lung emphysema402 (13.1%)11 (7.9%)ns Other58 (1.9%)5 (2.6%)nsChronic heart diseases, n (%)891 (29%)45 (23.4%)ns Congestive heart failure335 (10.9%)18 (9.4%)ns Myocardial infarction10 (0.3%)0 (0%)ns Ischemic heart disease440 (14.3%)23 (12%)ns Cardiac arrhythmias355 (11.6%)18 (9.4%)ns Other105 (3.4%)1 (0.5%)0.028Arterial hypertension, n (%)1949 (63.4%)119 (62%)nsVascular/cerebrovascular diseases, n (%)207 (6.7%)23 (12%)ns Stroke7 (0.2%)0 (0%)ns Other209 (6.8%)14 (7.3%)nsChronic liver disease, n (%)77 (2.5%)4 (2.1%)ns Hepatitis B5 (0.2%)0 (0%)ns Hepatitis C6 (0.2%)0 (0%)ns Other66 (2.2%)4 (2.1%)nsChronic renal disease, n (%)368 (12%)19 (9.9%)ns Renal insufficiency (dialysis)8 (0.3%)1 (0.5%)ns Renal insufficiency(non-dialysis)323 (10.5%)15 (7.8%)ns Other50 (1.6%)5 (2.6%)nsMalignant diseases, n (%)287 (9.3%)13 (6.8%)nsDiabetes mellitus, n (%)671 (21.8%)23 (12%)< 0.001 Type I20 (0.7%)0 (0%)ns Type II651 (21.2%)23 (12%)0.002Dyslipidemia, n (%)1307 (42.5%)82 (42.7%)nsSARS-CoV-2 infection within previous 12 months, n (%)321 (10.5%)33 (17.2%)nsImmunosuppression, n (%)64 (2.1%)2 (1%)ns Due to chronic systemic steroids10 (0.3%)1 (0.5%)ns Due to chemotherapy9 (0.3%)0 (0%)ns Other reasons45 (1.5%)1 (0.5%)nsAbbreviations: ARI, acute respiratory infection; RSV, respiratory syncytial virus; ns, not significant (p-value > 0.05); n, number. 1, ≥ 2 comorbiditiesStatistically significant values are bold
Disease burden and symptom duration
Among patients with RSV infection, the highest symptom prevalence was observed for cough (99.48%, 95% CI: 96.40; 99.93), rhinitis (90.10%, 95% CI: 85.01; 93.60) and fatigue (91.15%, 95% CI: 86.22; 94.42) (Table 3a). Comparison between pathogens revealed differences for symptoms of URTI, LRTI and systemic symptoms. RSV infection was associated with lower risk for rhinitis but higher risk cough, sputum and wheezing compared to certain other respiratory viruses.
The risk for myalgia and fever was lower compared to influenza (Table 3b).
Table 3aRisk analysis of RSV in comparison to other respiratory virus by symptom at baselinePathogenSymptomCoughSputumPharyngitisRhinitisWheezeMyalgiaFeverFatiguenRisk95% CInRisk95% CInRisk95% CInRisk95% CInRisk95% CInRisk95% CInRisk95% CInRisk95% CIRSVN = 19219199.4896.40; 99.9311358.8551.76; 65.6010353.6546.57; 60.5817390.1085.01; 93.6011559.9052.81; 66.5911861.4654.39; 68.089448.9641.95; 56.0017591.1586.22; 94.42InfluenzaN = 26626398.8796.56; 99.6412045.1139.23; 51.1316160.5354.53; 66.2221681.2076.05; 85.4612948.5042.54; 54.4919974.8169.25; 79.6618469.1763.37; 74.4324692.4888.63; 95.10SARS-CoV-2N = 36934392.9589.85; 95.1613035.2330.52; 40.2423563.6958.65; 68.4432487.8084.05; 90.779826.5622.30; 31.3025669.3864.48; 73.8720856.3751.26; 61.3533390.2486.77; 92.88Human CoronavirusN = 20319696.5592.95; 98.3510250.2543.41; 57.0813667.0060.24; 73.1218591.1386.37; 94.349747.7841.00; 54.6513867.9861.25; 74.0310350.7443.89; 57.5617887.6882.41; 91.54Rhino/EnterovirusN = 45141992.9090.14; 94.9420345.0140.47; 49.6328563.1958.64; 67.5238485.1481.55; 88.1421247.0142.44; 51.6323552.1147.49; 56.6917338.3633.98; 42.9338585.3781.79; 88.34OthersN = 14513895.1790.22; 97.688659.3151.14; 67.008558.6250.45; 66.3511277.2469.72; 83.348256.5548.38; 64.388457.9349.76; 65.696947.5939.59; 55.7112485.5278.81; 90.36Abbreviation: CI, confidence interval; n, number. RSV, respiratory syncytial virus
