Humans

Lung Cancer in Nonsmoking Individuals: A Review

Author/s: 
Cian Murphy, Tej Pandya, Charles Swanton

Importance: Lung cancer in nonsmoking individuals (defined as people who have smoked fewer than 100 cigarettes in their lifetime) accounts for 15% to 20% of all lung cancer cases worldwide. In the US, the annual incidence of lung cancer in nonsmoking individuals is 14.4 to 20.8 per 100 000 person-years in females and 4.8 to 12.7 per 100 000 person-years in males.

Observations: Most lung cancers in nonsmoking individuals are histologically adenocarcinomas (60%-80%) with the remainder being squamous or adenosquamous (10%-20%) and rarely small cell lung cancer (<10%). Risk factors include exposure to passive smoking, radon exposure, air pollution, asbestos, and history of lung cancer in a first-degree family member. Therapeutically targetable genomic variants, such as EGFR mutations or ALK gene rearrangements, are more common in tumors from nonsmoking individuals compared with those with a smoking history (defined as people who currently or formerly smoked) (43% vs 11% for EGFR and 12% vs 2% for ALK). In contrast, tumor mutation burden, the number of somatic mutations in a tumor cell, is lower in lung cancer among nonsmoking individuals (0-3 mutations/megabase [Mb] vs 0-30 mutations/Mb). Similar to individuals with a history of smoking, nonsmoking individuals with lung cancer may present with wheeze, chest pain, dyspnea, hemoptysis, or symptoms attributable to metastatic disease (eg, bone pain and headache) or be diagnosed with incidentally detected disease. The US Preventive Services Task Force does not currently recommend lung cancer screening with low-dose computed tomographic scans for nonsmoking individuals, although screening guidelines vary globally. Treatment typically involves a combination of surgery, radiotherapy, and systemic therapies depending on stage, performance status, and molecular features of the tumor. Comprehensive next-generation sequencing should be performed on stage Ib to IIIa lung cancer tumor tissue from nonsmoking individuals because actionable genomic alterations, such as EGFR mutations or ALK gene rearrangements, are treated with targeted therapy such as the tyrosine kinase inhibitors osimertinib or lorlatinib, respectively. Median survival among nonsmoking individuals with advanced non-small cell lung cancer (stage IIIb or higher) and actionable genomic alterations can exceed 3 to 5 years, while survival without these genomic alterations is similar to lung cancer in people with a history of smoking (1-2 years).

Conclusions: Lung cancer in nonsmoking individuals accounts for 15% to 20% of lung cancer cases worldwide. Among patients with lung cancer, nonsmoking individuals are more likely to have genomic alterations such as EGFR mutations or ALK gene rearrangements, and these patients have improved survival when treated with tyrosine kinase inhibitors compared with chemotherapy.

Long QT Syndrome

Author/s: 
Peter J. Schwartz, Lia Crotti

To assess a physician’s expertise on the basis of whether the doctor checks a patient’s QT interval would be excessive, but the fact remains that in many cases, checking it saves lives. The author of a respected textbook on electrocardiography1 wrote, “The measurement of the QT interval has little usefulness” in 1957 — the same year in which Jervell and Lange-Nielsen published their first report on the association between QT-interval prolongation and sudden death in a family with congenital deafness,2 which was soon followed by similar findings reported by Romano and colleagues3 and by Ward4 in patients with normal hearing. In 1975, Romano–Ward syndrome and Jervell–Lange-Nielsen syndrome were grouped under the name long QT syndrome.5
Long QT syndrome is an uncommon disease of genetic origin with a documented prevalence of 1 in 2000 live births6; however, the actual prevalence is probably higher because the original prospective study, which involved 44,000 infants,6 did not include genotype-positive–phenotype-negative persons. The syndrome is characterized by prolongation of the QT interval on an electrocardiogram (ECG) obtained when the patient was at rest and by a propensity for life-threatening arrhythmias that occur mostly under conditions of physical or emotional stress.5,7 The clinical importance of the timely diagnosis of the syndrome stems from the fact that sudden cardiac death is often the first symptom, which makes remedying diagnostic or therapeutic errors impossible. As stated 50 years ago,5 given the high efficacy of current therapies, the existence of patients with undiagnosed — and therefore untreated — long QT syndrome is nowadays inexcusable; unfortunately, missed diagnosis is still too often the case.

