Respiratory Syncytial Virus--Associated Respiratory Diseases in Children and Adults.

Background: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections (LRTI), particularly in neonates, infants and young children, with approximately 33 million infections worldwide each year. 1-2% of episodes lead to hospitalization. There are hardly any reliable epidemiological figures on hospitalization in adults, whose burden of disease from RSV is probably markedly underestimated.

Methods: This review is based on publications retrieved by a selective search in PubMed, with particular attention to recommendations for the prevention of RSV infection.

Results: There is no approved antiviral therapy for clinical practice, but preventive strategies are increasingly becoming available. Passive immunization in infants is well tolerated and highly effective, as is the active vaccination of pregnant women to prevent severe RSV infection in young infants. The former was found to lower the frequency of severe LRTI (5/4037 in the vaccination group vs. 19/4031 individuals in the placebo group), yielding an efficacy of 75.7%; for the latter, the corresponding findings were a reduction to 19/3682 in the vaccination group vs. 62/3676 in the placebo group, or 69.4% efficacy. For the active vaccination of older adults, both a recombinant vaccine with adjuvant and a bivalent vaccine have recently been approved. These, too, are well tolerated and highly effective: the former lowered the frequency of severe LRTI to 1 /12466 in the vaccination group vs. 17/12494 in the placebo group (94.1% efficacy), while the latter lowered the frequency of LRTI with 3 or more manifestations to 2/17215 in the vaccination group vs. 14/17069 in the placebo group (85.7% efficacy).

Conclusion: The approval of new RSV-specific monoclonal antibodies and active vaccinations enables targeted prevention of RSV infection in the main population groups at risk.

Cite this as:

Tenenbaum T, Liese J, Welte T, Rademacher J: Respiratory syncytial virus-associated respiratory diseases in children and adults. Dtsch Arztebl Int 2024; 121: 303-12. DOI: 10.3238/arztebl.m2024.0060

Respiratory syncytial virus (RSV) is the most common cause worldwide of respiratory-related hospitalizations of children under age five (1). Nearly all children have been infected with RSV by the age of two years. Recurrent, often oligo- or asymptomatic infections also occur, including in persons who are already infected, as there are different types of RSV (RSV A and RSV B) and further genotypes exist within these types (1). Moreover, immunity after infection is limited (1). RSV appears seasonally each year, with a season lasting approximately five months. In Germany the RSV season usually begins sometime between mid-October and late December and ends between late March and late June.

Infections can be more severe in certain population groups, such as young infants, children under age five, persons who were born prematurely, immunocompromised persons, children with chronic heart or lung disease, e.g., hemodynamically significant heart defects or bronchopulmonary dysplasia, and children with genetic syndromes such as trisomy 21 (2). Data from the USA show that 1-2% of all RSV infections lead to hospitalization, and approximately 10% of hospitalized patients are treated in an intensive care unit (3).

In a systematic analysis of the RSV-related disease burden in children under age 5, published in 2022, it was estimated that there were 33 million episodes of RSV-associated lower respiratory tract infection in 2019, causing 3.6 million hospitalizations and 26 300 inpatient deaths worldwide (4). Comparable figures were obtained in an earlier systematic estimate from 2015 (5). More than 97% of RSV-related deaths occur in low- and middle-income countries.

This shows that the health care system in these countries suffers from inadequate infrastructure and limited resources, resulting in difficulty coping with the RSV disease burden. In Germany, 205 352 hospitalizations with the ICD-10 code for RSV were registered in the years 2010 to 2019. Of these hospitalizations, 198 139 (96.4%) were of persons under age 18, 1 313 (0.6%) of persons aged 18 to 59, and 5,900 (2.9%) of persons aged 60 and above. Among persons hospitalized for RSV who were over 10 years of age, 612 died (0.3% of all hospitalizations): 103 (0.1%) were under age 18, 51 (3.9%) were aged 18 to 59, and 458 were over age 60. Assuming that most of the persons who died did so in the hospital, and that the children who died had probably also received a diagnosis of RSV, the resulting figures are of ca. 10 deaths per year of persons under age 18, 5 deaths per year of persons aged 18 to 59, and 45 deaths per year of persons aged 60 and above. The adults suffered more commonly from chronic underlying diseases and complications and were more frequently cared for in an intensive care unit (6). Nonetheless, in the study of Hartmann et al., no deaths were seen in children in any age group (including those up to 5 years of age) (7).

The morbidity associated with RSV infection in infants places a major burden on health care systems. In a retrospective analysis, RSV was 5 to 16 times more likely than influenza to cause admission to a hospital and/or emergency department in children under age 5 (8). It places a major burden on outpatient care as well: in a surveillance study, 21% of children under the age of 24 months in the emergency department, and 18% in pediatric practices, were RSV-positive (9).

