JOURNAL WATCH


https://doi.org/10.5005/jp-journals-10081-1449
Pediatric Infectious Disease
Volume 6 | Issue 4 | Year 2024

Insightful Journal Articles


Vikram S Kumarhttps://orcid.org/0000-0002-1369-7682

Department of Pediatrics, Subbaiah Medical College, Shivamogga, Karnataka, India

Corresponding Author: Vikram S Kumar, Department of Pediatrics, Subbaiah Medical College, Shivamogga, Karnataka, India, Phone: +91 9241495056, e-mail: vikramskumar@yahoo.co.in

How to cite this article: Kumar VS. Insightful Journal Articles. Pediatr Inf Dis 2024;6(4):143–148.

Source of support: Nil

Conflict of interest: None

1. Impact of Iron Supplementation on the Gut Microbiome in Children: Insights from a Large-scale Randomized Controlled Trial in High Anemia and Infection-burden Settings

This study addresses a critical question regarding the safety of universal iron supplementation in children from regions with high anemia prevalence and infectious disease exposure. Using a large randomized, placebo-controlled trial in rural Bangladesh, the authors assessed the impact of iron supplements and micronutrient powders (MNPs) on the gut microbiome. The study’s key strengths include its large sample size (nearly 1,000 children), rigorous bioinformatics, and the use of shotgun metagenomics to provide high-resolution analysis.

The main finding is that iron interventions, when analyzed with false discovery rate adjustments, do not significantly alter the gut microbiome. However, unadjusted analyses indicate a potential reduction in beneficial commensals and an increase in certain pathogenic species, particularly in iron-replete children. These findings align with previous studies from sub-Saharan Africa but are more robust due to careful statistical controls and higher sequencing resolution.

The study also highlights that iron-induced changes in Bacillota and Bacteroidota phyla were statistically significant, supporting the biological plausibility of these effects. Although the observed effect sizes are small and the clinical relevance remains uncertain, the findings suggest iron may be best reserved for treating iron deficiency rather than for universal use.

The authors appropriately acknowledge limitations, such as not evaluating nonbacterial organisms and not measuring other potential intestinal effects of iron. Their conclusions are cautious but reasonable; while their results do not definitively confirm adverse microbiome effects, they argue for careful consideration of the risk-benefit ratio in universal iron interventions.

Overall, this study provides valuable insights into the microbiome effects of iron in a high-risk population and supports the need for targeted iron supplementation rather than broad universal policies.

Source: Baldi A, Braat S, Hasan MI, et al. Effects of iron supplements and iron-containing micronutrient powders on the gut microbiome in Bangladeshi infants: a randomized controlled trial. Nat Commun 2024;15(1):8640. DOI: 10.1038/s41467-024-53013-x

2. Antibiotic Use in Animal Agriculture: Implications for Pediatric Health and Antimicrobial Resistance

This technical report examines antibiotic usage in animal agriculture and its effects on pediatric health. It highlights the serious public health threat of antimicrobial resistance (AMR) globally and notes how this issue is increasing among children. The transmission of AMR can occur through various pathways, including the food supply and direct contact with animals.

The report effectively outlines the connection between antibiotic use in livestock and the emergence of antimicrobial-resistant pathogens. It presents evidence of resistance in bacteria such as Salmonella, Escherichia coli, and Campylobacter, making a strong case for concern.

Additionally, the report provides an extensive review of US policies, particularly focusing on FDA regulations that aim to limit nontherapeutic antibiotic use. It discusses the impact of these regulations on reducing antibiotic use in agriculture.

The “One Health” approach discussed in the report is a significant strength. It supports the idea that human, animal, and environmental health sectors must work together to combat AMR.

However, the report has some weaknesses. While it identifies the problems linked to antibiotic overuse in agriculture, it could benefit from a clearer discussion on the effectiveness of recent policies. The long-term outcomes of these initiatives are not well defined, especially in terms of reducing resistant pathogens.

Moreover, the report does not consider the economic and logistical challenges that farmers face when transitioning to antibiotic-free or reduced-antibiotic practices. Addressing these challenges is critical for successful policy implementation.

