Intrapartum use of zidovudine in a large cohort of pregnant women living with HIV in Italy.

BACKGROUND: Intravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is <50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy. METHODS: Observational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT. RESULTS: A total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and <50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA < 50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI <0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group. CONCLUSIONS: In ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use.

Off-label use of combined antiretroviral therapy, analysis of data collected by the Italian Register for HIV-1 infection in paediatrics in a large cohort of children.

BACKGROUND: Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children < 2 years of age and 60% in those aged 2-12 years, due to the lack of adequate paediatric clinical studies on pharmacokinetics, pharmacodynamics and drug safety in children. METHODS: An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. RESULTS: 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13-5.19; p = 0.024). Moreover, children < 2 years of age were at increased risk for receiving off-label HAART with respect to older children (OR: 3.24; 95% CI 1063-7.3; p = 0.001). Even if our safety data regarding off-label regimens where poor, no adverse event was reported. CONCLUSION: The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

A case of unilateral acute hypertensive uveitis in a child.

A 6-year-old boy was referred to our hospital for sudden blurring vision in the left eye. An ophthalmological evaluation showed white endothelial keratic precipitates and increased intra-ocular pressure. To our knowledge, this is the first reported case of hypertensive uveitis in children under 10 years of age and we also discuss the role of Epstein-Barr virus as a possible infectious trigger.

The use of antiviral drugs in children.

Viral infections are particularly common among children. They often have a mild course, are self-limiting and do not need any specific treatment. However, in some cases, the disease can be severe and lead to permanent disabilities. A variety of antiviral drugs are available for the treatments of certain infectious agents: for instance, acyclovir is used to treat herpes simplex virus encephalitis. Recommendations for flu treatment may change according to the current epidemiological surveillance data, on the basis of which antiviral sensibility can be forecast: recommended drugs for the 2020-21 flu season are oseltamivir, zanamivir, peramivir and baloxavir. Some drugs are used to treat congenital infections, such as valganciclovir and ganciclovir in congenital cytomegalovirus infection. Antiretroviral prophylaxis in newborns from HIV-1 infected mothers must be initiated as soon as possible, with one or more drugs according to therapeutic regimens based on the baby's risk category. According to the most recent guidelines, antiretroviral therapy must be started at diagnosis. Several antiretroviral drugs are available today and approved for use in children, so several combinations can be made. However, out of the 29 antiretroviral drugs approved for adults, only 38% (11/29) are approved for children under the age of two and about 60% (18/29) for children under the age of twelve. Treatment with direct antiviral agents against hepatitis C virus is approved for children over the age of three; it consists in different therapeutic regimens chosen on the basis of the viral genotype (ledipasvir/sofosbuvir for genotypes 1, 4, 5 and 6, sofosbuvir/ribavirin for genotypes 2 and 3, sofosbuvir/velpatasvir and glecaprevir/pibrentasvir for all genotypes) and it has dramatically changed the course of the illness. Many molecules have been studied in order to treat SARS-CoV-2 infection, but only remdesivir seems to play a role in shortening recovery time, although inclusion criteria are very specific and data on the use in children is limited.

Tuberculosis burden in immigrants and natives, adults and children, in Tuscany between 2000-2018.

BACKGROUND: Updated data on epidemiology of tuberculosis are needed in Italy. The aim of this study is to evaluate trends in incidence and associated lethality of tuberculosis in immigrants compared with Italians. METHODS: All tuberculosis cases diagnosed from 2000 to 2018 in 31 Tuscan hospitals were retrospectively identified. RESULTS: In 10,827 tuberculosis cases 6715 were males (62%), 4312 (60%) were Italian-born. Hospitalization rate was 15.37/100,000 population/year. The most common comorbidity were liver disease (832/10,827; 7.7%), COPD (675/10,827; 6.2%), cancer (614/10,827; 5.7%). HIV was more frequent in the immigrants (p < 0.001). Extra-pulmonary tuberculosis cases (EPTB) were mainly localized in pleura (740/3,894, 19%) and lymph nodes (449/3,894, 11,5%). HIV was associated with an increased risk of EPTB (OR 3.51 95% CI 2.92-4.23, p < 0.0001). EPTB risk was increased in South Asian-born patients (OR 1.77, 95% CI 1.46-2.15, p < 0.0001) as well in African-born patients (OR 1.13, 95% CI 1.03-1.24, p = 0.0091), who were at risk for gastroenteric tuberculosis (OR 3.74, 95% CI 2.69-5.22, p < 0.0001). Overall mortality rate was 0.006 per 1000. Most of death cases (89%) were Italians (p < 0.02) and mainly affected by pulmonary tuberculosis (PTB). CONCLUSIONS: In Tuscany, tuberculosis is still a health concern in terms of both morbidity and mortality.