Metabolic Dysfunction–Associated Steatotic Liver Disease in Adults: A Review

Author/s: 
Herbert Tilg, Salvatore Petta, Norbert Stefan, Giovanni Targher

Importance Metabolic dysfunction–associated steatotic liver disease (MASLD) includes a range of liver conditions, progressing from isolated steatosis (characterized by fat accumulation in the liver without inflammation) to metabolic dysfunction–associated steatohepatitis (MASH), which involves fat accumulation and inflammation in the liver. The presence of MASLD is associated with increased morbidity and mortality due to liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers.

Observations The most common chronic liver disease worldwide, MASLD affects approximately 30% to 40% of the general adult population globally (with varying prevalence across continents), including approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of those with obesity. It is typically diagnosed based on an ultrasonographic finding of hepatic steatosis, along with at least 1 of 5 features of the metabolic syndrome (abdominal overweight or obesity, prediabetes or type 2 diabetes, hypertension, elevated level of plasma triglycerides, and low level of high-density lipoprotein cholesterol) for women who consume less than 140 g/wk of alcohol (<2 standard drinks/d) and for men who consume less than 210 g/wk (<3 standard drinks/d) and have no other known causes of steatosis such as use of a particular medication (eg, corticosteroids, tamoxifen, or methotrexate), hepatitis C, or iron overload. Other risk factors for MASLD include older age (≥50 years) and male sex (male:female ratio approximately 2). The Fibrosis-4 index (a scoring system incorporating age, serum levels of aspartate aminotransferase and alanine aminotransferase, and platelet count) and vibration-controlled transient elastography (a noninvasive imaging technique) are commonly used to stage hepatic fibrosis in patients with MASLD. Cardiovascular disease is the leading cause of death, followed by certain extrahepatic cancers (primarily gastrointestinal, breast, and gynecologic cancer) and liver-related complications, including cirrhosis, hepatic decompensation (ascites, hepatic encephalopathy, or variceal bleeding), and hepatocellular carcinoma. First-line treatment of MASLD involves behavioral modifications (including hypocaloric low-carbohydrate and low-fat diets, physical exercise, and avoidance of alcohol) and management of type 2 diabetes, obesity, hypertension, and hyperlipidemia. Bariatric surgery should be considered for patients with MASLD and a body mass index greater than 35. Resmetirom (a liver-directed, thyroid hormone receptor β-selective agonist) and subcutaneous semaglutide (a glucagon-like peptide-1 receptor agonist) are conditionally approved by the US Food and Drug Administration (FDA) for the treatment of adults with MASH who have moderate to advanced fibrosis.

Conclusions A highly prevalent condition among adults worldwide, MASLD is associated with liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers. First-line treatment includes behavioral modifications, including a weight-reducing diet, physical exercise, and avoidance of alcohol. Resmetirom and semaglutide are conditionally FDA-approved medications for the treatment of adults with MASH and moderate to advanced fibrosis.

Online Unsupervised Tai Chi Intervention for Knee Pain and Function in People With Knee Osteoarthritis: The RETREAT Randomized Clinical Trial

Author/s: 
Shiyi Julia Zhu, Rana S. Hinman, Rachel K. Nelligan

Importance: Tai chi is a type of exercise recommended for knee osteoarthritis, but access to in-person tai chi can be limited.

Objective: To evaluate the effects of an unsupervised multimodal online tai chi intervention on knee pain and function for people with knee osteoarthritis.