In conclusion, this report serves as an important resource, emphasizing the need to curb unnecessary antibiotic use in animal agriculture to protect pediatric health. There is a need for further studies and stronger surveillance to fully assess the impact of these interventions and to effectively reduce AMR. This report lays a solid groundwork for policymakers, but future iterations should also include economic considerations and broader international comparisons for a more comprehensive perspective.

Source: Katz SE, Banerjee R, Committee on Infectious Diseases, Council on Environmental Health and Climate Change. Use of antibiotics in animal agriculture: implications for pediatrics: technical report. Pediatrics 2024;154(4):e2024068467. DOI: 10.1542/peds.2024-068467

3. Preventing Food Allergies in Infants: Evidence-based Strategies for Early Allergen Introduction and Environmental Interventions

This technical report reviews current evidence on strategies to prevent food allergies in infants, with a focus on early allergen introduction, dietary diversity, maternal diet, skin barrier interventions, and infant diet supplementation. It draws on findings from pivotal studies such as the learning early about peanut allergy (LEAP) and enquiring about tolerance (EAT) trials, which provide strong evidence supporting the early introduction of peanut and egg as effective measures for reducing allergy risk. Infants with severe atopic dermatitis are identified as particularly benefiting from this approach due to their heightened risk of developing food allergies.

The report underscores that early and consistent introduction of peanut and egg around 6 months of age, but not before 4 months, can offer protective effects against allergy development. Importantly, it highlights that regular ingestion after introduction is crucial for maintaining this protection. It also notes that early diet diversity appears to lower the risk of food allergies while restricting allergenic foods during pregnancy or breastfeeding does not offer protective benefits.

The report explores the “dual allergen hypothesis,” suggesting that infants with atopic dermatitis are more prone to developing food allergies due to their compromised skin barrier, which allows environmental sensitization before ingestion of allergens. While interventions aimed at improving the skin barrier, such as emollient use, have shown promise in reducing the risk of atopic dermatitis, their role in food allergy prevention remains less clear.

In terms of infant diet supplementation, the report concludes that evidence is still lacking regarding the benefits of hydrolyzed formula, vitamin D, and probiotics in preventing food allergies. Current research does not support hydrolyzed formula as a preventive measure, while trials on vitamin D and probiotics are ongoing.

National and international guidelines have updated their recommendations based on this growing body of evidence. Current guidelines emphasize the importance of early introduction of peanuts and eggs without the need for preemptive allergy testing, except in cases of severe atopic dermatitis where shared decision-making may guide testing. These findings are significant for pediatric care, offering clear guidance on early allergen introduction to reduce the burden of food allergies.

In conclusion, the report strongly supports the early introduction of peanuts and eggs in infants and highlights the need for further research on other allergens and interventions. Pediatricians should incorporate these findings into practice to help prevent food allergies, especially in high-risk populations.

Source: Shah A, Sicherer SH, Tsuang A. Timing of food introduction and allergy prevention: an update. Dermatol Clin 2024;42(4):591–600. DOI: 10.1016/j.det.2024.04.003

4. Cardiometabolic Complications in Pediatric HIV: Addressing the Long-term Impact of Antiretroviral Therapy

This review provides an essential update on cardiometabolic complications in children and adolescents with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy (ART). With the introduction of ART, there has been a significant reduction in mortality and an improvement in quality of life for individuals living with HIV. However, the long-term use of ART is associated with various metabolic side effects, including dyslipidemia, insulin resistance, lipodystrophy, and increased risk for cardiovascular diseases.

The review highlights that while metabolic complications are a concern for pediatric populations, there is a notable lack of research in this area compared to adults. It emphasizes the importance of closely monitoring these complications in children and adolescents, as they can lead to the early development of noncommunicable diseases.

The majority of children and adolescents with HIV reside in low- and middle-income countries, where access to diagnostic tests and newer ART regimens is limited. This presents a challenge, as the scarcity of studies on integrase inhibitor-based regimens hinders the understanding of their impact on metabolic health in pediatric patients.

Prevalence rates for metabolic complications and diseases vary widely among different studies, reflecting differences in study design, sample size, and participant characteristics. This variability raises questions about the generalizability of findings and the need for standardized methodologies in future research.