Prevention of recurrent respiratory infections : Inter-society Consensus.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Real-World Analysis of Survival and Clinical Events in a Cohort of Italian Perinatally HIV-1 Infected Children From 2001 to 2018.

Background: Combined antiretroviral therapy (cART) has been associated with a steep decrease in mortality and morbidity in HIV-1 infected children. New antiretroviral molecules and drug classes have been developed and the management of HIV-infected children has improved, but recent data on survival are limited. Methods: An observational retrospective study investigating changes in mortality and morbidity was conducted on 1,091 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results: Three hundred and fifty-four (32%) AIDS events and 26 (2%) deaths occurred overtime. Mortality rates decreased from 0.4/100 person-years in 2001-2006 to 0.27/100 person-years in 2007-2012 and 0.07/100 person-years in 2013-2018. Notably, 92% of the dead children were born in Italy, but only 50% were followed-up since birth or within three months of age. Seventy three percent of children had started cART at age ≥6 months; 23% were treated for <30 days before death. B and C clinical events progressively decreased (P < 0.0001). Opportunistic infections significantly decreased over time, but still were the most common events in all the periods (6.76/100 person-years in 2013-2018). In the last period, severe bacterial infections were the most common ones. Cancer rates were 0.07/100; 0.17/100; 0.07/100 person-years in the three periods, respectively. Conclusions: Progressive reductions both in mortality and in rates of class B and C clinical events and OIs have been observed during the cART era. However, deaths were still registered; more than half of dead children were enrolled after birth and had belatedly started cART.

Infectious Diseases in Internationally Adopted Children and Intercountry Discrepancies Among Screening Protocols, A Narrative Review.

Internationally adopted children (IAC) require thorough health assessments at time of arrival in the host country. As these children are at higher risk for infectious diseases, such as gastrointestinal parasites, tuberculosis, hepatitis, syphilis, and human immunodeficiency virus, early diagnosis of infectious diseases is fundamental for the optimal management of the child and, also, to reduce the risk of transmission to the adopting community. Comparative analysis of the screening protocols adopted in Europe, the United States, and Canada revealed different approaches to the adopted children. A homogeneous and internationally shared standard of care in the management of IAC should be provided.

Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: Diagnosis.

BACKGROUND: In recent years, new progress has been made regarding the diagnosis, treatment and prevention of acute otitis media (AOM). The Italian Pediatric Society therefore decided to issue an update to the previous guidelines published in 2010. METHODS: Literature searches were conducted on MEDLINE by Pubmed, including studies in children, in English or Italian, published between January 1, 2010, and December 31, 2018. The quality of the included studies was assessed using the grading of recommendations, assessment, development and evaluations (GRADE) methodology. In particular, the quality of the systematic reviews was evaluated using the AMSTAR 2 appraisal tool. The guidelines were formulated using the GRADE methodology by a multidisciplinary panel of experts. RESULTS: The diagnosis of AOM is based on acute clinical symptoms and otoscopic evidence; alternatively, the presence of otorrhea associated with spontaneous tympanic membrane perforation allows the AOM diagnosis. The diagnosis of AOM must be certain and the use of a pneumatic otoscope is of fundamental importance. As an alternative to the pneumatic otoscope, pediatricians can use a static otoscope and a tympanometer. To objectively establish the severity of the episode for the formulation of a correct treatment program, an AOM severity scoring system taking into account clinical signs and otoscopic findings was developed. CONCLUSIONS: The diagnosis of AOM is clinical and requires the introduction of specific medical training programs. The use of pneumatic otoscopes must be promoted, as they are not sufficiently commonly used in routine practice in Italy.

Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: diagnosis

In recent years, new progress has been made regarding the diagnosis, treatment and prevention of acute otitis media (AOM). The Italian Pediatric Society therefore decided to issue an update to the previous guidelines published in 2010. Literature searches were conducted on MEDLINE by Pubmed, including studies in children, in English or Italian, published between January 1, 2010, and December 31, 2018. The quality of the included studies was assessed using the grading of recommendations, assessment, development and evaluations (GRADE) methodology. In particular, the quality of the systematic reviews was evaluated using the AMSTAR 2 appraisal tool. The guidelines were formulated using the GRADE methodology by a multidisciplinary panel of experts. The diagnosis of AOM is based on acute clinical symptoms and otoscopic evidence; alternatively, the presence of otorrhea associated with spontaneous tympanic membrane perforation allows the AOM diagnosis. The diagnosis of AOM must be certain and the use of a pneumatic otoscope is of fundamental importance. As an alternative to the pneumatic otoscope, pediatricians can use a static otoscope and a tympanometer. To objectively establish the severity of the episode for the formulation of a correct treatment program, an AOM severity scoring system taking into account clinical signs and otoscopic findings was developed.The diagnosis of AOM is clinical and requires the introduction of specific medical training programs. The use of pneumatic otoscopes must be promoted, as they are not sufficiently commonly used in routine practice in Italy.

Omalizumab and mepolizumab in the landscape of biological therapy for severe asthma in children: how to choose?

Severe asthma has a substantial epidemiological impact on children and biological treatments can be an option to take into account, as they target specific molecules and pathways involved in its pathogenesis. Modern medicine is continuously and progressively oriented towards tailored treatments designed specifically for the pathology patterns observed in individual patients and identified as endotypes with associated biomarkers. In this regard, biologic treatments in asthma are one of the best examples. Among the biological drugs currently available, omalizumab is the one with the greatest amount of data on efficacy and safety, and the one we have more real-life clinical experience with. However, mepolizumab will likely be accessible soon globally for clinical use. Moreover, research on biological drugs for the treatment of severe asthma is expanding rapidly, with some molecules currently used in adult patients that could be registered also for pediatric use and new molecules that could be available in the future. On the other hand, due to this potential abundance of therapeutic options, new criteria could become necessary to guide clinicians through an evidence-based choice between omalizumab and these new drugs. For the same reason, more data collected specifically from pediatric clinical trials are necessary. In this review we aim to analyze the factors that could help clinicians make their choice and to highlight the unmet need for a more evidence-based choice.

Antimicrobial stewardship in children: more shadows than lights?

Introduction: The aim of this review is to evaluate the effectiveness of antimicrobial stewardship (AMS) programmes in the pediatric population in improving clinical outcomes, altering prescribing behavior, controlling antimicrobial resistance and measuring the cost-effectiveness.Areas covered: Medline Ovid MEDLINE(R), Embase, and Cochrane Library were searched on 30 September 2018 combining MeSH and free terms for 'antimicrobial stewardship', 'clinical outcomes', 'antimicrobial resistance', 'cost-effectiveness' and 'prescribing behavior'. Several studies have been conducted on the impact of antimicrobial stewardship programmes (ASPs) in children, which showed a positive impact on length of hospital stay and days of therapy. Together with ASP bundles, the introduction of fast microbiology and point-of-care tests showed a positive impact in terms of rapid identification of the pathogen, time to optimal antimicrobial therapy and reduction of antibiotic use, without worsening clinical outcomes. These improvements turned out to be limited over time. Conflicting results were observed regarding the impact of ASPs on antimicrobial resistance and on cost-effectiveness and cost-benefits, due to the lack of homogeneity between studies.Expert opinion: Evidence regarding the impact of ASPs in children is limited to single center studies, with different study designs, making it impossible to draw unequivocal conclusions. High quality studies are needed. More feasable approaches should be designed both for inpatients and outpatients and for critical patients.

Immune Response to Mycobacterium tuberculosis: A Narrative Review.