Adults aged 60 and above have received increasing attention as a vulnerable group in recent years, as the case-fatality rate of RSV infection is as high as ca. 10% of hospitalized patients (10). It has recently been reported that RSV infection in adults can take a more severe clinical course than influenza (11, 12). A recently published study showed a significant reduction in the risk of cardiovascular events 25-28 days after influenza vaccination (incidence ratio 0.72, 95% confidence interval [0.70; 0.74]) (13). In patients with COPD, viruses act as a trigger for exacerbations and thus play an important role in disease progression Vaccination may be an effective preventive strategy (14). In a study from the German network for community-acquired pneumonia (CAPNETZ) that was recently presented at an international meeting, it was found that 57% of acute respiratory infections in the 2022/2023 season were of viral origin; RSV was present in 21% and influenza in 6% of this cohort. The most common comorbidity was asthma in 30.2% of patients, followed by chronic obstructive pulmonary disease (COPD) in 24.5% (15).

In adults, a high level of underreporting is suspected in both the inpatient and the outpatient sector as the result of insufficient diagnostic evaluation (16).

Given the frequency and importance of RSV infections in outpatient pediatrics and primary care, as well as in the hospital sector, this article is intended to give readers an overview of the following topics:

• the epidemiology and disease burden in children and adults,
• the clinical presentation of RSV infection,
• and the diagnosis, treatment, and prevention of RSV infection.

Diagnostic evaluation for an RSV infection is generally only carried out in the hospital, as RSV infection in outpatients most often needs no treatment. The evaluation in the hospital serves the purpose of differential diagnosis. Antigen tests from nasopharyngeal swabs and lavages are usually used, as these are of adequate sensitivity and specificity depending on age, especially in the RSV season (17). RSV polymerase chain reaction (PCR) testing of sputum or nasopharyngeal or pharyngeal swabs is increasingly being used in multiplex procedures because of its higher sensitivity and specificity (17). The increased use of multiplex PCR methods in hospitals during the COVID-19 pandemic led to an increase in the detection of RSV, especially in older adults, and to wider recognition that this pathogen causes disease in adults as well, and not just in children.

Vaccine GSK3844766A; RSVPreF3 OA PF-06928316; RSVpreF mRNA-1345 RSV PreF Trade name Arexvy Abrysvo not stated Formulation solution for injection in a prefilled syringe, protein + adjuvant solution for injection in a prefilled syringe, prefusion F protein without adjuvant, bivalent solution for injection in a prefilled syringe, mRNA Target antigen prefusion F prefusion F (RSV A and B) prefusion F Stage of development phase 3 (A ReSVI-006) phase 3 (RENOIR) phase 3 (MATISSE) phase 2/3 (ConquerRSV) Level of evidence Ib Ib Ib Ib Target group older adults > 60 years of age older adults > 60 years of age women in week 24-36 of pregnancy older adults > 60 years of age Endpoints prevention of an LRTI by RSV prevention of a severe LRTI prevention of LRTI by RSV with > 2 symptoms > 3 symptoms prevention of a: - severe RSV-LRTI - medically attended RSV-LRTI of the newborn prevention of LRTI by RSV with > 2 symptoms > 3 symptoms Events comparison of vaccination vs. placebo group RSV-LRTI 7/12 466 (0.06%) vs. 40/12 494 (0.32%) severe RSV-LRTI 1/12 466 (0.06%) vs. 17/12 494 (0.14%) RSV-LRTI ≥ 2 symptoms 11/17 215 (0.06%) vs. 33/17 069 (0.19%) RSV-LRTI ≥ 3 symptoms 2/17 215 (0.01%) vs. 14/17 069 (0.08%) severe RSV-LRTI 6/3 682 (0.16%) vs. 33/3 676 (0.99%) up to 90 d; 19/3 682 (0.51%) vs. 62/3 676 (1.68%) up to 180 d; medically attended RSV-LRTI 24/3 682 (0.65%) vs. 56/3 676 (1.52%) RSV-LRTI ≥ 2 symptoms 9/17 793 (0.05%) vs. 55/17 748 (0.31%) RSV-LRTI ≥ 3 symptoms 3/17 793 (0.02%) vs. 17/17 748 (0.09%) Efficacy* LRTI 82.6% (96.95%, 95% CI [57.9; 94.1]) severe RSV-LRTI 94.1% (95% [62.4; 99.9]) (33) RSV ≥ 2 symptoms: 66.7% (96.66% [28.8; 85.8]) RSV ≥ 3 symptoms: 85.7% (96.66% [32; 98.7]) (24) severe RSV-LRTI 81.8% (99.5% [40.6;96.3]) to 90 d; 69.4% (97.58% [44.3;84.1]) to 180 d; medically attended RSV-LRTI : 57.1% (99.5% [14.7; 79.8]) (37) RSV ≥ 2 symptoms: 83.7% (95.88% [66; 92.2]) RSV ≥ 3 symptoms: 82.4% (96.36% [34.8; 95.3] (38) Dosage 1 × 120 μg i.m. 1 × 120 μg i.m. 1 × 120 μg i.m. 1 * 50 μg i.m. Approval Europe and USA Europe and USA Europe and USA not approved to date

* Efficacy with respect to primary endpoint of trial

CI, confidence interval; d, days; i.m. intramuscular; LRTI, lower respiraatory tract infection; mRNA, messenger ribonucleic acid; RSV, respiratory syncytial virus

Before hospital admission, validated point-of-care RSV testing (by antigen test or PCR) should be performed during the RSV season in all children and adults with respiratory infections, so that individual or cohort isolation can ensue if necessary. The results of RSV tests should be available before admission to a hospital ward (18).