Addressing metabolic complications in children and adolescents with HIV is crucial for preventing long-term health issues, especially considering that young individuals with perinatal HIV may face decades of ART exposure. The review suggests that improvements in access to treatment, reduction of side effects, and enhancements in diagnostic capabilities are essential. Overcoming these challenges will require collaborative efforts across disciplines, advances in technology, and targeted interventions to address socioeconomic disparities.

Overall, this review underscores the importance of early detection and intervention in managing the metabolic complications of ART in children and adolescents with HIV, aiming to mitigate the risk of future cardiovascular disease and other health problems.

Source: Muccini C, Bottanelli M, Castagna A, et al. Cardiometabolic complications in children and adolescents with HIV on antiretroviral therapy. Expert Opin Drug Metab Toxicol 2024;20(9):893–905. DOI: 10.1080/17425255.2024.2395562

5. Validation of Transcriptomic Signatures Using NanoString Technology: Enhancing Diagnostic Accuracy in Childhood Febrile Illnesses

This review explores the use of NanoString technology for the validation of multiple transcriptomic signatures, demonstrating its potential for efficient parallel evaluation in clinical diagnostics for infectious diseases. The study confirms that the performance of various transcriptomic signatures remains consistent with their original studies, indicating robustness against changes in study design and methodology. This is significant, as it suggests that overfitting to discovery cohorts is not a prevalent issue. The minimal performance gains when models were retrained support this conclusion, although exceptions exist, such as with the Kawasaki disease (KD) signature, which may exhibit overfitting.

A primary challenge identified is the study-specific bias in transcript selection, which can limit the applicability of signatures in diverse clinical settings. This bias can result in poor performance when external datasets or different patient populations are assessed. The review acknowledges that reduced performance may arise from overfitting, under-representative discovery cohorts, or translational challenges between technologies. Addressing these issues requires careful machine-learning methodologies during signature development and representative clinical recruitment.

The authors propose the need for multiclass models in situations where a broader range of pathologies exists, arguing that these models may offer a more accurate diagnostic approach compared to binary models, particularly in cases of undifferentiated febrile illness. The exploratory analysis demonstrates promising results for multiclass diagnostic methods, highlighting their ability to classify patients into multiple diagnostic categories effectively.

Notably, the study introduces a novel three-transcript tuberculosis (TB) signature that exhibited high sensitivity and specificity, outperforming existing signatures that often struggle to distinguish TB from viral infections. This signature’s design, which avoids reliance on interferon-stimulated genes, contributes to its superior performance.

However, the review acknowledges limitations, including a small sample size and the heterogeneity of the studies used. Further large-scale investigations are recommended to assess different conceptual frameworks for the clinical application of transcriptomic signatures, including optimizing multiclass model setups.

The findings also emphasize the necessity of cross-platform assessments to maximize transcript detection, particularly given the challenges of low-abundance transcripts in diagnostic settings. While the study shows the promise of NanoString technology as a bridge between complex gene expression quantification methods and rapid, cost-effective diagnostics, it stresses that many existing signatures have yet to be effectively translated into clinical practice.

In conclusion, this review demonstrates the utility of NanoString for the efficient parallel validation of transcriptomic signatures, with implications for enhancing diagnostic accuracy and reducing delays in acute pediatric care. Further research is needed to refine these models and facilitate their integration into clinical workflows.

Source: Channon-Wells S, Habgood-Coote D, Vito O, et al. Integration and validation of host transcript signatures, including a novel 3-transcript tuberculosis signature, to enable one-step multiclass diagnosis of childhood febrile disease. J Transl Med 2024;22(1):802. DOI: 10.1186/s12967-024-05241-4

6. Evaluating Diaskintest for Tuberculosis Diagnosis in Children: A Retrospective Comparison with Tuberculin Skin Testing in the Russian Federation

This observational study evaluates the diagnostic performance of a novel skin test, Diaskintest (DT), containing specific “Mycobacterium tuberculosis” antigens, in comparison to the traditional tuberculin skin test (TST) in a large pediatric population within the Russian Federation. The findings indicate that while a high number of children tested positive for TST, fewer were positive for DT, and suggesting a higher specificity for DT. This difference may reflect the limitations of TST, especially in a population with nearly universal Bacillus Calmette–Guérin (BCG) vaccination, where TST can yield false positives due to prior exposure to the vaccine.