The encounter between Mycobacterium tuberculosis (Mtb) and the host leads to a complex and multifaceted immune response possibly resulting in latent infection, tubercular disease or to the complete clearance of the pathogen. Macrophages and CD4+ T lymphocytes, together with granuloma formation, are traditionally considered the pillars of immune defense against Mtb and their role stands out clearly. However, there is no component of the immune system that does not take part in the response to this pathogen. On the other side, Mtb displays a complex artillery of immune-escaping mechanisms capable of responding in an equally varied manner. In addition, the role of each cellular line has become discussed and uncertain further than ever before. Each defense mechanism is based on a subtle balance that, if altered, can lean to one side to favor Mtb proliferation, resulting in disease progression and on the other to the host tissue damage by the immune system itself. Through a brief and complete overview of the role of each cell type involved in the Mtb response, we aimed to highlight the main literature reviews and the most relevant studies in order to facilitate the approach to such a complex and changeable topic. In conclusion, this narrative mini-review summarizes the various immunologic mechanisms which modulate the individual ability to fight Mtb infection taking in account the major host and pathogen determinants in the susceptibility to tuberculosis.

Use of Second-line Medications and Treatment Outcomes in Children With Tuberculosis in a Single Center From 2007 to 2018.

BACKGROUND: The incidence of drug-resistant forms of tuberculosis (DR-TB) and the number of children treated with second-line drugs (SLDs) are increasing. However, limited amount of information is available regarding the use of SLDs in this population. METHODS: To describe the treatment of pediatric TB with SLDs and factors associated with use of SLDs in children with and without documented DR-TB, records of pediatric TB patients referred to a center in Italy from 2007 to 2018 were reviewed retrospectively. RESULTS: Of 204 children diagnosed with active TB during the study period, 42 were treated with SLDs because of confirmed or probable drug resistance (42.8%), adverse reactions to first-line drugs (7.1%), central nervous system involvement (11.9%) or unconfirmed possible drug resistance (38.1%). There were no deaths or adverse reactions to SLDs reported. Treatment was successful in 85.2% children treated with first-line drugs and 92.9% children treated with SLDs. After adjusting for calendar period, the only factor associated with DR-TB was <2 years old [odds ratio (OR): 5.24 for <2 years vs. 5-18 years; P = 0.008]. Factors associated with treatment with SLDs were TB at 2 or more sites (OR: 11.30; P < 0.001), extrapulmonary TB (OR: 8.48; P < 0.001) or adverse reactions to first-line drugs (OR: 7.48; P = 0.002). No differences were noted in age or region of origin. CONCLUSIONS: A substantial proportion of TB children were treated with SLDs. The main reason for using SLDs was failure of a first-line drug regimen, suggesting possible DR-TB and underestimation of DR-TB in children. The use of SLD regimens was associated with a high success rate and good tolerability profile.

Knowledge, attitude and disinformation regarding vaccination and immunization practices among healthcare workers of a third-level paediatric hospital.

BACKGROUND: Vaccination represents one of the most effective means of preventing infections for the population and for the public health in general. Recently there has been a decline in vaccinations, also among healthcare workers (HCWs). The aim of the study is to detect the knowledge, skills, attitudes and barriers of HCWs regarding vaccinations in a tertiary children's hospital in order to support clinical management in immunisation practices. METHODS: An observational study was conducted on 255 subjects over a period of 8 months. The 31-item questionnaire considered profession, level of instruction and different ages. It included questions taken from a questionnaire used for a Canadian research and one used by the Bellinzona hospital. A 4-point Likert scale and closed-ended questions were used. A confidence interval of 95%, p value ≤ 0.05, Chi-square, ANOVA and the Kruskal-Wallis test were considered. RESULTS: In the last 5 years less than one third of the sample were vaccinated against flu. 77.8% (n.130) of nurses and 45.8% (n.19) of doctors were not vaccinated (p < 0.0001). As for risk perception, 51.5% of nurses and 90.6% of doctors believe that their risk of contracting influenza is greater than that of the general population. In relation to the injection site, in all the age ranges there was a high level of knowledge except for those aged over 61 who responded incorrectly. Doctors were more prepared (p < 0.0001). 50% of the sample used internet only as a source of information for vaccines. Generally, scientific sources were used infrequently. The higher the education level, the more frequent the utilisation of trustworthy scientific resources and literature. (p = 0.0002). CONCLUSIONS: In line with the attitude observed in recent years, nurses are not inclined to get vaccinated themselves although they agree to having their children vaccinated. HCWs have a good level of knowledge about vaccines and immunisation practices. With the nurses we found that the higher the education level, the greater the knowledge about vaccines which leads to the conclusion that low levels of adherence are not due to a lack of knowledge, but rather, to a low perception of risks. Hence the need to strengthen the vaccination strategies inside the companies.