Design, setting, and participants: The RETREAT study was a 2-group superiority randomized clinical trial enrolling participants who met clinical criteria for knee osteoarthritis in Australian communities from August 2023 and November 2024.

Interventions: Participants in the control group received access to a purpose-built website containing information about osteoarthritis and exercise benefits. Participants in the intervention group received the My Joint Tai Chi intervention comprising access to the same website plus tai chi information, a 12-week unsupervised video-based Yang-style tai chi program, and encouragement to use an app to facilitate program adherence.

Main outcomes and measures: Changes in knee pain during walking (Numeric Rating Scale; range 0-10 with higher scores indicating greater pain) and difficulty with physical function (Western Ontario and McMaster Universities Osteoarthritis Index; range 0-68 with higher scores indicating greater dysfunction) during 12 weeks. Secondary outcomes included another knee pain measure, sport and recreation function, quality of life, physical and mental well-being, fear of movement, self-efficacy, balance confidence, positive activated affect, sleep quality, global improvement, and oral medication use.

Results: Of 2106 patients screened, 178 met inclusion criteria and were randomized, 89 (mean [SD] age, 61.0 [8.7] years; 66 female [74%] and 23 [26%] male participants) to the control group and 89 (mean [SD] age, 62.1 [7.3] years; 59 [66%] female and 30 male [34%] participants) to the tai chi intervention. Of the total, 170 (96%) completed both of the primary outcomes at 12 weeks. The tai chi group reported greater improvements in knee pain (control, -1.3; tai chi, -2.7; mean difference, -1.4 [95% CI, -2.1 to -0.7] units; P < .001) and function (control, -6.9; tai chi, -12.0; mean difference, -5.6 [95% CI, -9.0 to -2.3] units; P < .001) compared to the control group. More participants in the tai chi than in the control group achieved a minimal clinically important difference in pain (73% vs 47%; risk difference, 0.3; 95% CI, 0.1 to 0.4; P < .001) and function (72% vs 52%; risk difference, 0.2; 95% CI, 0.1 to 0.3; P = .007). Between-group differences for most secondary outcomes favored tai chi, including another knee pain measure, sport and recreation function, quality of life, physical and mental well-being, global improvement, pain self-efficacy, and balance confidence. No associated serious adverse events were reported.

Conclusions and relevance: This randomized clinical trial found that this unsupervised multimodal online tai chi intervention improved knee pain and function compared with the control at 12 weeks. This free-to-access web-based intervention offers an effective, safe, accessible, and scalable option for guideline-recommended osteoarthritis exercise.

Hemorrhoidal Disease: A Review

Author/s: 
Jean H. Ashburn

Importance Hemorrhoidal disease, pathology of the tissue lining of the anal canal, affects approximately 10 million individuals in the US. Hemorrhoidal disease may impair quality of life due to bleeding, pain, anal irritation, and tissue prolapse.

Observations Hemorrhoids are classified as internal, external, or mixed (concurrent internal and external hemorrhoidal disease). Internal hemorrhoids originate above the dentate line, the boundary between the upper and lower anal canal, and may cause rectal bleeding, discomfort, and tissue prolapse from the anal canal. Internal hemorrhoid prolapse is classified as grade I (into anal canal), grade II (beyond the anus with spontaneous reduction), grade III (requiring manual reduction), and grade IV (irreducible). External hemorrhoids, arising below the dentate line, cause rectal pain when engorged or thrombosed. Initial treatment of all hemorrhoidal disease involves increasing intake of dietary fiber and water and avoiding straining during defecation. Phlebotonics (eg, flavonoids [thought to improve venous tone]) reduce bleeding, rectal pain, and swelling, although symptom recurrence reaches 80% within 3 to 6 months after treatment cessation. If dietary modification and phlebotonics are ineffective, grade I to grade III internal hemorrhoidal disease can be treated with office-based interventions. Rubber band ligation—placing a band around the base of hemorrhoid tissue during anoscopy to restrict blood flow—resolves symptoms in 89% of patients, but repeated banding is needed in up to 20%. Sclerotherapy, which induces fibrosis with a sclerosant injection, is efficacious in the short term (weeks to months) among 70% to 85% of patients, but long-term remission occurs in only one-third of patients. Infrared coagulation uses heat to coagulate hemorrhoidal tissue, yielding 70% to 80% success in reducing bleeding and prolapse. Excisional hemorrhoidectomy, for disease unresponsive to office-based therapy or for mixed hemorrhoidal disease, achieves low recurrence (2%-10%), although with longer recovery (9-14 days). External hemorrhoidal disease rarely requires surgery unless acutely thrombosed. Outpatient clot evacuation within 72 hours of onset of a thrombosed external hemorrhoid is associated with decreased pain and reduced risk of repeat thrombosis. Patients presenting more than 72 hours after external hemorrhoid acute thrombosis should receive medical treatment (eg, stool softeners, oral and topical analgesics such as 5% lidocaine).