The study reports a relatively low incidence of diagnosed TB disease among children, which may be attributed to effective screening practices that facilitate timely diagnosis and treatment of latent TB infection. The poor agreement between TST and DT results raises concerns about the sensitivity and specificity of the tests, with DT showing improved specificity and potential sensitivity, especially in children with known exposure to smear-positive TB cases.

The authors highlight several limitations, including a lack of data comparing DT to interferon-gamma release assays (IGRAs), the retrospective nature of the study, and the exclusion of many children due to unavailable skin test results. The generalizability of the findings is limited by these factors, particularly since IGRA is not routinely used in the Russian context, making it difficult to assess DT’s performance against a gold standard.

The strengths of this study lie in its large sample size and real-world clinical application of DT in routine care. It emphasizes the need for further research to validate DT, including prospective studies that compare outcomes in children tested with DT and TST and those receiving preventive treatment for TB infection.

In conclusion, the study suggests that DT is a promising diagnostic tool for TB infection in a pediatric population, particularly in settings with high BCG coverage. Future work should focus on head-to-head comparisons with IGRA, as well as exploring the implications of these findings for public health strategies aimed at TB elimination.

Source: Fritschi N, Gureva T, Eliseev P, et al. Diagnosis of tuberculosis infection in children with a novel skin test and the traditional tuberculin skin test: an observational study. PLoS One 2024;19(8):e0293272. DOI: 10.1371/journal.pone.0293272

7. Integrating Point-of-care CRP Testing into Community Health Worker Care: A Randomized Trial to Reduce Antibiotic Use in Children with Acute Respiratory Illness in Uganda

This study evaluates the impact of point-of-care C-reactive protein (CRP) measurement on antibiotic use among children with acute respiratory illness (ARI) seeking care from community health workers (CHWs) in rural Uganda. The trial employed a stepped wedge cluster randomized design to compare the standard integrated community case management (iCCM) algorithm with the STAR SCJA (simplified treatment algorithm for respiratory symptoms–study of community health worker judgment algorithm), which incorporates CRP testing. Results indicate that CRP testing significantly reduced antibiotic prescriptions without a corresponding increase in adverse outcomes, demonstrating that CHWs can effectively implement and interpret CRP tests.

The findings align with previous studies demonstrating the potential of CRP measurement to guide antibiotic stewardship. For instance, studies in Vietnam have shown a reduction in unnecessary antibiotic use with CRP testing in primary care settings, while a Tanzanian study reported even greater decreases in antibiotic prescriptions when CRP was used as part of a broader diagnostic package. In these contexts, the integration of multiple rapid diagnostics, including CRP, contributed to lower antibiotic usage, particularly with the higher cutoff of 80 mg/L in the Tanzanian study compared to the 40 mg/L used in the Ugandan study. The choice of a lower CRP cutoff in Uganda was intended to prioritize sensitivity, recognizing the limited training of CHWs.

Interestingly, a study in Myanmar and Thailand, which used the same CRP cutoff of 40 mg/L, reported a smaller absolute difference in antibiotic prescribing. This may be due to differences in study populations and a lower baseline frequency of antibiotic prescribing. In contrast, the Ugandan study achieved a very high uptake of CRP use, with adherence to the STAR SCJA being notably strong, indicating a positive community perception of health-related interventions.

Importantly, the study does not report any increase in adverse clinical outcomes associated with reduced antibiotic use, consistent with findings from numerous studies, including those that have validated the safety of CRP testing for antibiotic stewardship. The authors recommend that future studies of CRP use by CHWs be adequately powered to detect differences in clinical outcomes.

Strengths of the study include its real-world applicability, given the community-based setting, and the thorough training provided to CHWs to ensure accurate CRP testing. Limitations include the trial’s retrospective registration, potential biases inherent in stepped wedge designs, and the lack of systematic evaluation of CHW performance compared to laboratory technicians.