In the guideline for high-risk children issued by the Association of the Scientific Medical Societies in Germany (AWMF), RSV testing is also recommended during the RSV season before admission to high-risk areas of the hospital, e.g. transplantation wards, even for asymptomatic children, to prevent the nosocomial spread of infection (18). According to Section 7(1)(38a) of the Infection Protection Act (IfSG) in Germany, which went into effect in July 2023, any direct or indirect detection of RSV that indicates an acute infection must be reported to the local public health department.

In the first two years of life, almost all children contract an RSV infection; in 90% of cases, this manifests itself as an acute respiratory disease of the upper respiratory tract woith a mild and self-limiting course (1). In the remaining 10%, RSV infection progresses to affect the lower respiratory tract, and for this reason RSV is the most common cause of bronchitis, bronchiolitis, and pneumonia in neonates, infants, and preschool children. Little is known about long-term immunity after primary RSV disease in childhood; reinfections can occur but have not been systematically studied to date (19, 20).

RSV is transmitted through the air by coughing and sneezing, but also via contaminated surfaces. Children who require hospitalization usually present with bronchiolitis or pneumonia (Figure 1). Typical manifestations of RSV infection include low-grade fever, rhinitis and dry cough, and (in acute bronchiolitis or pneumonia) crackles, tachypnea, retractions, and occasional wheezing, sometimes accompanied by refusal to take nourishment and by cyanosis.

The clinical presentation is highly age-dependent. Bronchiolitis occurs up to the age of 24 months as a manifestation of a lower respiratory tract infection. Older infants usually develop RSV bronchitis or RSV pneumonia. RSV bronchitis often has an obstructive component and may be accompanied by hypoxemia. RSV-associated laryngitis subglottica is also part of the clinical spectrum (croup syndrome) (18). It has also been shown that RSV infection can precede bacterial pneumonia, e.g., pneumococcal pneumonia (21).

Although children can develop recurrent obstructive bronchitis after a severe RSV infection, a causal relationship between early childhood RSV disease and later bronchial asthma has not yet been shown (22).

RSV has long been underestimated as a cause of respiratory infection in adults. Severe infections have so far been reported mainly in the fields of hematology/- oncology and stem-cell transplantation. In young adults, RSV infection resembles a common cold and is largely indistinguishable from diseases caused by other respiratory viruses (23). Most patients (89%) report symptoms such as cough, nasal congestion, increased sputum production, and physical weakness (24). In persons with comorbidities, RSV infection can worsen the underlying disease (asthma, COPD, congestive heart failure) (25). Immunosuppressed persons are at increased risk of RSV-related pneumonia (Figure) (4, 25). Age, too, is a risk factor for severe disease progression (26). In a retrospective study from Germany, older patients with RSV more frequently developed pneumonia or bacterial superinfections than older patients with influenza; they had a higher rate of needing mechanical ventilation and a higher mortality (odds ratio 1.65 [0.98; 2.74]) (11).

In otherwise healthy children and adults, symptomatic treatment usually suffices. Aerosolized ribavirin is no longer available for the treatment of RSV in children and adults and was only partially effective and incompletely safe (27). there have been case reports of oral or intravenous ribavirin administration off label to treat severe RSV infections in immunocompromised patients (28). In uncontrolled case series of high-risk adult patients in hematology/oncology, oral ribavirin treatment yielded high cure and survival rates comparable to those of inhaled ribavirin treatment (29).

