Tuberculosis Disease in Immunocompromised Children and Adolescents: A Pediatric Tuberculosis Network European Trials Group Multicenter Case-control Study.

BACKGROUND: In high-resource settings, the survival of children with immunocompromise (IC) has increased and immunosuppressive therapies are increasingly being used. This study aimed to determine the clinical characteristics, performance of diagnostic tools, and outcome of IC children with tuberculosis (TB) in Europe. METHODS: Multicenter, matched case-control study within the Pediatric Tuberculosis Network European Trials Group, capturing TB cases <18 years diagnosed 2000-2020. RESULTS: A total of 417 TB cases were included, comprising 139 children who are IC (human immunodeficiency virus, inborn errors of immunity, drug-induced immunosuppression, and other immunocompromising conditions) and 278 non-IC children as controls. Nonrespiratory TB was more frequent among cases than controls (32.4% vs 21.2%; P = .013). Patients with IC had an increased likelihood of presenting with severe disease (57.6% vs 38.5%; P < .001; odds ratio [95% confidence interval], 2.073 [1.37-3.13]). Children with IC had higher rates of false-negative tuberculin skin test (31.9% vs 6.0%; P < .001) and QuantiFERON-TB Gold assay (30.0% vs 7.3%; P < .001) results at diagnosis. Overall, the microbiological confirmation rate was similar in IC and non-IC cases (58.3% vs 49.3%; P = .083). Although the mortality in children with IC was <1%, the rate of long-term sequelae was significantly higher than in non-IC cases (14.8% vs 6.1%; P = .004). CONCLUSIONS: Children with IC and TB in Europe have increased rates of nonrespiratory TB, severe disease, and long-term sequelae. Immune-based TB tests have poor sensitivity in those children. Future research should focus on developing improved immunological TB tests that perform better in patients with IC, and determining the reasons for the increased risk of long-term sequelae, with the aim to design preventive management strategies.

Schistosomiasis in migrant children and adolescents in a paediatric tropical referral unit in Spain: diagnosis and long-term management challenges.

Globalisation and population movement have led to an increasing number of migrant children residing in areas non-endemic for schistosomiasis. However, diagnosing and managing schistosomiasis in children remain controversial. This study aims to investigate the prevalence of schistosomiasis in migrant children and to describe the diagnostic approach and management strategies, including long-term follow-up, to explore the potential role of serological tests in evaluating treatment response. We conducted a retrospective descriptive study spanning from January 2014-July 2021 at a referral unit for Paediatric Tropical Diseases in Madrid (Spain). The study included patients under 18 years diagnosed with schistosomiasis. Of 679 children screened for schistosomiasis, 73 (10.8%) tested positive. The median age was 16.3 years [IQR 9-17.6], 74% male. The majority originated from Sub-Saharan Africa (47%) and Asia (47%). Only 40% presented with symptoms, with gastrointestinal (18%) and cutaneous (17%) manifestations being the most common. Eosinophilia was observed in 43% (median [IQR]: 1103/mm3 [671-1536]), and ova were visualised in the urine of 2/50 (4.0%). Praziquantel treatment was administered to 92%, and 5 patients required retreatment. Follow-up data were available for 58 (80%) over a median period of 9 months [IQR 6-19.8], revealing a progressive decline in eosinophil count, IgE titres, and ELISA optical density.    Conclusion: In this series, the prevalence of schistosomiasis among migrant children was significant (10%), highlighting the importance of including serological tests in migrant health screening. The disease is largely asymptomatic, eosinophilia is often absent, and visualisation of ova in urine is exceedingly rare. Eosinophil count, IgE titres, and ELISA optical density could prove valuable as an initial approach for monitoring inflammation during follow-up assessments. What is Known: • The burden of disease related to schistosomiasis is significant, particulary in children, and it is advisable to screen this vulnerable population. What is New: • Eosinophilia may not be present in parasitic infections, so serological tests are crucial for screening migrant children. • Serological monitoring facilitates long-term management of migrant children with schistosomiasis.