In conclusion, integrating point-of-care CRP testing into routine care by CHWs presents a feasible strategy to optimize antibiotic use for ARI in resource-limited settings. This study supports the need for expanded access to diagnostics to enhance antibiotic stewardship and improve child health outcomes in rural communities.

Source: Ciccone EJ, Hu D, Preisser JS, et al. Point-of-care C-reactive protein measurement by community health workers safely reduces antimicrobial use among children with respiratory illness in rural Uganda: a stepped wedge cluster randomized trial. PLoS Med 2024;21(8):e1004416. DOI: 10.1371/journal.pmed.1004416

8. Development and Validation of a Clinical Algorithm for Distinguishing Transient Synovitis of the Hip in Children Presenting with Nontraumatic Limping

This retrospective cohort study aims to develop and validate an algorithm for rapidly distinguishing transient synovitis (TS) of the hip from other differential diagnoses in children presenting with nontraumatic limping in the emergency department. Conducted at Lille University Hospital between 2016 and 2020, the study analyzed data from 995 patients, with the gold standard being a definitive diagnosis at follow-up. The study identified 337 cases of TS, of which 210 were confirmed at follow-up. Key variables associated with TS included age between 3 and 10 years, absence of fever, lack of local inflammation, and sudden onset of limping upon awakening. The developed algorithm, tested on 297 patients and validated internally on 175 patients, demonstrated a specificity of 98.2% and a positive likelihood ratio of 19.6, successfully identifying TS without missing serious differential diagnoses.

The findings are consistent with prior studies suggesting that fever does not exclude TS but indicates the need for further investigation due to its association with conditions like septic arthritis. Additionally, while weight-bearing status is often cited as a distinguishing factor, it was not significant in this study, highlighting the complexity of diagnosing TS based solely on clinical signs. The algorithm also accounted for localized pain and hip limitation, though these factors were not consistently more frequent in TS cases compared to other conditions.

The study’s strengths include a large sample size and the comprehensive collection of clinical data, allowing for a detailed analysis of factors related to TS. However, limitations include the lack of systematic follow-up after emergency department visits and the retrospective design, which may have introduced bias in some variables. The findings may also be less generalizable due to the single-center nature of the study, although multicenter validation is recommended to confirm the algorithm’s applicability.

In conclusion, the algorithm developed in this study provides a clinical tool that enables accurate diagnosis of TS without the need for additional tests, thereby minimizing unnecessary examinations and hospital stays for children. The authors suggest further multicenter studies to validate and generalize the algorithm for broader clinical use.

Source: Benoit J, El Khalifi S, Saoudi C, et al. Transient synovitis of the hip: development and validation of a new diagnostic algorithm. Acta Paediatr 2024;113(6):1396–1403. DOI: 10.1111/apa.17144

9. Evaluating Etiologies of Eosinophilia in Children: A Systematic Review and Proposed Diagnostic Algorithm

This systematic review aims to evaluate the etiologies of eosinophilia in children from various socioeconomic backgrounds and to propose a diagnostic algorithm for its assessment. The review encompasses studies published from January 2012 to June 2023, focusing on the incidence and causes of peripheral eosinophilia in pediatric populations.

The review included 15 observational studies involving a total of 3,409 children. Findings revealed significant variations in the causes of eosinophilia based on the children’s socioeconomic status. In high-income countries, allergic diseases were the predominant cause, accounting for 7.7–78.2% of cases, whereas parasitosis was the leading cause in low-income countries, with prevalence rates ranging from 17.7 to 88.3%. This distinction highlights the necessity of considering the child’s geographic and socioeconomic context when evaluating eosinophilia.

The authors developed a step-up diagnostic algorithm that classifies eosinophilia based on severity and origin, which could enhance resource allocation and diagnostic efficiency in clinical settings. The algorithm identifies four key clinical variables: age between 3 and 10 years, absence of fever, lack of local inflammation, and sudden onset of limping upon awakening. The review underscores that although eosinophilia is associated with various conditions—including infectious diseases, malignancies, and immune disorders—most high-income studies inadequately screened for parasitic infections, potentially underestimating their prevalence.