Conclusions and Relevance Hemorrhoidal disease affects 10 million people in the US. First-line treatment is increased fiber intake, avoidance of straining during defecation, and phlebotonics. In-office rubber band ligation for grade I to III internal hemorrhoid disease is first-line procedural treatment for persistent symptoms despite conservative therapies. Excisional hemorrhoidectomy is recommended for grade III to IV prolapse, thrombosis, or mixed hemorrhoidal disease that does not improve with less invasive approaches.

Pharmacologic Treatment of Heart Failure With Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis

Author/s: 
Bart J. van Essen, Daan C.H. Ceelen, Wouter Ouwerkerk, Tiew-Hwa K. Teng, Ganash N. Tharshana, Fook Ming Hew, Javed Butler, Faiez Zannad, Carolyn S. Lam, Justin Ezekowitz, Adriaan A. Voors, Jasper Tromp

Background: In 2022, a network meta-analysis showed that a combination of β-blockers, angiotensin receptor-neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was most effective in reducing all-cause mortality in heart failure with reduced ejection fraction (HFrEF). This study updates the treatment benefit by including additional large randomized controlled trials (RCTs) since 2022, including the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial.

Objectives: The goal of this study was to evaluate and compare regimens of pharmacotherapy in patients with HFrEF.

Methods: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs in patients with HFrEF through April 2025. Using frequentist network meta-analysis, HRs for all-cause mortality (primary outcome), cardiovascular death, and the composite of cardiovascular death or heart failure hospitalization (secondary outcomes) were estimated. Absolute benefits were quantified as life-years gained by using BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) and ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) cohort data.

Results: The analysis included 103,754 patients across 89 randomized controlled trials. Relative to placebo, quintuple therapy with ARNi, β-blockers, MRAs, SGLT2i, and vericiguat most effectively reduced all-cause mortality (HR: 0.35; 95% CI: 0.27-0.45), followed by quadruple therapy with ARNi, β-blockers, MRAs, and SGLT2i (HR: 0.39; 95% CI: 0.32-0.49). For a representative 70-year-old patient, quadruple therapy (ARNi/β-blockers/MRAs/SGLT2i) provided 5.3 additional life-years (95% CI: 2.8-7.7) vs no treatment, while quintuple therapy (ARNi/β-blockers/MRA/SGLT2i/vericiguat) provided 6.0 additional life-years (95% CI: 3.7-8.4).

Conclusions: This analysis reinforces the substantial mortality and morbidity benefit associated with the currently recommended quadruple therapy regimen (ARNi, β-blockers, MRAs, and SGLT2i) in patients with HFrEF. The addition of vericiguat may provide an incremental survival gain of approximately 0.7 year beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial.

Keywords: HFrEF; drug therapy; pharmacotherapy.

