Hexavalent vaccines in preterm infants: an update by Italian Society of Pediatric Allergy and Immunology jointly with the Italian Society of Neonatology.

Hexavalent vaccines, protecting against six diseases (diphtheria, tetanus, pertussis [DTaP], poliovirus, hepatitis B virus [HBV], and Haemophilus influenzae type b [Hib], are routinely the standard of care in Europe. The use of combined vaccines allows the reduction of number of injections and side effects, the reduction of costs, and the increase in adherence of the family to the vaccination schedule both in terms of the number of doses and timing. The safety profile, efficacy and effectiveness of hexavalent vaccines have been extensively documented in infants and children born at term, and data are accumulating in preterm infants. Hexavalent vaccines are particularly important for preterm infants, who are at increased risk for severe forms of vaccine preventable diseases. However, immunization delay has been commonly reported in this age group. All the three hexavalent vaccines currently marketed in Italy can be used in preterm infants, and recent data confirm that hexavalent vaccines have a similar or lower incidence of adverse events in preterm compared to full-term infants; this is likely due to a weaker immune system response and reduced ability to induce an inflammatory response in preterm infants. Apnoea episodes are the adverse events that can occur in the most severe preterm infants and / or with history of respiratory distress. The risk of apnoea after vaccination seems to be related to a lower gestational age and a lower birth weight, supporting the hypothesis that it represents an unspecific response of the preterm infant to different procedures. High seroprotection rates have been reported in preterm infants vaccinated with hexavalent vaccine. However, a lower gestational age seems to be associated with lower antibody titres against some vaccine antigens (e.g. HBV, Hib, poliovirus serotype 1, and pertussis), regardless of the type of hexavalent vaccine used. Waiting for large effectiveness studies, hexavalent vaccines should be administered in preterm infants according to the same schedule recommended for infants born at term, considering their chronological age and providing an adequate monitoring for cardio-respiratory events in the 48-72 h after vaccination, especially for infants at risk of recurrence of apnoea.

Missed opportunities to prevent mother-to-child transmission of HIV in Italy.

OBJECTIVES: Vertical transmission of HIV can be effectively controlled through antenatal screening, antiretroviral treatment and the services provided during and after childbirth for mother and newborn. In Italy, the National Health Service guarantees universal access to prenatal care for all women, including women with HIV infection. Despite this, children are diagnosed with HIV infection every year. The aim of the study was to identify missed opportunities for prevention of mother-to-child transmission of HIV. METHODS: The Italian Register for HIV Infection in Children, which was started in 1985 and involves 106 hospitals throughout the country, collects data on all new cases of HIV infection in children. For this analysis, we reviewed the database for the period 2005 to 2015. RESULTS: We found 79 HIV-1-infected children newly diagnosed after birth in Italy. Thirty-two of the mothers were Italian. During the pregnancy, only 15 of 19 women with a known HIV diagnosis were treated with antiretroviral treatment, while, of 34 women who had received an HIV diagnosis before labour began, only 23 delivered by caesarean section and 17 received intrapartum prophylaxis. In 25 mothers, HIV infection was diagnosed during pregnancy or in the peripartum period. Thirty-one newborns received antiretroviral prophylaxis and 39 received infant formula. CONCLUSIONS: We found an unacceptable number of missed opportunities to prevent mother-to-child transmission (MCTC). Eliminating HIV MTCT is a universal World Health Organization goal. Elucidating organization failures in Italy over the past decade should help to improve early diagnosis and to reach the zero transmission target in newborns.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Optimizing the management of children with latent tuberculosis infection.

INTRODUCTION: The management of latent tuberculosis (LTBI) in children represents an important issue for paediatricians because of the disease burden, the lack of a gold standard for the diagnosis and the high annual risk of progression to active disease. Areas covered: A review of English language articles on LTBI in children, published between the 1st of January 2010 and the 1st of July 2016, was conducted using multiple keywords and standardized terminology in PubMed database. This review provides an updated overview of the available tests for LTBI diagnosis in children, management strategies and treatment options. Expert commentary: Two tests are available for LTBI diagnosis: tuberculin skin test and interferon-gamma release assays, both with a suboptimal specificity and sensitivity, and both with the lack of capability in distinguishing between infection and disease. Several new markers have been identified but further studies are needed. Among all treatment regimes, because of the high safety and efficacy profile showed and to avoid the poor completion rate, the treatment with a three-month course of isoniazid and rifampicin is currently recommended. New vaccines are needed because of the spread of the disease despite BCG vaccination in high risk countries. Currently, 15 new vaccines are in the pipeline.