Palivizumab Nirsevimab Trade name Synagis Beyfortus Formulation solution for injection in a prefilled syringe with monoclonal antibody solution for injection in a prefilled syringe with monoclonal antibody Target antigen A-epitope of the fusion protein (F protein) RSV prefusion protein Stage of development phase 3 IMpact study phase 2b phase 3 (MELODY) phase 3b (HARMONIE) Level of evidence Ib Ib Ib Ib Target group premature infants < 35 weeks gestation (high-risk infants) neonates (week > 29 to < 35 of gestation) term & late preterm infants (week > 35 of gestation) term & late preterm infants (week > 35 of gestation) Endpoints reduction of RSV-associated hospitalization for lower respiratory tract infection reduction of medically attended lower respiratory tract infections and of RSV-associated hospitalization for lower respiratory tract infections Events comparison of vaccination vs. placebo group 53/500 (10.6%) vs. 48/1002 (4.8%) (primary analysis) 34/266 (12.8%) vs. 39/496 (7.9%) (bronchopulmonary dysplasia) 19/234 (8.1%) vs. 9/506 (1.8%) (preterm infants < 35 weeks gestation without bronchopulmonary dysplasia) reduction in medically attended lower respiratory tract infection: 25/969 (2.6%) vs. 46/484 (9.5%) infants reduction in RSV-associated hospitalization for lower respiratory tract infection: 8/969 (0.8%) vs. 20/484 (4.1%) infants reduction of medically attended lower respiratory tract infection: 12/994 (1.2%) vs. 25/496 (5.0%) infants reduction of RSV-associated hospitalization for lower respiratory tract infection: 6/994 (0.6%) vs. 8/496 (1.6%) infants reduction of medically attended severe lower respiratory tract infection: 5/4037 (0.1%) vs. 19/4021 (0.5%) infants reduction of RSV-associated hospitalization for lower respiratory tract infection: 11/4037 (0.3%) vs. 60/4021 (1.5%) infants Efficacy* 55% (all premature babies ≤ 35 weeks gestation) 39% (bronchopulmonary dysplasia) 78% (premature babies < 35 weeks gestation without bronchopulmonary dysplasia) (40) LRTI: 70.1%, 95% CI [52.3; 81.2] hospitalization: 78.4% [51.9; 90.1] (e1) LRTI: 74.5 [49.6; 87.1] hospitalization: 62.1% [-8.6; 86.8] (e3) severe LRTI: 75.7% [32.8; 92.9] hospitalization: 83.2% [67.8; 92] (e4) Dosage 15 mg per kilogram body weight, a total of 5 times in the RSV season, i.m. 50 mg for infants < 5 kg i.m. 100 mg for infants ≥ 5 kg i.m. Approval Palivizumab is indicated for the prevention of lower respiratory tract RSV disease in preterm infants (< 6 months), children with bronchopulmonary dysplasia (< 2 years), and children with hemodynamically significant congenital heart defects (< 2 years). Nirsevimab is indicated for the prevention of lower respiratory tract RSV disease in newborns and infants during their first RSV season. In addition to the risk factors defined for palivizumab (see left), the Federal Joint Committee considers the administration of RSV antibodies to be justifiable in children who are up to 6 months old at the start of the RSV season and were born before the 35th week of gestation.

* Efficacy with respect to primary endpoint of trial

CI, confidence interval; i.m., intramuscular; LRTI, lower respirator tract infaction; RSV, respiratory syncytial virus

Oxygen therapy is indicated for children with hypoxemia and a peripheral oxygen saturation below 92%, and in all children with a peripheral oxygen saturation below 90%. In children with severe respiratory distress and hypercapnia, (additional) high-flow therapy may shorten the illness. For the symptomatic treatment of RSV respiratory tract infection, decongestant nasal drops and -- in the case of obstructive bronchitis/bronchiolitis -- inhalation therapy with salbutamol, (concentrated) saline inhalation, and adrenaline can be used on a trial basis after individual testing (30). Of all these measures, only oxygen therapy has been shown by adequate evidence to be beneficial (31). Oxygen therapy should also be initiated in adults with acute respiratory insufficiency (oxygen saturation < 90%). Antipyretic drugs and fluids can be given as symptomatic treatment (32). In children and especially in adults with known bronchial hyperreactivity, inhaled and/or systemic steroids can also be used on a trial basis as the disease progresses. Steroid therapy may be beneficial in adults, as it is already a standard treatment for exacerbations of severe asthma or COPD. Antibiotics are indicated when there is clinical and radiological suspicion of a bacterial superinfection.

Two vaccines for active immunization have been approved in Europe and the USA since 2023 (Table 1 ). Both are protein-based vaccines with the target antigen of prefusion F, the primary docking site of neutralizing antibodies.

The first vaccine is the adjuvanted protein vaccine RSVpreF3, which is mainly intended for older adults. The study included 24 966 participants aged 60 and above, half of whom were vaccinated with RSVPreF3 OA and the other with placebo. A single-dose vaccine efficacy of 82.6% (7 / 12 466 in the vaccine group vs. 40 / 12 494 in the placebo group) was achieved for the prevention of RSV-associated lower respiratory tract infection (LRTI) (33). Vaccine efficacy for preventing severe LRTI was 94.1% (1 / 12 466 vs. 17 / 12 494) (33). The vaccine was generally well tolerated, with frequent but transient side effects of mild or moderate severity (pain, redness, swelling at the injection site, as well as fever, headache, fatigue, myalgia and arthralgia) in 71.9% of those vaccinated. High efficacy was also achieved for patients with pre-existing comorbidities (> 1 pre-existing comorbidity, 30 / 12 469 in the vaccination group vs. 139 / 12 498 in the placebo group; 94.6% efficacy ) (34). The induction of the humoral immune response was independent of comorbidities and showed high efficacy for both RSV A and B. One month after the injection, the RSVPreF3-specific IgG antibodies were elevated by a factor of 13.1. One year into the study, the vaccination group was randomized 1:1 into two groups that received either a booster vaccination or placebo. One dose of RSVPreF3 vaccination had an efficacy of 67.2% (30 / 12 470 in the vaccination group vs. 139 / 12 498 in the placebo group) for preventing RSV LRTI over two RSV seasons. Two doses were no more effective than a single dose (20 / 6 242 in the revaccination group vs. 20 / 6 227 in the single-dose vaccination group ) (35). A single preseason coadministration with a quadrivalent influenza vaccine can be performed without loss of efficacy and without increased side effects (36).

The second approved RSV vaccine, RSVpreF, is a bivalent, recombinant protein-based, non-adjuvanted RSV vaccine. It is approved both for the vaccination of older persons (Table 1) and for the vaccination of pregnant women to prevent RSV-associated LRTI in infants (24, 37) (Figure 2).