Use of Ambient AI Scribes to Reduce Administrative Burden and Professional Burnout

Author/s: 
Kristine D. Olson, Daniella Meeker, Matt Troup

Importance: While in short supply and high demand, ambulatory care clinicians spend more time on administrative tasks and documentation in the electronic health record than on direct patient care, which has been associated with burnout, intention to leave, and reduced quality of care.

Objective: To examine whether ambient AI scribes are associated with reducing clinician administrative burden and burnout.

Design, setting, and participants: This quality improvement study used preintervention and 30-day postintervention surveys to evaluate the use of the same ambient AI platform for clinical note documentation among ambulatory care physicians and advanced practice practitioners of 6 academic and community-based health care systems across the US. Clinicians were recruited by the health systems' digital health leaders; participation was voluntary. The study was conducted between February 1 and October 31, 2024.

Exposure: Use of an ambient AI scribe for 30 days.

Main outcomes and measures: The primary outcome was change in self-reported burnout, estimated using hierarchical logistic regression. Secondary outcomes of burnout evaluated were changes in note-related cognitive task load, focused attention on patients, patient understandability of notes, ability to add patients to the clinic schedule if urgently needed, and time spent documenting after hours. Outcome measures were linearly transformed to 10-point scales to ease interpretation and comparison. Differences between preintervention and postintervention scores were determined using paired t tests.

Results: Of the 451 clinicians enrolled, 272 completed the preintervention and postintervention surveys (60.3% completion rate), and 263 with direct patient care in ambulatory clinics (mean [SD] years in practice, 15.1 [9.3]; 141 female [53.6%]) were included in the analysis. The sample included 131 primary care practitioners (49.7%), 232 attending physicians (88.2%), and 168 academic faculty (63.9%). After 30 days with the ambient AI scribe, the proportion of participants experiencing burnout decreased significantly from 51.9% to 38.8% (odds ratio, 0.26; 95% CI, 0.13-0.54). On 10-point scales, the ambient AI scribe was associated with significant improvements in secondary outcomes of burnout (mean [SE] difference, 0.47 [0.12] points), note-related cognitive task load (mean [SE] difference, 2.64 [0.13] points), ability to provide undivided attention (mean [SE] difference, 2.05 [0.18] points), patient understandability of their care plans from reading the notes (mean [SE] difference, -0.44 [0.17] points), ability to add patients to the clinic schedule if urgently needed (mean [SE] difference, 0.51 [0.24] points), and time spent documenting after hours (mean [SE] difference, 0.90 [0.19] hours).

Conclusions and relevance: This multicenter quality improvement study found that use of an ambient AI scribe platform was associated with a significant reduction in burnout, cognitive task load, and time spent documenting, as well as the perception that it could improve patient access to care and increase attention on patient concerns in an ambulatory environment. These findings suggest that AI may help reduce administrative burdens for clinicians and allow more time for meaningful work and professional well-being.

Online Unsupervised Tai Chi Intervention for Knee Pain and Function in People With Knee Osteoarthritis: The RETREAT Randomized Clinical Trial

Author/s: 
Shiyi Julia Zhu, Rana S Hinman, Rachel K Nelligan, Peixuan Li, Anurika P De Silva, Jenny Harrison, Alexander J Kimp, Kim L Bennell

Importance: Tai chi is a type of exercise recommended for knee osteoarthritis, but access to in-person tai chi can be limited.

Objective: To evaluate the effects of an unsupervised multimodal online tai chi intervention on knee pain and function for people with knee osteoarthritis.

Design, setting, and participants: The RETREAT study was a 2-group superiority randomized clinical trial enrolling participants who met clinical criteria for knee osteoarthritis in Australian communities from August 2023 and November 2024.

Interventions: Participants in the control group received access to a purpose-built website containing information about osteoarthritis and exercise benefits. Participants in the intervention group received the My Joint Tai Chi intervention comprising access to the same website plus tai chi information, a 12-week unsupervised video-based Yang-style tai chi program, and encouragement to use an app to facilitate program adherence.