The review highlights a notable challenge in diagnosing unexplained eosinophilia, which occurred in 5.4–70.2% of cases across studies, often attributed to incomplete diagnostic evaluations. Factors such as being under 2 years of age, absence of symptoms, and mild eosinophilia were identified as independent risk factors for unexplained cases.

Limitations of the review include the potential for omitted studies, inconsistency in diagnostic testing across included studies, and a lack of symptom evaluation in many cases. The authors caution that their proposed algorithm requires further validation through clinical studies to assess its practicality in diverse healthcare settings.

In conclusion, this review presents a comprehensive assessment of eosinophilia in children, advocating for a diagnostic algorithm that could improve resource allocation, testing accuracy, and patient outcomes. Further research is essential to validate the proposed algorithm’s effectiveness across various populations and healthcare environments.

Source: Pellegrino R, Tosca M, Timitilli E, et al. From evidence to practice: a systematic review-based diagnostic algorithm for paediatric eosinophilia across socioeconomic context. Acta Paediatr 2024;113(7):1506–1515. DOI: 10.1111/apa.17266

10. Characteristics of Gut Flora in Children: Impact of Sleep Patterns on Microbial Diversity and Metabolism

This study investigates the characteristics of gut flora in children with varying sleep patterns, specifically focusing on those who go to bed early vs late. The sample comprised 88 healthy children aged 2–14 years, balanced by sex. The researchers collected fecal samples and sequenced the gut microbiome to assess differences in bacterial diversity, abundance, and metabolic pathways.

Results indicated statistically significant differences in β diversity at the genus level (p = 0.045) between early and late sleepers. Notably, α diversity measures, including Simpson’s index (p = 0.0011) and Shannon’s index (p = 0.0013), were higher in the early sleeper group. Key gut microbes identified in children with an early bedtime included Akkermansia muciniphila, Bacteroidetes, Verrucomicrobia, and Firmicutes. These findings suggest that establishing a healthy circadian rhythm may influence gut microbiota, which in turn affects sleep regulation through the gut–brain axis.

The study underscores the connection between sleep disturbances and cognitive development, noting that specific gut microbes like A. muciniphila are crucial for maintaining neural homeostasis. The review references previous research indicating that sleep deprivation alters gut flora composition, potentially leading to detrimental effects on cognitive function and behavior.

However, the study has several limitations. It did not further explore the relationship between gut microbiota and small molecule metabolism, which could provide deeper insights into the metabolic mechanisms involved. The sample size was limited, restricting the generalizability of the findings, and the reliance on parental reporting for sleep habits introduces potential bias. The study also lacked participants from rural settings, limiting diversity in lifestyle habits.

In conclusion, this investigation reveals significant variations in gut flora characteristics based on sleep patterns, emphasizing the importance of adequate sleep for healthy cognitive and physical development in children. The findings pave the way for exploring pharmacological interventions targeting gut microbiota to address pediatric sleep disorders. Future research should aim to expand sample sizes, include diverse populations, and delve deeper into the metabolic pathways associated with gut flora in relation to sleep patterns.

Source: Mao C, Xi C, Du R, et al. Characteristics of gut flora in children who go to bed early versus late. Sci Rep 2024;14:23256. DOI: 10.1038/s41598-024-75006-y

11. Risk of Congenital Anomalies in Newborns Exposed to Dolutegravir-based Regimens During Pregnancy: A Systematic Review and Meta-analysis

This systematic review and meta-analysis explores the risk of congenital anomalies in newborns exposed to dolutegravir-based antiretroviral regimens during pregnancy, compared to those exposed to nondolutegravir regimens. Dolutegravir is a first-line treatment for human immunodeficiency virus (HIV) due to its superior efficacy, but concerns regarding potential congenital anomalies have raised questions about its safety in pregnant populations.

The researchers conducted an extensive literature search across multiple databases, including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Google Scholar, and ClinicalTrials.gov, with a cutoff date of November 30, 2023. They included studies that reported data on congenital anomalies following antenatal exposure to dolutegravir. To assess the risk of bias, they utilized appropriate tools for different study designs: RoB2 for randomized controlled trials, ROBINS-I, and ROBINS-E for nonrandomized controlled and observational studies, respectively. The meta-analysis was performed using a random-effects model in RevMan 5.4.1, and the researchers evaluated heterogeneity with the Q statistic and I2 value.