Pediatric perspective: the microbiome in vertical HIV-infection: unravelling gaps, challenges, and therapeutic potential.

PURPOSE OF REVIEW: The intricate interplay between HIV and the host microbiota has emerged as a significant area of investigation with therapeutic potential. Despite numerous studies on this complex interaction in adults, vertically acquired infections, which have distinct immunological and virological characteristics, remain relatively understudied. RECENT FINDINGS: Disturbances, including prolonged exposure to HIV and antiretroviral therapy, significantly impact the gut microbiome, though isolating these effects from other influencing factors is challenging. Children and adolescents living with HIV exhibit reduced microbiome diversity and potential imbalances between beneficial and pathogenic taxa. However, most available data focus on microbiome composition rather than function. The observed variations in specific microbial phyla are intriguing, but their health effects are unknown. Although modulating the microbiota may be theoretically easier during childhood, few interventional trials have included children. SUMMARY: Therapeutic interventions aimed at modulating the gut microbiome in children with HIV have shown limited impact, and their ability to induce long-term microbiome changes remains uncertain. A more functional, longitudinal approach, along with an ecological perspective, is needed to understand the complex interplay between the microbiome and the host. This will help clarify the relevance of microbiota alterations and their potential implications for clinical outcomes, such as inflammation and immune reconstitution in pediatric HIV.

Violence as a Health Problem.

Violence is a public health problem, and when it affects childhood, it can cause illness throughout the individual's life. Apart from being able to cause damage in the physical, mental and social spheres, it represents a violation of the rights of the affected children, and a high consumption of resources, both economic and social. A multitude of investigations have improved attention to this violence. However, these advances are not consistent with the practical management of victims, both in Primary and Hospital Care. There is a significant area of improvement for paediatric care. Through this article, different professionals from all established paediatric health care facilities develop general lines of knowledge and action regarding violence against children. An overview is taken of the legislation related to childhood, the different types of abuse that exist, their effects, management and prevention. It concludes with an epilogue, through which we aim to move sensibilities. In summary, this work aims to promote the training and awareness of all professionals specialized in children's health, so that they pursue the goal of achieving their patients' greatest potential in life, and in this way, to help create a healthier society, with less disease, and more justice.

CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis.

Background: In people living with HIV (PLHIV), the CD4/CD8 ratio has been proposed as a useful marker for non-AIDS events. However, its predictive ability on mortality over CD4 counts, and the role of CD8+ T-cell counts remain controversial. Methods: We conducted a systematic review and meta-analysis of published studies from 1996 to 2023, including PLHIV on antiretroviral treatment, and reporting CD4/CD8 ratio or CD8+ counts. The primary outcome was non-AIDS mortality or all-cause mortality. We performed a standard random-effects pairwise meta-analysis comparing low versus high CD4/CD8 ratio with a predefined cut-off point of 0.5. (CRD42020170931). Findings: We identified 2,479 studies for screening. 20 studies were included in the systematic review. Seven studies found an association between low CD4/CD8 ratio categories and increased mortality risk, with variable cut-off points between 0.4-1. Four studies were selected for meta-analysis, including 12,893 participants and 618 reported deaths. Patients with values of CD4/CD8 ratio below 0.5 showed a higher mortality risk (OR 3.65; 95% CI 3.04 - 4.35; I2 = 0.00%) compared to those with higher values. While the meta-analysis of CD8+ T-cell counts was not feasible due to methodological differences between studies, the systematic review suggests a negative prognostic impact of higher values (>1,138 to 1,500 cells/uL) in the long term. Conclusions: Our results support the use of the CD4/CD8 ratio as a prognostic marker in clinical practice, especially in patients with values below 0.5, but consensus criteria on ratio timing measurement, cut-off values, and time to event are needed in future studies to get more robust conclusions. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020170931, identifier CRD42020170931.