Table 3bRisk analysis of RSV in comparison to other respiratory virus by symptom at baselineSymptomPairwise Comparisons to RSVRisk Ratio; 95% CI; p-valueInfluenzaSARS-CoV-2HumanCoronavirusRhino/EnterovirusOthersPharyngitisp = 0.094p[RSV] = 0.0180.89 (0.75; 1.04)0.1480.84 (0.72; 0.98)0.0270.80 (0.68; 0.94)0.0080.85 (0.73; 0.99)0.0310.92 (0.76; 1.11)0.36Rhinitisp < 0.001p[RSV] = 0.070.89 (0.75; 1.04)0.1480.84 (0.72; 0.98)0.0270.80 (0.68; 0.94)0.0080.85 (0.73; 0.99)0.0310.92 (0.76; 1.11)0.36Coughp = 0.002p[RSV] = 0.0421.01 (0.99; 1.02)0.4651.07 (1.04; 1.10) < 0.0011.03 (1.00; 1.06)0.0361.07 (1.04; 1.10) < 0.0011.05 (1.01; 1.09)0.023Sputump < 0.001p[RSV] = 0.0021.30 (1.09; 1.56)0.0031.67 (1.39; 2.00) < 0.0011.17 (0.98; 1.40)0.0871.31 (1.12; 1.53) < 0.0010.99 (0.83; 1.19)0.933Wheezep < 0.001p[RSV] = < 0.0011.24 (1.04; 1.46)0.0152.26 (1.84; 2.77) < 0.0011.25 (1.04; 1.51)0.0161.27 (1.09; 1.48)0.0021.06 (0.88; 1.27)0.54Myalgiap < 0.001p[RSV] = 0.3620.82 (0.72; 0.94)0.0030.89 (0.78; 1.01)0.070.90 (0.78; 1.05)0.1771.18 (1.02; 1.3690.0231.06 (0.89; 1.27)0.516Feverp < 0.001p[RSV] = 0.3480.71 (0.60; 0.83) < 0.0010.87 (0.73; 1.03)0.1040.96 (0.79; 1.18)0.7241.28 (1.06; 1.54)0.011.03 (0.82; 1.29)0.803Fatiguep = 0.033p[RSV] = 0.2920.99 (0.93; 1.04)0.611.01 (0.96; 1.07)0.7251.04 (0.97; 1.11)0.2631.07 (1.01; 1.13)0.0281.07 (0.98; 1.15)0.119Abbreviation: CI, confidence interval. RSV, respiratory syncytial virusStatistically significant values (p < 0.05) are indicated as bold
Within the 28-day observation period in RSV patients, cough and fatigue were the longest-lasting symptoms, with a median duration of 13 and 11 days, respectively, whereas fever was reported for a median of only four days. At the end of the observation period, 13.7% still reported coughing and 12.6% reported fatigue, which thus remained the longest-lasting symptoms (Fig. 2, table S6).
Fig. 2Kaplan-Meier analysis of symptom duration due to RSV infection. Symptom duration probability is given for every symptom over 28 daysSymptom duration probability declines over time for all eight symptoms.
Cough and fatigue persist longest, with probabilities of about 14 percent at day 28. Fever declines fastest, reaching nearly zero by day 23. Pain, pharyngitis, rhinitis, sputum, and wheeze fall to about 3 to 6 percent by day 28.
Within the same period, the median HRQoL at study inclusion (day 0) was 56.50 (43.75-70.00) on the EQ-5D-3L VAS for URTI and 50.00 (35.00–60.00) for LRTI. On day 14 and day 28, an increase to initially 85.00 (73.75-95.00) and subsequently 87.00 (80.00–91.00) was observed in URTI compared to 75.00 (65.00–75.00) and subsequently to 85.00 (75.00–90.00) in LRTI (Fig. 3, table S7).
Fig. 3Health-related quality of life by infection type in RSV-infected patients over 28 days. Boxplots showing EQ-5D-3L (y-axis) visual analogue scale (VAS) scores across visit timepoints (x-axis) after infection for patients with URTI and LRTI.
Boxplots display the median and interquartile range, with whiskers indicating data spread; individual outliers are marked as pointsMedian quality-of-life scores rise in both groups from day 0 to day 28. For URTI, the median increases from about 56 to 85 at day 14 and 87 at day 28. For LRTI, it increases from 50 to 75 and then 85.