In approval trials for the vaccination of older persons, 34 284 subjects from seven countries were included, and an efficacy against RSV-LRTI of 66.7-85.7% -- depending on disease manifestations -- was shown in all age groups (RSV-LRTI with at least two manifestations: 11 / 17 215 in the vaccination group vs. 33 / 17 069 in the placebo group; RSV-LRTI with at least 3 manifestations: 2 / 17 215 in the vaccination group vs. 14 / 17 069 in the placebo group) (24). Most local reactions, such as pain (12% vaccination vs. 7% placebo), and systemic events, such as fatigue, were of mild or moderate severity (27% vs. 26%).

In the MATISSE study with the RSV vaccine RSVpreF, 7126 women worldwide who were in weeks 24 to 26 of pregnancy were included. Vaccination lowered both the rate of severe LRTI (6 / 3 682 in the vaccination group vs. 33 / 3 676 in the placebo group, efficacy 81.8% at 90 days; 19 / 3 682 vs. 62 / 3 676, efficacy 69.4% at 180 days) and the rate of non-severe LRTI (24 / 3 682 vs. 56 / 3 676 , efficacy 57.1%) in the infants (37). Overall, there was no clear evidence of reduced safety, although the number of preeclampsia cases and the preterm birth rate were insignificantly higher than in the control group (66 cases (1.8%) vs. 51 cases (1.4%), and 209 cases (5.7%) vs. 167 cases (4.7%), respectively). In view of these findings, additional post-marketing approval studies on the safety of the vaccine are being carried out, and vaccination is currently only recommended in the USA for women in weeks 32 to 36 of pregnancy.

The third RSV vaccine, which is currently undergoing further development in phase 3, is an mRNA (messenger ribonucleic acid) vaccine; it, too, targets the pre-fusion F antigen. In the ConquerRSV approval trial, persons aged 60 and above were randomized 1:1. 35 541 subjects were included in the trial, half of whom were vaccinated with mRNA-135 (38). The efficacy of the vaccine was 83.7% against LRTIs with at least 2 manifestations (9 / 17 793 in the vaccination group vs. 55 / 17 748 in the placebo group) and 82.4% (96.36% [34.8; 95.3]) against LRTIs with at least 3 manifestations (3 / 17 793 vs. 17 / 17 748). The protective effect was demonstrated against both RSV subtypes (A and B). The median follow-up interval was 112 days. The rates of local reactions (58.7 % vs. 16.2 %) and systemic side effects (47.7 % vs. 32.9 %) were higher in the vaccination group; most reactions were mild to moderate.

Immunosuppressed persons were excluded from the approval trials for RSV vaccines. RSV poses a significantly increased risk for this group in particular. Further studies are therefore urgently needed here. A position paper on RSV vaccination for high-risk patients was issued under the aegis of the German Respiratory Society, in collaboration with a number of other German specialist societies (39).

The recommendations of other countries for RSV vaccination in older persons are summarized in eTable 1.

The monoclonal anti-RSV-F antibody palivizumab has been approved for many years for the prevention of RSV-associated severe lower respiratory tract disease in children at elevated risk. Its administration is complex and costly; five doses are required for a protective effect of 50-70% in an RSV season (40).

In the A WMF S2k guideline (AWMF-LL 048-012) on the prophylaxis of severe respiratory syncytial virus (RSV) disease in high-risk infants, palivizumab is recommended, particularly for premature infants with chronic lung disease and infants with hemodynamically significant heart defects, especially in the first year of life. There is also an optional recommendation for preterm infants of gestational age less than 28 weeks (18).

Another monoclonal anti-RSV-F antibody, nirse-vimab, has been approved since the fall of 2022 for the prevention of RSV lower respiratory tract disease in new-borns, infants, and pre-school children during or before their first RSV season. Nirsevimab has the advantage of a longer half-life than palivizumab owing to a modification of its Fc portion; a single dose exerts a protective effect for six months.

The efficacy and safety of nirsevimab were investigated primarily in healthy infants in the first six months of life and in preterm infants born at 29 or more weeks of gestation in four randomized, double-blind, placebo-controlled, multicenter trials: one phase 2b trial (el), the MEDLEY trial (phase 2/3)(e2), the MELODY trial (phase 3) (e3) and the HARMONIE trial (phase 3b) (e4). The primary endpoint for all three efficacy trials was the incidence of medically treated (severe) lower respiratory tract infections (including hospitalization).

The phase 2b trial included 1 453 preterm infants (gestational age > 29 to < 35 weeks) in 23 countries (northern and southern hemispheres) (el). Compared to placebo, nirsevimab was 70.1% effective in reducing medically attended lower respiratory tract infection (25/969 in the vaccination group vs. 46/484 in the placebo group [52.3; 81.2]; p < 0.001). The hospitalization rate was reduced by 78.4% (8/969 vs. 20/484 placebo [51.9; 90.1], p < 0.001) (Table 2).