Main outcomes and measures: Changes in knee pain during walking (Numeric Rating Scale; range 0-10 with higher scores indicating greater pain) and difficulty with physical function (Western Ontario and McMaster Universities Osteoarthritis Index; range 0-68 with higher scores indicating greater dysfunction) during 12 weeks. Secondary outcomes included another knee pain measure, sport and recreation function, quality of life, physical and mental well-being, fear of movement, self-efficacy, balance confidence, positive activated affect, sleep quality, global improvement, and oral medication use.

Results: Of 2106 patients screened, 178 met inclusion criteria and were randomized, 89 (mean [SD] age, 61.0 [8.7] years; 66 female [74%] and 23 [26%] male participants) to the control group and 89 (mean [SD] age, 62.1 [7.3] years; 59 [66%] female and 30 male [34%] participants) to the tai chi intervention. Of the total, 170 (96%) completed both of the primary outcomes at 12 weeks. The tai chi group reported greater improvements in knee pain (control, -1.3; tai chi, -2.7; mean difference, -1.4 [95% CI, -2.1 to -0.7] units; P < .001) and function (control, -6.9; tai chi, -12.0; mean difference, -5.6 [95% CI, -9.0 to -2.3] units; P < .001) compared to the control group. More participants in the tai chi than in the control group achieved a minimal clinically important difference in pain (73% vs 47%; risk difference, 0.3; 95% CI, 0.1 to 0.4; P < .001) and function (72% vs 52%; risk difference, 0.2; 95% CI, 0.1 to 0.3; P = .007). Between-group differences for most secondary outcomes favored tai chi, including another knee pain measure, sport and recreation function, quality of life, physical and mental well-being, global improvement, pain self-efficacy, and balance confidence. No associated serious adverse events were reported.

Conclusions and relevance: This randomized clinical trial found that this unsupervised multimodal online tai chi intervention improved knee pain and function compared with the control at 12 weeks. This free-to-access web-based intervention offers an effective, safe, accessible, and scalable option for guideline-recommended osteoarthritis exercise.

Comparative efficacy and safety of exercise modalities in knee osteoarthritis: systematic review and network meta-analysis

Author/s: 
Lei Yan, Dijun Li, Dan Xing, Zijuan Fan, Guangyuan Du, Jingwei Jiu, Xiaoke Li, Janne Estill, Qi Wang, Ahmed Atef Belal, Chen Tian, Jiao Jiao Li, Songyan Li, Haifeng Liu, Xuanbo Liu, Yijia Ren, Yiqi Yang, Jinxiu Chen, Yihe Hu, Long Ge, Bin Wang

Objective: To assess the efficacy and safety of various exercise modalities as therapeutic interventions for managing knee osteoarthritis.

Design: Systematic review with network meta-analysis.

Data sources: PubMed, Embase, Cochrane Library, Web of Science, CINAHL, PsycINFO, AMED, PEDro, Scopus, ClinicalTrials.gov, ICTRP, and ClinicalTrialsRegister.eu from database inception to August 2024.

Eligibility criteria for selecting studies: Randomised controlled trials comparing different exercise modalities, including aerobic exercise, flexibility exercise, mind-body exercise, neuromotor exercise, strengthening exercise, mixed exercise, and control group for patients with knee osteoarthritis.

Main outcome measures: Primary outcomes included pain, function, gait performance, and quality of life, assessed at short term (four weeks), mid-term (12 weeks), and long term (24 weeks) follow-up. When exact time points were unavailable, data from adjacent time windows were used.