Out of 26 eligible studies, the meta-analysis included 12 studies—six randomized controlled trials and six observational studies—totaling 32,617 participants. The meta-analysis found no statistically significant difference in the risk of congenital anomalies between newborns exposed to dolutegravir-based regimens and those exposed to nondolutegravir regimens, reporting a risk ratio of 1.10 (95% confidence interval 0.79–1.53; p = 0.59). Moderate heterogeneity was present (I2 = 47%), and the pooled results from randomized controlled trials and observational studies, as well as sensitivity analyses, showed consistent findings.

In conclusion, this study suggests that there is no significant difference in the risk of congenital anomalies associated with antenatal exposure to dolutegravir compared to other regimens. These findings contribute valuable information regarding the safety of dolutegravir during pregnancy, indicating that its use may not increase the risk of congenital anomalies. Ongoing research is essential to continue evaluating safety profiles as additional data become available.

Source: Payra S, Harsha D, Kumar K, et al. Risk of congenital anomalies with dolutegravir-based anti-retroviral regimens: a systematic review and meta-analysis. Clin Drug Investig 2024;44(9):667–685. DOI: 10.1007/s40261-024-01390-y

12. Efficacy of Amoxicillin vs Placebo in Treating Group A Streptococcus Pharyngitis in Children: A Randomized Controlled Trial

This study investigates the efficacy of amoxicillin compared to placebo in treating group A streptococcus (GAS) pharyngitis in children, focusing on fever duration and pain intensity. Given the ongoing debate about the role of antibiotics in preventing complications, particularly in high-income countries where nonsuppurative complications are rare, this randomized, double-blind, placebo-controlled trial aimed to evaluate whether a placebo is noninferior to amoxicillin for reducing fever.

The study involved 88 children aged 3–15 years, who were randomized to receive either amoxicillin or placebo for 6 days. The primary outcome measured was the difference in fever duration, with a noninferiority threshold of 12 hours set for the analysis. Secondary outcomes included pain intensity and complications associated with streptococcal pharyngitis.

Results indicated that the mean difference in fever duration was 2 hours in the per-protocol analysis and 2.8 hours in the intention-to-treat analysis, neither of which reached the predefined noninferiority margin of 12 hours. There was no significant difference in pain intensity between the two groups over the 7 days following treatment. Adverse events were similarly distributed between groups, with no significant safety concerns.

The findings suggest that amoxicillin may offer marginal benefits in fever duration and pain intensity, leading the authors to advocate for a more restrictive approach to antibiotic prescribing for GAS pharyngitis. They emphasize that effective monitoring and symptomatic treatment could be sufficient for managing this condition, particularly in high-income settings where access to healthcare is readily available.

The study acknowledges several limitations, including a relatively small sample size, reliance on parental reporting for outcomes, and a high dropout rate related to parents’ decisions to initiate antibiotic treatment. The results are considered generalizable to primary care settings in countries with good medical access, particularly as the study used rapid antigen detection tests for inclusion, aligning with current clinical practices.

In conclusion, the research indicates that the impact of antibiotic treatment on both fever duration and pain intensity in children with GAS pharyngitis is limited. The findings support a careful, judicious approach to antibiotic use, considering the potential risks associated with overprescription and the effectiveness of symptom-based management.

Source: Gualtieri R, Verolet C, Mardegan C, et al. Amoxicillin vs. placebo to reduce symptoms in children with group A streptococcal pharyngitis: a randomized, multicenter, double-blind, non-inferiority trial. Eur J Pediatr 2024;183(11):4773–4782. DOI: 10.1007/s00431-024-05705-1

13. Comparative Efficacy and Safety of Antibiotic Regimens for Brucellosis in Children and Adolescents: A Systematic Review and Network Meta-analysis

This systematic review and network meta-analysis investigates the efficacy and safety of various antibiotic treatments for brucellosis, a zoonotic disease affecting nearly 5,00,000 individuals annually. Given the lack of consensus in clinical guidelines regarding initial treatment options for brucellosis, the authors aim to provide evidence-based recommendations.