In the phase 3 MELODY trial (e3), 1490 newborns and late preterm infants born at 35 weeks of gestation or later were included (Table 2). This trial yielded a reduction of medically attended LRTI by 74.5% ([49.6; 87.1]; p < 0.001; 12/994 in the vaccination group vs. 25/496 in the placebo group) and of RSV-associated hospitalization in LRTI by 62.1% ([-8.6; -86.8]; p < 0.001; 6/994 vs. 8/496).

925 infants were included in the phase 2/3 MEDLEY trial (e2); 650 were healthy preterm infants of less than 35 weeks' gestation (200 of less than 29 weeks' gestation) and 310 had chronic lung disease due to preterm birth and/or hemodynamically significant congenital heart disease. In the nirsevimab group, 4 out of 616 children (0.6 %) developed RSV; in the palivizumab group, 3 out of 309 (1 %).

The Phase 3b HARMONIE trial included 8058 infants from the UK, France, and Germany. The inclusion criterion was a gestational age of at least 29 weeks. The recently published findings resemble the pre-published findings with respect to safety and efficacy (e4) (Table 2). There was a reduction of medically attended severe LRTI by 75.7% ([32.8; 92.9]; 5/4037 vaccination group versus 19/4021 placebo) and of RSV-associated hospitalization for LRTI by 83.2% ([67.8; 92.0]; 11/4 037 vaccination group versus 60/4 021 placebo). This trial, unlike previous ones, was conducted in a strong RSV season.

The nirsevimab development program thus mainly concerned late preterm infants (> 35 weeks' gestation) and infants born at term without risk factors. Thus, few data are available for patients at high risk of severe RSV infection as defined in the AWMF guideline (3, e5). In absolute terms, far more children without risk factors (around 70%) develop RSV infection of the lower respiratory tract, many of whom also require hospitalization; Yet only a small percentage of all infected children need to be hospitalized. Initial data from Spain and Luxembourg provide further evidence for the benefit of nirsevimab (e6, e7). Other countries' recommendations for RSV prevention in children are listed in eTable 2.

The development of new means to prevent RSV infection or disease is now in a highly dynamic phase (e8). Alongside RSV prevention in high-risk patients, prevention of severe RSV disease in childhood will be possible in the future both through the immunization of healthy infants, including newborns, with monoclonal antibodies and through vaccination of expecting mothers with active RSV vaccines during pregnancy. Since RSV in adults is probably a viral disease with a course at least as severe as influenza, the potential benefits of vaccination in terms of reducing the disease burden are obvious (13). the improvement of vaccination rates and the establishment of vaccination programs have the potential to be a major step forward in primary, secondary, and tertiary prevention (e9). In the current AWMF recommendations, passive immunization with nirsevimab and palivizumab is reserved for high-risk groups. Whether active immunization against RSV in older persons and in patients with underlying diseases is medically appropriate and economically viable cannot be conclusively assessed at this time.

We mourn the loss of our highly esteemed colleague Prof. Toblas Welte, who contributed to the creation of this manuscript to the very end with his rich scientific and clinical knowledge and his easygoing manner.

JL has received third-party research funding from GSK Rixensart, MSD and Janssen R/D. He is coordinator of the AWMF guideline for the prophylaxis of severe respiratory syncytial virus (RSV) disease in high-risk children.

JR has received funding, consultancy fees and grants for presentations from GSK and Pfizer.

TT has received third-party research funding from Sanofi and Pfizer. He has received payment for presentations from Sanofi. He is a member of the Advisory Boards of Sanofi and MSD.

TW (t) received funding, consultancy fees, and lecture honoraria from GSK and Pfizer. He was a member of the Advisory Boards of GSK and Pfizer.

Manuscript received on 2 November 2023, revised version accepted on 21 March 2024.

Translated from the original German by Ethan Taub, M.D.

Tenenbaum T, Liese J, Welte T, Rademacher J: Respiratory syncytial virus-associated respiratory diseases in children and adults. Dtsch Arztebl Int 2024; 121: 303-12. DOI: 10.3238/arztebl.m2024.0060

• Participation in the CME certification program is possible only over the Internet: cme.aerzteblatt.de. This unit can be accessed until 2 May 2025. Submissions by letter, e-mail or fax cannot be considered.
• The completion time for all newly started CME units is 12 months. The results can be accessed 4 weeks following the start of the CME unit. Please note the respective submission deadline at: cme.aerzteblatt.de.
• This article has been certified by the North Rhine Academy for Continuing Medical Education. CME points can be managed using the "uniform CME number" (einheitliche Fortbildungsnummer, EFN). The EFN must be stated during registration on www.aerzteblatt.de ("Mein DÄ") or entered in "Meine Daten," and consent must be given for results to be communicated. The 15-digit EFN can be found on the CME card (802 7XXXXXXXXXXX)

Respiratory syncytial virus (RSV) is the most common cause of respiratory-related hospitalizations in children under age 5 worldwide. By the age of two, almost all children have been infected with RSV. RSV infections continue to occur seasonally after the COVI D-19 pandemic.

The disease burden of RSV infections is high in young infants and underestimated in older adults (with comorbidities).

According to recent studies, ICD-10-coded hospitalizations due to RSV infection in Germany were mainly registered in children. However, unlike children, hospitalized adults with respiratory infections are not regularly tested for RSV.