Multiplex PCR and Antibiotic Use in Children with Community-Acquired Pneumonia.

Antibiotics are frequently prescribed to children with pneumonia, although viruses are responsible for most cases. We aimed to evaluate the impact of multiplex polymerase chain reaction (mPCR) on antibiotic use. We conducted a prospective study of children under 14 years of age admitted for suspected viral pneumonia, from October 2019 to June 2022 (except March-November 2020). A mPCR respiratory panel (FilmArray® 2plus, bioMérieux, Marcy-l'Étoile, France) was performed within 72 h of admission. Patients with positive reverse transcription PCR for respiratory syncytial virus, influenza, or SARS-CoV-2 were excluded. We compared the patients with historical controls (2017-2018) who had suspected viral pneumonia but did not undergo an aetiological study. We included 64 patients and 50 controls, with a median age of 26 months. The respiratory panel detected viral pathogens in 55 patients (88%), including 17 (31%) with co-infections. Rhinovirus/enterovirus (n = 26) and human metapneumovirus (n = 22) were the most common pathogens, followed by adenovirus and parainfluenza (n = 10). There were no statistically significant differences in the total antibiotic consumption (83% of cases and 86% of controls) or antibiotics given for ≥72 h (58% vs. 66%). Antibiotics were prescribed in 41% of the cases and 72% of the controls at discharge (p = 0.001). Ampicillin was the most commonly prescribed antibiotic among the patients (44% vs. 18% for controls, p = 0.004), while azithromycin was the most commonly prescribed among the controls (19% vs. 48% for patients and controls, respectively; p = 0.001). Our findings underscore the need for additional interventions alongside molecular diagnosis to reduce antibiotic usage in paediatric community-acquired pneumonia.

Corrigendum: CD4/CD8 ratio and CD8+ T-cell count as prognostic markers for non-AIDS mortality in people living with HIV. A systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fimmu.2024.1343124.].

The role of veterinarians in zoonosis prevention: Advising families of immunocompromised children with pets.

Background: Pet ownership is widespread, offering numerous benefits to individuals and families. However, the risk of zoonotic diseases must be carefully considered, especially for immunosuppressed patients. Knowledge gaps in preventive measures for zoonoses have been identified, underscoring the vital role of veterinarians in addressing this issue. Objectives: This study aimed to assess the knowledge and recommendations of veterinarians regarding pet ownership by immunocompromised individuals. Additionally, we compared these insights with responses from European healthcare professionals specializing in pediatric transplant recipients. Methods: We conducted an observational, cross-sectional study involving small animal veterinarians in Spain. An online survey was administered to gather information on veterinarians' knowledge of zoonoses and their recommendations for immunocompromised pet owners. Results: A survey of 514 individuals was collected from experienced veterinarians mainly working in primary care clinics. Surprisingly, 63% of respondents did not routinely inquire about the presence of immunocompromised individuals among pet owners, although 54% offered specific recommendations for this group. Most respondents adhered to deworming guidelines for pets owned by immunocompromised individuals and demonstrated sound practices in Leishmania and Leptospira prevention, as well as the avoidance of raw food. However, gaps were noted concerning Bordetella bronchiseptica vaccination. Notably, veterinarians outperformed medical professionals in their knowledge of zoonotic cases and identification of zoonotic microorganisms. The presence of specific recommendations in veterinary clinics was viewed positively by nearly all respondents. Conclusions: Our findings indicate that veterinarians possess a superior understanding of zoonotic pathogens and exhibit greater proficiency in diagnosing zoonoses compared with physicians. They stay well-informed about recommendations outlined in established guidelines and are more likely to provide written recommendations in their clinics than physicians. Nevertheless, knowledge gaps among veterinarians emphasize the need for enhanced communication between medical and veterinary professionals. Reinforcing the "One Health" concept is imperative, with veterinarians playing a pivotal role in this collaborative effort.

