Long-term antibiotic prophylaxis for prevention of rheumatic fever recurrence and progression to rheumatic heart disease.

BACKGROUND: Rheumatic fever is a non-suppurative, inflammatory sequela of group A Streptococcus pharyngitis that can occur at two to four weeks after infection. Following an episode of rheumatic fever, there is a risk of developing rheumatic heart disease (RHD) later in life that carries significant risk of morbidity and mortality. RHD remains the largest global cause of cardiovascular disease in the young (age < 25 years). The historical literature provides inconclusive evidence that antibiotic prophylaxis is beneficial in reducing the risk of recurrence of rheumatic fever and development of RHD. Antibiotics are thought to work by reducing the carriage of group A Streptococcus and thus reducing the risk of infection. This review was commissioned by the World Health Organization (WHO) for an upcoming guideline. OBJECTIVES: 1. To assess the effects of long-term antibiotics versus no antibiotics (control) for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. 2. To assess the effects of long-term intramuscular penicillin versus long-term oral antibiotics for secondary prevention of rheumatic fever recurrence and associated sequelae in people with previous rheumatic fever or RHD. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science, clinical trial registers, ISRCTN.com and reference lists without restrictions on language or date up to 10 March 2024. SELECTION CRITERIA: We sought randomised controlled trials or quasi-randomised trials, described in any language, including participants with previous rheumatic fever and/or RHD of any age, based in community or hospital settings. Studies were included if they compared firstly antibiotic prophylaxis with no antibiotic prophylaxis, and, secondly, intramuscular penicillin prophylaxis versus oral antibiotic prophylaxis. DATA COLLECTION AND ANALYSIS: We used standardised methodological, Cochrane-endorsed procedures and performed meta-analyses with risk ratios (RR) and Peto odds ratios (Peto OR). Our primary outcomes were recurrence of rheumatic fever, progression or severity of RHD and cardiac complications. Our secondary outcomes were obstetric complications (maternal and foetal events), mortality, treatment adherence, adverse events and acceptability to participants. We performed comprehensive assessments of risk of bias and certainty of evidence, applying the GRADE methodology. MAIN RESULTS: We included 11 studies (seven RCTs and four quasi-randomised trials) including 3951 participants. The majority of the included studies were conducted in the USA, UK and Canada during the 1950s to 1960s. Most participants with previous rheumatic fever had been diagnosed using the modified Jones criteria (mJC) (four studies), were an average of 12.3 years of age and 50.6% male. We assessed the majority of the included studies to be at high risk of bias, predominantly relating to blinding and attrition bias. Comparison one: antibiotics versus no antibiotics Pooled meta-analysis of six RCTs provides moderate-certainty evidence that antibiotics overall (oral or intramuscular) probably reduce the risk of recurrence of rheumatic fever substantially (0.7% versus 1.7%, respectively) (risk ratio (RR) 0.39, 95% confidence interval (CI) 0.22 to 0.69; 1721 participants). People with early or mild RHD likely have the greatest capacity to benefit from intramuscular antibiotic prophylaxis (8.1%) compared to no antibiotics (0.7%) (RR 0.09, 95% CI 0.03 to 0.29; 1 study, 818 participants; moderate-certainty evidence). Antibiotics may not affect mortality in people with late-stage RHD (RR 1.23, 95% CI 0.78 to 1.94; 1 study, 994 participants; low-certainty evidence). Antibiotics may not affect the risk of anaphylaxis (Peto odds ratio (OR) 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) or sciatic nerve injury (Peto OR 7.39, 95% CI 0.15 to 372; 1 study, 818 participants; low-certainty evidence) compared with no antibiotics, but probably have an increased risk of hypersensitivity reactions (RR 137, 8.51 to 2210; 2 studies, 894 participants; moderate-certainty evidence) and local reactions (RR 29, 1.74 to 485; 1 study, 818 participants; moderate-certainty evidence). Comparison two: intramuscular antibiotics versus oral antibiotics Pooled analysis of two RCTs showed that prophylactic intramuscular benzathine benzylpenicillin likely reduces recurrence of rheumatic fever substantially when compared to oral antibiotics (0.1% versus 1%, respectively) (RR 0.07, 95% CI 0.02 to 0.26; 395 participants; moderate-certainty evidence). Furthermore, it is unclear whether intramuscular benzyl penicillin is superior to oral antibiotics in reducing the risk of mortality in the context of RHD (Peto OR 0.22, 95% CI 0.01 to 4.12; 1 study, 431 participants; very low-certainty evidence). There were no data available on progression of latent RHD or adverse events including anaphylaxis, sciatic nerve injury, delayed hypersensitivity/allergic reactions and local reactions to injection. AUTHORS' CONCLUSIONS: This review provides evidence that antibiotic prophylaxis likely reduces the risk of recurrence of rheumatic fever compared to no antibiotics, and that intramuscular benzathine benzylpenicillin is probably superior to oral antibiotics (approximately 10 times better). Moreover, intramuscular benzathine benzylpenicillin likely reduces the risk of progression of latent RHD. Evidence is scarce, but antibiotics compared with no antibiotics may not affect the risk of anaphylaxis or sciatic nerve injury, but probably carry an increased risk of hypersensitivity reactions and local reactions. Antibiotics may not affect all-cause mortality in late-stage RHD compared to no antibiotics. There is no evidence available to comment on the effect of intramuscular penicillin over oral antibiotics for progression of latent RHD and adverse events, and little evidence for all-cause mortality. It is important to interpret these findings in the context of major limitations, including the following: the vast majority of the included studies were conducted more than 50 years ago, many before contemporary echocardiographic studies; methodology was often at high risk of bias; outdated treatments were used; only one study was in latent RHD; and there are concerns regarding generalisability to low socioeconomic regions. This underlines the need for ongoing research to understand who benefits most from prophylaxis.