Results: 217 randomised controlled trials involving 15 684 participants were included. Moderate certainty evidence showed that, compared with the control group, aerobic exercise probably results in large improvements in pain at short term (standardised mean difference -1.10, 95% confidence interval -1.68 to -0.52) and mid-term follow-up (-1.19, -1.59 to -0.79), function at mid-term (1.78, 1.05 to 2.51), gait performance at mid-term (0.85, 0.55 to 1.14), and quality of life at short term (1.53, 0.47 to 2.59). Mind-body exercise probably results in a large increase in function at short term follow-up (0.88, 0.03 to 1.73; moderate certainty), while neuromotor exercise probably results in a large increase in gait performance at short term follow-up (1.04, 0.51 to 1.57; moderate certainty). Strengthening (0.86, 0.53 to 1.18) and mixed exercise (1.07, 0.68 to 1.46) probably result in a large increase in function at mid-term follow-up, all with moderate certainty evidence. Regarding long term follow-up, flexibility exercise may result in a large reduction in pain (-0.99, -1.63 to -0.36; low certainty); aerobic exercise may result in a large increase in function (0.87, 0.02 to 1.72, low certainty); and mixed exercise may increase function (0.56, 0.26 to 0.86; low certainty) and probably increases gait performance (0.57, 0.21 to 0.92, moderate certainty). Overall, aerobic exercise consistently showed the highest probability of being the best treatment, as reflected by surface under the cumulative ranking curve values (mean 0.72) across outcomes. The safety outcome was reported in a small proportion of studies (40 studies, 18%), and no clear differences were observed between exercise interventions and control.

Conclusions: In patients with knee osteoarthritis, aerobic exercise is likely the most beneficial exercise modality for improving pain, function, gait performance, and quality of life, with moderate certainty.

Systematic review registration: PROSPERO CRD42023469762.

Efficacy and safety of respiratory syncytial virus vaccines

Author/s: 
K M Saif-Ur-Rahman, Catherine King, Seán Olann Whelan, Matthew Blair, Seán Donohue, Caoimhe Madden, Kavita Kothari, Isolde Sommer, Thomas Harder, Nicolas Dauby, Ida Rask Moustsen-Helms, Simona Ruta, Julie Frère, Viktoria Schönfeld, Eero Poukka, Irja Lutsar, Kate Olsson, Angeliki Melidou, Karam Adel Ali, Kerry Dwan, Declan Devane

Rationale: Respiratory syncytial virus (RSV) is a highly transmissible pathogen that causes varying degrees of respiratory illness across all age groups. The safety and efficacy profiles of available RSV vaccines, a critical consideration for their integration into public health strategies and clinical practice, remain uncertain.

Objectives: To assess the benefits and harms of RSV vaccines compared to placebo, no intervention, vaccines for other respiratory infections, other RSV vaccines, or monoclonal antibodies (mAbs) across all human populations.

Search methods: We conducted a comprehensive literature search of CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the WHO ICTRP following standard systematic review methodology from 2000 to April 2024.

Eligibility criteria: We included both randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) involving all human populations comparing RSV vaccines with placebo, no intervention, vaccines for other respiratory infections, other RSV vaccines, or mAbs. We excluded studies focused on dose-finding schedules and immunogenicity assessment.

Outcomes: Benefits included frequency of RSV illness (both lower and upper respiratory illness) confirmed by laboratory tests (RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness); hospitalisation due to RSV disease (both lower and upper respiratory illness) confirmed by laboratory tests; mortality from illness caused by RSV (confirmed by laboratory test); all-cause mortality; and admission to an intensive care unit. Harms included serious adverse events (SAEs) related to vaccination, including neurological disorders such as Guillain-Barré syndrome.

Risk of bias: We assessed risk of bias in RCTs using Cochrane's RoB 2 tool.

Synthesis methods: We used standard Cochrane methods.

Included studies: We identified 14 RCTs: five trials (101,825 participants) on older adults; three trials (12,010 participants) on maternal vaccination and effects on infants; one trial (300 participants) on women of childbearing age; and five trials (192 participants) on infants and children. We identified no NRSIs.