URTI scores are higher at each visit, but the difference narrows by day 28. Several low outliers occur at days 14 and 28.
Complications due to RSV infection
Over the 28-day observation period, 58 RSV-infected patients (30%) experienced at least one complication. Pulmonary complications were most prevalent, with COPD or asthma exacerbations occurring in 31 cases (16%) and bronchitis in 28 cases (15%). Pneumonia due to RSV infection was observed in three cases (2%), four patients required hospitalization (2%) (Table 4a).
Table 4aComplications in patients with RSV infection within 28 daysRSV-ARI(N = 192)Any complication, n (%)58 (30)Hospitalization, n (%)4 (2)Pulmonary complications, n (%)47 (25) Bronchitis28 (15) Pneumonia3 (2) Asthma or COPD exacerbation31 (16)Cardiovascular complications, n (%)1 (1) Myocardial infarction0 (0) Pulmonary embolism0 (0) Thrombosis0 (0) Other11 (1)Worsening of pre-existing conditions, n (%)9 (5)Other complications2, n (%)10 (5)Abbreviations: ARI, acute respiratory infection; RSV, respiratory syncytial virus;1: Atrial fibrillation2: Urinary tract infection, headaches and dizziness, circulatory dysregulation problems, new-onset inguinal hernia, Mycoplasma pneumoniae co-infection, otitis media on both sides, otitis media on the left requiring tympanic membrane incision and high-dose prednisolone therapy, since then personal hypoacusis in left ear, hearing loss, dizziness when standing for long periods, TF rupture in left ear, simultaneous pertussis infection
Table 4bLogistic regression to identify risk factors for any complications due to RSV infectionPredictor(yes/no)Risk No95% CIRisk Yes95% CIunivariableRisk Ratio95% CIp-valuemultivariableRisk Ratio95% CIp-valueAge > 70100/9220.65(13.58; 30.13)39.00(29.96; 48.86)1.89(1.18; 3.02)0.0081.44(0.87; 2.38)0.156Female Sex111/8125.93(17.56; 36.52)33.33(25.20; 42.59)1.29(0.82; 2.02)0.2761.35(0.87; 2.08)0.176Chronic pulmonary diseases85/8923.60(15.92; 33.50)42.35(32.33; 53.04)1.79(1.15; 2.81)0.0111.62(0.95; 2.77)0.077Chronic heart diseases45/12932.56(25.04; 41.10)33.33(21.20; 48.17)1.02(0.63; 1.66)0.9240.94(0.64; 1.37)0.738Vascular / cerebrovascular diseases23/15129.80(23.05; 37.56)52.17(32.49; 71.20)1.75(1.1; 2.78)0.0171.65(0.96; 2.82)0.078Chronic liver disease4/17032.35(25.75; 39.74)50.00(12.35; 87.65)1.55(0.57; 4.22)0.3951.69(0.8; 3.59)0.168Chronic renal disease19/15530.97(24.19; 38.67)47.37(26.78; 68.89)1.53(0.9; 2.6)0.1151.02(0.63; 1.64)0.944Diabetes mellitus Type II23/16928.99(22.65; 36.28)39.13(21.77; 59.76)1.35(0.77; 2.37)0.2951.26(0.83; 1.92)0.281Dyslipidemia82/11021.82(15.07; 30.50)41.46(31.34; 52.36)1.9(1.23; 2.94)0.0041.41(0.88; 2.28)0.155LRTI120/7212.50(6.63; 22.31)40.83(32.41; 49.83)3.27(1.71; 6.24) < 0.0011.78(0.92; 3.45)0.087Abbreviations: LRTI, lower respiratory tract infection, CI, confidence intervalStatistically significant values (p < 0.05) are indicated as bold
In multivariate model, we identified a trend for chronic pulmonary diseases (RR 1.62 (95% CI: 0.95; 2.77), p = 0.077) and presence of LRTI (RR 1.78 (95% CI: 0.92; 3.45), p = 0.087) as potential risk factors for RSV-related complications (Table 4b).
Discussion
To our knowledge, this is the largest prospective, actively monitored surveillance study evaluating incidence, prevalence and disease burden of respiratory pathogens with focus on RSV in adults ≥ 60 years in the outpatient setting in Germany.
Over three consecutive seasons, we calculated a cumulative incidence of 1,030.63 per 100,000 outpatients aged ≥ 60 years with valid RT-PCR results. During three-season observation periods, RSV prevalence in our cohort was 5.49% (95% CI: 2.96–8.03), reflecting the probability of diagnosing RSV in an older adult presenting with ARI. This estimate is consistent with results from north America with PCR-confirmed RSV-positive rates of 5.5–5.8% over three seasons from 2022 to 2024 [17].