Routine Antenatal Echocardiography in High-Prevalence Areas of Rheumatic Heart Disease: A WHO-Guideline Systematic Review.

Background: Rheumatic Heart Disease (RHD) is the most common cause of valvular heart disease worldwide. Undiagnosed or untreated RHD can complicate pregnancy and lead to poor maternal and fetal outcomes and is a significant factor in non-obstetric morbidity. Echocardiography has an emerging role in screening for RHD. We aimed to critically analyse the evidence on the use of echocardiography for screening pregnant women for RHD in high-prevalence areas. Methods: We searched MEDLINE and Embase to identify the relevant reports. Two independent reviewers assessed the reports against the eligibility criteria in a double-blind process. Results: The searches (date: 4 April 2023) identified 432 records for screening. Ten non-controlled observational studies were identified, five using portable or handheld echocardiography, comprising data from 23,166 women. Prevalence of RHD varied across the studies, ranging from 0.4 to 6.6% (I2, heterogeneity >90%). Other cardiac abnormalities (e.g., congenital heart disease and left ventricular systolic dysfunction) were also detected <1% to 2% of cases. Certainty of evidence was very low. Conclusion: Echocardiography as part of antenatal care in high-prevalence areas may detect RHD or other cardiac abnormalities in asymptomatic pregnant women, potentially reducing the rates of disease progression and adverse labor-associated outcomes. However, this evidence is affected by the low certainty of evidence, and lack of studies comparing echocardiography versus standard antenatal care. Prospective Registration: PROSPERO 2022 July 4; CRD42022344081 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=344081. Research question: 'In areas with a high prevalence of rheumatic heart disease, should handheld echocardiography be added to routine antenatal care?'

Medical Emergencies in Pulmonary Hypertension.