The researchers conducted a comprehensive literature search across four English and three Chinese databases, including randomized controlled trials (RCTs) involving children and adolescents diagnosed with brucellosis. Studies targeting specific conditions such as spondylitis brucellosis, endocarditis brucellosis, and neurobrucellosis were excluded. Primary outcomes focused on overall treatment failure (efficacy) and adverse effects (safety), while secondary outcomes included relapse and therapeutic failure. The data were analyzed using a random effects model in a network meta-analysis, and the protocol was preregistered in PROSPERO (CRD42023491331).

From 11,747 records screened, 43 RCTs were identified, with 12 studies included in the meta-analysis. The results indicated that standard therapy (doxycycline + rifampicin) was less effective compared to combinations involving doxycycline + gentamicin and triple therapy. Notably, doxycycline + gentamicin ranked highest in efficacy (SUCRA value: 0.94), followed by triple therapy (0.87) and doxycycline + streptomycin (0.78). The analysis revealed no significant differences in treatment failure or adverse events between groups, and the overall quality of evidence was rated low to moderate.

The authors concluded that certain antibiotic regimens, particularly doxycycline + gentamicin and triple therapy, demonstrated superior efficacy and safety profiles. They recommended a cautious and judicious approach to antibiotic prescribing for brucellosis, emphasizing the need for cost-effective and practical treatment strategies, especially in resource-limited settings. The study highlights the importance of addressing antibiotic resistance and ensuring treatment regimens are manageable.

Limitations of the review include the potential risk of missing relevant studies, inconsistencies in reported outcomes like time to defervescence, and the narrow sample sizes for some drug comparisons, which resulted in wider confidence intervals. The authors suggest that future research should focus on well-designed, larger-scale studies to validate the findings and improve understanding of optimal treatment protocols for brucellosis.

Source: Huang S, Xu J, Wang H, et al. Updated therapeutic options for human brucellosis: a systematic review and network meta-analysis of randomized controlled trials. PLoS Negl Trop Dis 2024;18(8):e0012405. DOI: 10.1371/journal.pntd.0012405

14. Viral Infections and Sudden Noncardiac Death: A Systematic Review of Causes and Implications Across Age Groups

This systematic review examines the relationship between viral infections and sudden noncardiac death (SNCD), a clinical entity characterized by deaths that occur unexpectedly without prior significant symptoms. The review highlights the significant role infections, particularly viral infections, play in SNCD, especially among children.

The study adhered to PRISMA guidelines and included a comprehensive search across multiple databases, identifying relevant autopsy series and cohort studies that demonstrated evidence of viral disease as a cause of death. A total of 12 studies published between 1996 and 2020 were analyzed, categorizing the study populations into three groups: infants and young children (up to 4 years), presumed sudden infant death syndrome (SIDS) patients, and older individuals (5 years and older).

The findings reveal that SNCD with viral implications constitutes a minority of sudden deaths across all age-groups, with a higher prevalence observed in infants and young children. The leading cause of viral SNCD was respiratory infection, with respiratory syncytial virus and herpes simplex virus identified as the most common viral agents responsible for fatalities in infants and older children, respectively. Other identified causes of SNCD in children included disseminated infections, gastrointestinal infections, and meningitis.

Despite the considerable prevalence of viral SNCD in younger populations, the review points out the lack of studies directly assessing its frequency and specific causes, particularly in adults. The authors advocate for the implementation of postmortem virological molecular testing to identify previously unrecognized viral contributions to SNCD. They emphasize the need for further research to better characterize the associations between viral infections and SNCD and to identify potential risk factors and preventive strategies.

In conclusion, the review highlights that viral infections are a significant but understudied contributor to SNCD. It underscores the necessity for enhanced postmortem investigations to accurately identify viral causes of sudden death, thereby informing public health strategies aimed at prevention and management.

Source: Cordeiro FP, Cainé L. Viral infection and sudden non-cardiac death: a systematic review. J Forensic Leg Med 2024;106:102727. DOI: 10.1016/j.jflm.2024.102727

ORCID

Vikram S Kumar https://orcid.org/0000-0002-1369-7682

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