Adults aged 60 and above have received increasing attention as a vulnerable group in recent years, as the case-fatality rate of RSV infection is as high as ca. 10% of hospitalized patients.

Antigen tests from nasopharyngeal swabs and lavages are usually used, as these are of adequate sensitivity and specificity depending on age, especially in the RSV season. RSV polymerase chain reaction (PCR) testing of sputum or nasopharyngeal or pharyngeal swabs is of higher sensitivity and specificity.

Before hospital admission, validated point-of-care RSV testing (by antigen test or PCR) should be performed during the RSV season in all children and adults with respiratory infections, so that individual or cohort isolation can ensue if necessary.

Severe RSV infections in children usually present with bronchiolitis and/or pneumonia.

In older adults, patients with comorbidities are especially prone to a severe course. Bacterial co-infection contributes to disease severity.

In a retrospective study from Germany, older patients with RSV more frequently developed pneumonia or bacterial superinfections than older patients with influenza; they had a higher rate of needing mechanical ventilation and a higher mortality.

No effective specific treatment for RSV infection in children and adults is available to date.

Two vaccines for active immunization have been approved in Europe and the USA since 2023. Both are protein-based vaccines with the target antigen of prefusion F, the primary docking site of neutralizing antibodies.

The active vaccination of older adults, and of pregnant women to protect the newborn, has recently become available as an effective preventive measure.

Immunosuppressed patients were excluded from the vaccine approval trials. As this group is at markedly increased risk of RSV, further studies are urgently needed.

The efficacy and tolerability of passive immunization in infants to prevent severe RSV infection is well documented in young infants.

Alongside RSV prevention in high-risk patients, prevention of severe RSV disease in childhood will be possible in the future both through the immunization of healthy infants, including newborns, with monoclonal antibodies and through vaccination of expecting mothers with active RSV vaccines during pregnancy.

Questions on this article in issue 9/2024

The submission deadline is 2 May 2025. Only one answer is possible per question. Please select the answer that is most appropriate.

a) RSV infections were also common during the COVID-19 pandemic.

b) RSV infections are more common than influenza infections.

c) RSV infections occur more frequently in the fall/winter season.

d) RSV infections only affect at-risk groups.

e) Adults fall ill more frequently than children under 3 years of age.

a) the polymerase chain reaction

b) an antigen test

c) chest x-ray

d) bronchoscopy

e) positron emission tomography of the upper respiratory tract

a) pruritus

b) gastroenteritis

c) tachycardia

d) atrial fibrillation

e) bronchiolitis/pneumonia

a) Otherwise healthy children and adults are treated with ribavirin.

b) In otherwise healthy children and adults, symptomatic treatment usually suffices.

c) Oxygen therapy is often necessary.

d) High-flow therapy is standard treatment.

e) Antibiotics are necessary because of frequent bacterial co-infection.

a) healthy children up to age 2

b) premature infants with chronic lung disease

c) healthy full-term infants with siblings under age 3

d) healthy mature twins

e) simultaneous administration to mother and child up to age 3

a) It should be offered to all adults.

b) According to studies, older adults (> 60 years) and people with risk factors in particular should be vaccinated.

c) It should not be administered, because it is only effective in children.

d) In view of the expected adverse drug reactions, only healthy adults should be vaccinated.

e) Vaccination in adults has been part of the recommended vaccination scheme of the Standing Vaccination Commission in Germany since 2022.

a) high-dose intravenous administration of corticosteroids

b) administration of oseltamivir

c) combination therapy of acyclovir with lamivudine

d) high-flow therapy

e) elevation of the upper body and administration of an antipyretic agent

a) It only protects the mother against RSV infection.

b) It only leads to maternal passive immunization via breastfeeding of the newborn.

c) It offers no advantage over passive immunization.

d) It is most effective in the first trimester and should be given during this period.

e) It affords maternal passive immunization via transplacental antibody transfer and via breastfeeding of the newborn, as well as protection against RSV disease in the mother.

a) protein-based vaccine

b) live vaccine

c) RNA vaccine

d) vector-based vaccine

e) polysaccharide vaccine

a) bronchial asthma

b) chronic obstructive pulmonary disease

c) a cardiovascular disease

d) a cataract

e) a neoplasia

Supplementary material to:

by Tobias Tenenbaum, Johannes Liese, Tobias Welte (f), and Jessica Rademacher

Dtsch Arztebl Int 2024; 121: 303-12. DOI: 10.3238/arztebl.m2024.0060

Country Recommending organization/group Recommendation Reimbursed? References USA Advisory Committee on Immunization Practices (ACIP) all persons aged > 60 years yes (e10) UK Joint Committee on Vaccination and Immunisation (JCVI) all persons aged > 75 years yes (e11) Austria Austrian Federal Ministry of Social Affairs, Health Care, and Consumer Protection atandard vaccination in persons > 60 years of age; also indicated for persons > 18 years of age with immunosuppression or chronic pre-existing lung diseases - (e12) Belgium Working Group of the Organization for Vaccination Strategy persons aged > 60 years with > 1 pre-existing disease (chronic lung, heart and kidney disease, obesity, immunosuppression) - (e13) Norway Norwegian Institute of Public Health persons aged > 60 years with > 1 pre-existing disease (chronic lung, heart, liver or kidney disease, obesity, immunosuppression) - (e14) Sweden Public Health Authority all persons aged > 75 years, and all persons aged > 60 years with a pre-existing disease (chronic lung, heart, liver and kidney disease, obesity, immunosuppression) - (e15) Poland Narodowy Program Szczepien Ochronnych (NPSO) persons aged > 60 years persons with pre-existing diseases (heart disease, lung disease, immunosuppression) - (e16)