QuantiFERON-TB reversion in children and adolescents with tuberculosis.

We analyzed 136 children with tuberculosis disease or infection and a positive QuantiFERON-TB (QFT) assay, followed-up for a median of 21 months (0.4-11years). QFT reversed in 16.9% of cases, with significant decreases in TB1 (-1.72 vs. -0.03 IU/ml, p=0.001) and TB2 (-1.65 vs. -0.43 IU/ml, p=0.005) levels compared to non-reverters. We found a higher QFT reversion rate among children under 5 years (25.0% vs 11.9%, p=0.042), and those with TST induration <15mm (29% vs 13.3%, p=0.055). Our data reveal that, although QFT test remained positive in the majority of children, reversion occurred in 16% of cases in a progressive and stable pattern. Younger age and reduced TST induration were associated with QFT reversion.

Zoonosis screening in Spanish immunocompromised children and their pets.

Introduction: Although pets provide several social-emotional benefits for children, the risk of zoonosis must be considered among immunocompromised individuals. Methods: A prospective study was conducted in a tertiary hospital including immunocompromised patients younger than 20 years owning dogs and/or cats. Colonization and/or infection was evaluated by stool studies, bacterial swabs, blood polymerase chain reaction and serological studies in both patients and their pets, to evaluate potential zoonotic transmission occurrence. Results: We included 74 patients and their 92 pets (63 dogs, 29 cats). Up to 44.6% of the patients and 31.5% of the pets had at least 1 positive result. Up to 18.4% of pets' fecal samples were positive (bacteria, parasites or hepatitis E virus). No helminths were observed despite the high frequency of incorrect intestinal deworming practices. Among children, gastrointestinal microorganisms were found in 37.3% (primarily Clostridium difficile). Colonization by Staphylococcus pseudintermedius was common among pets (8.0%) but not among children (0.0%). No shared colonization between owners and pets was observed, except in one case (Blastocystis in both patient and pet feces). Among patients, serologies were positive for Strongyloides stercoralis (14.8%), Toxocara canis (3.2%), Bartonella henselae (19.1%) and hepatitis E (5.6%). Serology was positive for Rickettsia spp. (22.6%) and Babesia spp. (6.5%) in dogs and for Leishmania spp. (14.3%) and Toxoplasma spp. (14.3%) in cats. Conclusion: Exposure to zoonotic agents was detected in both patients and pets; however, shared colonization events were almost nonexistent. In our cohort, dogs and cats do not appear to entail high zoonosis transmission risk for immunocompromised patients.

The Association of HIV-1 Neutralization in Aviremic Children and Adults with Time to ART Initiation and CD4+/CD8+ Ratios.

Broadly neutralizing antibodies (bnAbs) bind and neutralize diverse HIV isolates and demonstrate protective effects in primate models and humans against specific isolates. To develop an effective HIV vaccine, it is widely believed that inducing these antibodies is crucial. However, the high somatic hypermutation in bnAbs and the limited affinity of HIV Env proteins for bnAb germline precursors suggest that extended antigen exposure is necessary for their production. Consequently, HIV vaccine research is exploring complex sequential vaccination strategies to guide the immune response through maturation stages. In this context, the exploration of the factors linked to the generation of these antibodies across diverse age groups becomes critical. In this study, we assessed the anti-HIV-1 neutralization potency and breadth in 108 aviremic adults and 109 aviremic children under 15 years of age who were receiving ART. We used a previously described minipanel of recombinant viruses and investigated the factors associated with neutralization in these individuals. We identified individuals in both groups who were capable of neutralizing viruses from three different subtypes, with greater cross-neutralization observed in the adult group (49.0% vs. 9.2%). In both groups, we observed an inverse association between neutralization breadth and the CD4+/CD8+ ratio, as well as a direct association with the time to ART initiation. However, we found no association with time post-infection, cumulative ART duration, or CD8+ cell levels. The present study demonstrates that children receiving antiretroviral therapy generate broadly neutralizing responses to HIV-1, albeit with lower magnitude compared to adults. We also observed that neutralization breadth is associated with CD4+/CD8+ levels and time to treatment initiation in both children and adults living with HIV-1. Our interpretation of these results is that a delay in ART initiation could have prolonged the antigenic stimulation associated with viral replication and thus facilitate the capacity to elicit long-lasting broadly neutralizing responses. These results corroborate prior findings that show that HIV-1-neutralizing responses can persist for years, even at low antigen levels, implying an HIV-1 vaccine may induce lasting neutralizing antibody response.