Synthesis of results: RSV prefusion vaccine versus placebo in older adults These vaccines reduced RSV-associated lower respiratory tract illness with vaccine efficacy (VE) of 77% (95% confidence interval (CI) 0.70 to 0.83; risk ratio (RR) 0.23, 95% CI 0.17 to 0.30; 4 RCTs, 99,931 participants; high-certainty evidence) and RSV-associated acute respiratory illness with VE of 67% (95% CI 0.60 to 0.73; RR 0.33, 95% CI 0.27 to 0.40; 3 RCTs, 94,339 participants; high-certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all-cause mortality, and SAEs related to vaccination (low-certainty evidence). RSV postfusion F protein-based vaccine versus placebo in older adults There is probably little to no difference in RSV-associated lower respiratory tract illness with VE of -0.37% (95% CI -1.96 to 0.37; RR 1.37, 95% CI 0.63 to 2.96; 1 RCT, 1894 participants; moderate-certainty evidence) and RSV-associated acute respiratory illness with VE of -0.07% (95% CI -1.15 to 0.47; RR 1.07, 95% CI 0.53 to 2.15; 1 RCT, 1894 participants; moderate-certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all-cause mortality, and SAEs related to vaccination (low-certainty evidence). Maternal RSV F protein-based vaccine versus placebo in infants These vaccines reduced medically attended RSV-associated lower respiratory tract illness with VE of 54% (95% CI 0.28 to 0.71; RR 0.46, 95% CI 0.29 to 0.72; 3 RCTs, 12,010 participants; high-certainty evidence), medically attended RSV-associated severe lower respiratory tract illness with VE of 74% (95% CI 0.44 to 0.88; RR 0.26, 95% CI 0.12 to 0.56; 3 RCTs, 12,010 participants; high-certainty evidence), and hospitalisation due to RSV disease with VE of 54% (95% CI 0.27 to 0.71; RR 0.46, 95% CI 0.29 to 0.73; 2 RCTs, 11,502 participants; high-certainty evidence) in infants. There may be little to no difference in mortality from illness caused by RSV, all-cause mortality, and SAEs related to vaccination in mothers and infants (low-certainty evidence). Live-attenuated RSV vaccines versus placebo in infants and children The evidence is very uncertain regarding all-cause medically attended acute respiratory illness (MAARI) with VE of 26% (95% CI -0.01 to 0.46; RR 0.74, 95% CI 0.54 to 1.01; 5 RCTs, 171 participants; very low-certainty evidence) and RSV-associated MAARI with VE of 38% (95% CI -0.24 to 0.69; RR 0.62, 95% CI 0.31 to 1.24; 5 RCTs, 192 participants; very low-certainty evidence). There may be little to no difference in SAEs related to vaccination (low-certainty evidence). RSV recombinant F nanoparticle vaccine versus placebo in women of childbearing age The evidence is very uncertain regarding new RSV infections with VE of 50% (95% CI 0.08 to 0.73; RR 0.50, 95% CI 0.27 to 0.92; 1 RCT, 300 participants; very low-certainty evidence). There may be little to no difference in mortality from illness caused by RSV, all-cause mortality, and SAEs related to vaccination (low-certainty evidence). Phase III trials consistently demonstrated low risk of bias. Whilst phase I and II trials occasionally raised concerns about selection bias in the randomisation process, the overall evidence was deemed robust.

Authors' conclusions: RSV prefusion vaccines reduced RSV-associated lower respiratory tract illness and acute respiratory illness in older adults. There may be little to no difference in SAEs related to vaccination in older adults. Maternal vaccination with RSV F protein-based vaccines reduced medically attended RSV-associated lower respiratory tract illness and severe cases in infants. There may be little to no difference in SAEs related to vaccination in mothers and infants. The evidence is very uncertain regarding the effects of RSV vaccine on women of childbearing age, and the effects of live-attenuated RSV vaccines on infants and children; there may be little to no difference in SAEs related to vaccination.

Funding: This review was funded by the EU4Health Programme under a service contract with the European Health and Digital Executive Agency (HaDEA).

Registration: The review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42023439128).

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