The management of acute medical emergencies in patients with pulmonary hypertension (PH) can be challenging. Patients with preexisting PH can rapidly deteriorate due to right ventricular decompensation when faced with acute physiological challenges that would usually be considered low-risk scenarios. This review considers the assessment and management of acute medical emergencies in patients with PH, encompassing both pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), acknowledging these comprise the more severe groups of PH. Management protocols are described in a systems-based approach. Respiratory emergencies include pulmonary embolism, airways disease, and pneumonia; cardiac emergencies including arrhythmia and chest pain with acute myocardial infarction are discussed, alongside PH-specific emergencies such as pulmonary artery dissection and extrinsic coronary artery compression by a dilated proximal pulmonary artery. Other emergencies including sepsis, severe gastroenteritis with dehydration, syncope, and liver failure are also considered. We propose management recommendations for medical emergencies based on available evidence, international guidelines, and expert consensus. We aim to provide advice to the specialist alongside the generalist, and emergency doctors, nurses, and acute physicians in nonspecialist centers. A multidisciplinary team approach is essential in the management of patients with PH, and communication with local and specialist PH centers is paramount. Close hemodynamic monitoring during medical emergencies in patients with preexisting PH is vital, with early referral to critical care recommended given the frequent deterioration and high mortality in this setting.

Systolic anterior motion of the anterior mitral valve leaflet begins in subclinical hypertrophic cardiomyopathy.

AIMS: Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM. METHODS AND RESULTS: Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008). CONCLUSION: Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.

Cardiac imaging in rheumatic heart disease and future developments.

Rheumatic heart disease (RHD) is the most common cause of valvular heart disease worldwide, affecting millions, especially in low- and middle-income countries. Multiple imaging modalities such as cardiac CT, cardiac MRI, and three-dimensional echocardiography may be utilized in diagnosing, screening, and managing RHD. However, two-dimensional transthoracic echocardiography remains the cornerstone of imaging in RHD. Criteria developed by the World Heart Foundation in 2012 sought to unify the diagnostic imaging criteria for RHD, but concerns remain regarding their complexity and reproducibility. In the intervening years, further measures have been developed to find a balance between simplicity and accuracy. Nonetheless, there remain significant unresolved problems within imaging in RHD, including the development of a practical and sensitive screening tool to identify patients with RHD. The emergence of handheld echocardiography has the potential to revolutionize RHD management in resource-poor settings, but its role as a screening or diagnostic tool is yet to be fully established. The dramatic evolution of imaging modalities over the last few decades has not addressed RHD compared to other forms of structural heart disease. In this review, we examine the current and latest developments concerning cardiac imaging and RHD.

Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival. METHODS: Consecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods. RESULTS: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: -0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). CONCLUSION: PDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

Follow the Lead: The Challenges of Cardiogenic Shock in Device-Related Infective Endocarditis.

We present the challenging case of a young man with congenital heart disease who survived severe device-related infective endocarditis and new pulmonary hypertension. He required prolonged mechanical circulatory support and had multiple significant complications. His case posed a management dilemma that was successfully resolved by effective multidisciplinary, tertiary center care. (Level of Difficulty: Beginner.).

Don't Stop Beleafing: A Unique Case of Fungal Infective Endocarditis.

We present the case of a 60-year-old man who was successfully treated for obstructive fungal infective endocarditis of the ascending aorta caused by Geotrichum capitatum. This extremely rare cause of fungal infective endocarditis required surgical and prolonged medical management, facilitated by effective multidisciplinary cooperation. (Level of Difficulty: Intermediate.).

Back to basics: a rare and aggressive case of Aggregatibacter aphrophilus endocarditis.

We present the case of a 25-year-old with a history of bicuspid aortic valve and ascending aortopathy who was successfully treated for infective endocarditis (IE) due to Aggregatibacter aphrophilus. His clinical course was complicated by a large aortic root abscess not initially visualised on transthoracic echocardiography or computerised tomography. The cardinal feature of progressive prolongation of the PR interval on serial electrocardiograms was the only sign associated with clinical deterioration and was the trigger for rapid investigation and urgent management. Our case emphasises the importance of simple bedside tests to identify dynamic clinical scenarios and the requirement for early further imaging in the management of IE.