Lung Ultrasound: A Useful Prognostic Tool in the Management of Bronchiolitis in the Emergency Department.

Lung ultrasound, a non-invasive bedside technique for assessing paediatric patients with acute respiratory diseases, is becoming increasingly widespread. The aim of this prospective, observational cohort study was to evaluate the effectiveness of a clinical ultrasound score in assessing infants with acute bronchiolitis in the emergency department and its ability to accurately identify patients at a higher risk of clinical deterioration. Infants under 6 months of age with clinical symptoms compatible with acute bronchiolitis were enrolled and underwent clinical and lung ultrasound evaluations. The study included 50 patients, the median age of which was 2.2 months (IQR: 1-5), and the primary outcome was respiratory support. Infants requiring invasive or non-invasive ventilation showed higher scores (5 points [IQR: 3.5-5.5] vs. 2.5 [IQR: 1.5-4]). The outcome had an AUC of 0.85 (95%CI: 0.7-0.98), with a sensitivity of 87%, specificity of 64%, and negative predictive value of 96.4% for a score <3.5 points. Children who scored ≥3.5 points were more likely to require respiratory support within the next 24 h (estimated event-free survival of 82.9% compared to 100%, log-rank test p-value = 0.02). The results suggest that integrating lung ultrasound findings into clinical scores when evaluating infants with acute bronchiolitis could be a promising tool for improving prognosis.

Immunogenicity of the Conjugate Meningococcal ACWY-TT Vaccine in Children and Adolescents Living with HIV.

BACKGROUND: Children and adolescents living with HIV (CALHIV) are at high risk of meningococcal infections and may present lower immune responses to vaccines. The objectives of this study were to assess the immunogenicity of the quadrivalent Men ACWY-TT vaccine (Nimenrix®) in CALHIV after a two-dose schedule and to describe possible HIV-related factors that may affect the immunogenic response. METHODS: A multicenter prospective study was designed, including CALHIV followed in five hospitals in Madrid, between 2019 and 2021. Two doses of the Men ACWY-TT vaccine were administered. Serum bactericidal antibody (SBA) assays using rabbit complement (rSBA) against serogroups C, W, and Y were used to determine seroprotection and vaccine response (the proportion achieving a putative protective titer of ≥eight or a ≥four-fold rise in titer from baseline). Serum was collected at baseline, and at 3 and 12 months after vaccination. RESULTS: There were 29 CALHIV included, 76% of whom were perinatally infected. All were receiving TAR and presented a good immunovirological and clinical status overall. At baseline, 45% of CALHIV had seroprotective titers to at least one serogroup, with individual seroprotection rates of 24%, 28%, and 32% against C, W, and Y, respectively. After a two-dose schedule, vaccine response was 83% for each serogroup, eliciting a vaccine response to all serogroups in 69% of them. One year after vaccination, 75% of CALHIV maintained seroprotective titers against the C serogroup, and 96% against W and Y. None of the HIV-related characteristics analyzed could predict vaccine response or antibody duration. CONCLUSIONS: CALHIV who received effective TAR and presented a good immuno-virological situation achieved an appropriate vaccine response after two doses of the Men ACWY-TT vaccine, and antibody-mediated protection against serogroups C, W, and Y was maintained in more than 70% of the patients one year after vaccination.