Comparable outpatient studies from Italy and the Netherlands over two seasons reported higher RT-PCR-confirmed detection rates for RSV (13.2%) and influenza (14.2%). In contrast, surveillance data from Greece demonstrated substantially higher detection rates for influenza (32%) and RSV (23.5%), with lower proportions for rhinovirus (2.6%) and coronaviruses (0.2%) [18, 19]. Data from the United States in adults aged ≥ 60 years further illustrate the heterogeneity in viral distribution.
In one cohort, influenza (23%) and RSV (11%) were among the most frequently detected pathogens but RSV detection exceeded that of several other respiratory viruses, contrary to our results [20].
A multi-seasonal outpatient study from Washington State reported a mean annual RSV incidence of 23.2 per 1,000 among individuals aged ≥ 65 years, exceeding that observed in our cohort [21].
McClure et al. reported an overall RSV incidence of 154 per 10,000 over four seasons (2006–2010) in a large cohort of adults aged ≥ 50 years [10]. Likewise, data from a large prospective study in Wisconsin (USA) demonstrated a seasonal incidence of 139 per 10,000 in a comparable age group, closely corresponding to our estimates [9]. Together, these findings suggest that our incidence calculations are within the range reported in prospective outpatient studies employing systematic viral testing.
It is noteworthy that studies relying on large administrative or claims databases for retrospective incidence calculations have generally yielded lower estimates than those observed in our cohort [22]. This discrepancy likely reflects underestimation due to limited or inconsistent virological testing in routine care. Furthermore, incidence estimates derived from similarly designed studies of hospitalized populations are often lower than those reported in outpatient cohorts [22].
In line with our results, Jackson et al. reported higher incidence rates for influenza compared to RSV in older adults [21]. However, large prospective studies systematically evaluating RSV incidence in the outpatient setting in direct comparison with other common respiratory viruses remain scarce. Such comparative data is essential to more precisely define the relative contribution of RSV to the overall burden of medically attended ARI in older adults.
Taken together, our incidence and prevalence estimate partly align with data from prospective outpatient studies. However, seasonal and regional influences limit the comparability and the proportion of different viruses in the total share of ARI also varies. Nevertheless, our study reinforces the substantial contribution of RSV to the burden of medically attended ARI in adults aged ≥ 60 years.
Systematic comparison of symptom profiles across viral pathogens delineates clinically meaningful differences between RSV and other respiratory viruses with respect to the risk of URTI and LRTI as well as the extent of systemic involvement. Patients with LRTI reported significantly lower HRQoL compared with URTI. Consistent with prior results, RSV infection was characterized by fewer systemic symptoms than influenza [12, 23–27].
Conversely, respiratory manifestations suggestive of lower airway involvement, such as wheezing and sputum production, were more frequently observed in RSV-positive patients in our cohort, in line with findings from other outpatient studies [12, 23]. A Japanese study of adults aged ≥ 60 years similarly identified a higher burden of LRTI-associated features in RSV infection relative to overall ARI, accompanied by a pronounced reduction in HRQoL, particularly at symptom onset [28]. These findings corroborate the notion that RSV in older adults frequently manifests with predominant lower respiratory tract involvement.
However, cross-study comparisons warrant caution given variability in comparator group composition, age structure, and the considerable overlap in clinical presentation across respiratory viruses, rendering symptom-based etiological differentiation unreliable. Thus, targeted virological diagnostics remain warranted. An additional consideration applies to comparisons involving influenza and SARS-CoV-2.
Vaccination against these pathogens was common in our cohort, whereas patients vaccinated against RSV were excluded, and vaccination may attenuate symptom severity. The symptom profiles reported here for influenza and SARS-CoV-2 therefore reflect a largely vaccinated population and may understate the presentation of these infections in unvaccinated individuals, whereas those for RSV describe an essentially unvaccinated population.
Our longitudinal follow-up revealed cough and fatigue as the most persistent symptoms following RSV infection, with median durations of 13 and 11 days, respectively. Notably, even at the end of the 28-day observation period, up to 14% of patients continued to report these symptoms. These findings align with previous outpatient studies describing median overall symptom durations of 14 to 19 days in RSV infection [29, 30].
An Italian outpatient cohort further reported persistent cough in approximately 20% of patients after 30 days of follow-up, closely matching our observations [31]. The structured follow-up design of our study provides detailed insights into the prolonged disease burden of RSV, which extends beyond acute respiratory manifestations to include sustained systemic symptoms, underscoring the broader and longer-lasting impact of RSV infection in older adults. Whether this prolonged symptom burden translates into persistent functional impairment, as described following hospitalization for respiratory infection in older adults [32], could not be determined within our 28-day observation period and warrants investigation in studies with longer follow-up.