RSV, respiratory syncytial virus

Country Recommending organization/group Recommendation Reimbursed? References Spain •Asociación Española de Pediatria • Comité Asesor de Vacunas for children at high risk of severe RSV infection: a) single dose for preterm Infants up to 12 months of age b) before each RSV season In infants up to 24 months of age with congenital heart disease, chronic lung disease and certain other conditions (EMA approval first season only) and infants less than 6 months of age at the start of the RSV season regionally (e17, e18) Galicia (Spain) • Xunta de Galicia catch-up: all Infants < 6 months at the start of the season and all Infants born between September 25 and March 31 within the season; high-risk infants aged 6-24 months at the start of the season (as part of a hospital-based vaccination campaign) (e19) Italy • Board of the Calendar for Life (Italian Society of Hygiene [Siti], Italian Society of Pediatrics [SIP], Italian Federation of Paediatricians [Flmp], Italian Federation of General Practitioners [Fimmg]) • Italian Society of Neonatology (SIN) • SITI (Italian Society of Public Health) • S1 MIT (Italian Society for Infectious and Tropical Diseases) all Infants < 1 year of age In their first RSV season (e20) Luxembourg • Conseil supérieur des maladies Infectieuses catch-up: all infants < 6 months at the start of the season and all infants born between October and March within the season; high-risk infants > 12 months up to 2 years of age yes (e21) UK • Joint Committee on Vaccination and Immunisation (JCVI) recommendation of a year-round immunization program; equal preference for monoclonal antibodies and maternal Immunization - (e22) Israel • Israeli Society for Pediatric Infectious Diseases (ISPID) • Israel Pediatric Association (IPA) • Israel Neonatal Society (INS) • Israeli Association of Pediatric Pulmonology (IAPP) all Infants up to 1 year of age; for those eligible for palivlzumab, the first two RSV seasons (e23) France • Society of Pediatric Pneumology and Allergology (SP2A) • Société Française de Pédiatrie • Groupe de Pathologie Infectieuse Pédiatrique •Association Française de Pédiatrie Ambulatoire • Conseil National Professionnel de Pédiatrie all infants < 6 months at the start of the season; high-risk infants < 12 months at the start of the season yes (e24, e25) Austria •Federal Ministry of Social Affairs, Health Care, and Consumer Protection -Members of the National Vaccination Committee all infants in their first season - (e12) USA • Advisory Committee on Immunization Practices (ACIP) • American Academy of Pediatrics (AAP) all infants < 8 months at the start of the season; plus high-risk infants between 8-19 months at the start of the season yes (e10, e26) Belgium • Superior Health Council all infants whose mothers have not been immunized against RSV; premature Infants < 30 weeks' gestation; Infants born 2 weeks after the mother's Immunization; high-risk infants whose mothers have been immunized against RSV - (e27) Sweden • Läkemedelsverket Swedish Medical Products Agency high-risk infants up to 12 months in their first RSV season - (e28) Madeira (Portugal) • Regiao Autonoma da Madeira all Infants yes, the government assumes the costs (e29) Brazil • SBP (Socledade Brasileira de Pediatria) • SBIM (Socledade Brasileira de Imunizaçôes) all Infants In their first RSV season; high-risk infants with a double dose (2 * 100 mg) In the second season - (e30) Chile • Comité Asesor en Vacunas y Estrateglas de Inmunización (CAVEI) all Infants In their first RSV season; all high-risk Infants In their second RSV season yes, the government assumes the costs (e31) Latin America • SLIPE (Sociedad Latinoamericana de Infectologia Pediatrica) all Infants In their first RSV season - (e32) Netherlands • Health Council of the Netherlands all Infants In their first RSV season - (e33) Ireland • National Immunisation Advisory Committee (NIAC) all Infants In their first RSV season - (e34) Canada • Canada's Drug and Health Technology Agency (CADTH) high-risk Infants - (e35) Switzerland • Office fédéral de la santé publique (OFSP) • Division Maladies transmissibles all Infants In their first RSV season; all high-risk Infants In their second RSV season - (e36)

EMA, European Medicines Agency; RSV, respiratory syncytial virus

A selective literature search on respiratory syncytial virus (RSV) was conducted in PubMed. Current treatment recommendations, meta-analyses, systematic reviews, randomized controlled trials, cohort studies and observational studies were included. Publications in English and German from 1998 to 2023 were included. The following search terms were used: "RSV" [AND] "children", "adults", "epidemiology", "diagnostics", "therapy", "clinical trial", "vaccine".