Our study identified pulmonary complications as main complications due to RSV-infection within an observation period of 28 days with small percentage of patients requiring hospitalization (2%). Results from three different US health care databases revealed all-cause hospitalization of RSV patients between 8.9% and 10.3% for patients 65 years and older as well as 12% RSV-related hospitalization in a prospective study of patients > 60 years within the same observation period [9, 33]. A hospitalization rate of approximately 4% was calculated in a study estimating the costs of RSV infection in patients over 60 [34].
Data from the REspiratory Syncytial virus Consortium in EUrope (RESCEU) did not report any hospitalization due to RSV infection in two infection seasons [35].
Data about RSV infection in adults > 60 years extracted from Centers for Medicare & Medicaid Services reported worsening of chronic respiratory diseases, including asthma and COPD in approximately a quarter of patients, comparable to our results. Notably, rates of pneumonia were substantially higher [36]. In contrast to earlier studies, there were a low number of RSV-related cardiovascular events in our cohort.
Comparable studies mainly included patients hospitalized due to RSV infection. Woodruff et al. reported a prevalence of an acute cardiac event up to 22.4% [37]. Hospitalized patients from a Danish register study exhibited a relevant higher risk for cardiovascular complication compared to non-hospitalized patients due to RSV infection [38].
It must also be taken into consideration that the definition of cardiovascular events is not standardized. Short-term follow-up as in our study is often not available whereas our study does not provide long-term follow-up data. Overall, RSV-associated complications appear common but rarely necessitate hospitalization, with pulmonary complications predominating and cardiovascular complications occurring at low frequency in the outpatient setting.
This study has several strengths and limitations. Strengths include a clear and standardized definition of acute respiratory infection (ARI) with pathogen confirmation using multiplex PCR, ensuring high diagnostic accuracy. The large sample size and inclusion of patients over three seasons from multiple outpatient practices enhance statistical power and generalizability.
In addition, the prospective design with active patient observation and follow-up resulted in high data quality and an exceptionally low dropout rate.
Nevertheless, some limitations should be acknowledged when interpreting the results. Follow-up was restricted to 28 days and conducted exclusively in patients with RSV infection, precluding the assessment of long-term outcomes (e.g. functional impairments) and limiting longitudinal comparisons across different pathogens. Furthermore, while comparisons between pathogens were feasible at baseline, pathogen-specific differences during follow-up could not be evaluated.
As RSV vaccines were unlicensed at study initiation and vaccinated patients were excluded, our findings describe an essentially unvaccinated population and may not be generalizable in the future as vaccine uptake increases. Covariates for multivariable models were selected on clinical grounds rather than by data-driven procedures with limited number of events relative to the number of covariates. Thus, these models are susceptible to overfitting and the resulting effect estimates should be interpreted with caution.
Finally, patient characteristics, particularly comorbidities, were derived from medical records and were not independently verified, introducing the potential for misclassification.
Conclusion
In this large, multi-season outpatient ARI cohort of adults aged ≥ 60 years with a high prevalence of chronic comorbidities, RSV occurred at a lower incidence but exhibited a distinct clinical profile compared with other respiratory viruses. Clinically, RSV was characterized by a pronounced burden of lower respiratory tract symptoms, including cough, sputum production and wheezing along with prolonged symptom duration and a substantial short-term impact on HRQoL. Although severe outcomes were infrequent, complications occurred in nearly one-third of RSV cases, primarily pulmonary in nature, with chronic lung disease and LRTI symptoms as potential risk factors for RSV-related complications.
Supplementary Information
Below is the link to the electronic supplementary material.
Supplementary Material 1: Additional file 1 (.docx). Additional file 1: Supplementary Tables and Methods. Table S1: Pathogens included in Qiagen® QIAStat Respiratory SARS-CoV-2-Panel.
Table S2: Classification of comorbidities for risk analysis. Table S3: Vaccination rates for influenza and SARS-CoV-2. Table S4: Co-detected pathogens in RSV-positive patients.
Table S5a: Baseline comorbidity profile by respiratory virus. Table S5b: Pairwise comparison between RSV and other respiratory virus by comorbidity. Table S6: Duration of RSV-ARI related symptoms over 28 days.
Table S7: Health related Quality of Life (EQ-5D-3L) in RSV infected patients over 28 days. Detailed description of incidence and prevalence calculation
Supplementary Material 2