Preventing the spread of multidrug-resistant tuberculosis and protecting contacts of infectious cases.

Prevention of multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is a top priority for global TB control, given the need to limit epidemic spread and considering the high cost, toxicity and poor treatment outcomes with available therapies. We performed a systematic literature review to evaluate the evidence for strategies to reduce MDR/XDR-TB transmission and disease progression. Rapid detection and timely initiation of effective treatment is critical to rendering MDR/XDR-TB cases non-infectious. The scale-up of rapid molecular testing has transformed the capacity of high-incidence settings to identify and treat patients with MDR/XDR-TB. Optimized infection control measures in hospitals and clinics are critical to protect other patients and healthcare workers, whereas creative measures to reduce transmission within community hotspots require consideration. Targeted screening of high-risk communities may enhance early case-detection and limit the spread of MDR/XDR-TB. Among infected contacts, preventive therapy promises to reduce the risk of disease progression. This is supported by observational cohort studies, but randomized trials are urgently needed to confirm these observations and guide policy formulation. Substantial investment in MDR/XDR-TB prevention and care will be critical if the ambitious global goal of TB elimination is to be realized.

Analysis of measles-related hospitalizations in Tuscany from 2000 to 2014.

To evaluate measles incidence and its relevant changes over a 14-year period (2000-2014), we analysed data from the regional hospital discharge database on children and adults hospitalized in Tuscany, Italy. A total of 181 paediatric and 413 adult cases were identified. Despite all the efforts towards regional measles elimination, we observed that the overall measles hospitalization rates for children and adults living in Tuscany globally increased from 0·45 to 0·85/100 000 during the study period (P = 0·001) showing fluctuations due to periodic measles outbreaks. Data stratified by age group showed that the hospitalization rate significantly increased in young adults over the study period, confirming an increase in susceptibility to measles in this subpopulation. Conversely, no statistically significant difference was observed in the hospitalization rate in the other age groups. However, children aged <1 year still exhibit the highest hospitalization rate. Pneumonia represented the most common complication in both the adult and children subsets. No death was reported. Measles still represents a public health problem, and national strategies should be implemented, focusing on emergent susceptible subsets, such as infants and young adults.

Use, abuse and misuse of biomarkers in paediatrics.

Currently, a gold standard for distinguishing between infectious, inflammatory, auto-immune diseases and malignancy in infants and children is not available. The combination of biomarkers with clinical features and other diagnostic tests could help clinicians in the diagnostic process. Ideally, a biomarker should have high sensitivity, specificity, and predictive value, as well as being easily obtained also in preterm babies and infants, requiring a small amount of blood and being quickly measured. The available literature agrees on the fact that a “perfect” biomarker is not currently available in paediatric practice. Thus, clinicians must consider time by time the balance between marker characteristics and their sensitivity and specificity in different conditions. The development of new tests with higher sensitivity and specificity in distinguishing different pathological situations is auspicable. Moreover, future efforts should be focused on validating also in children the recently developed biomarkers including CD64, IL-27 and IL-8.

Recommendations for the diagnosis of pediatric tuberculosis.

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease.

Skin prick test results to artesunate in children sensitized to Artemisia vulgaris L.

Artemisia vulgaris L and Artemisia annua L (Chinese: qinghao) are similar plants of the Asterbaceae family. Artesunate, a semi-synthetic derivate of artemisin which is the active principle extract of the plant qinghao, has antimalarial properties. Some cases of severe allergic reactions to artesunate have been described. The purpose of this study was to evaluate the association between positive skin tests to Artemisia vulgaris L allergen and a preparation of injectable artesunate. A total of 531 children were skin prick tested with inhalants (including Artemisia vulgaris L), foods, and artesunate. Among the 59 patients positive to Artemisia vulgaris L only one child was also positive to artesunate. No child was positive to artesunate in those negative to Artemisia vulgaris L. We conclude that Artemisia vulgaris L sensitization is not associated with sensitization to artesunate; consequently, skin test to artesunate should not be carried out before using the drug considering the rare allergic reactions.

Systematic review and meta-analysis on the utility of Interferon-gamma release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a 2013 update.

BACKGROUND: Previous meta-analyses regarding the performance of interferon-gamma release assays (IGRAs) for tuberculosis diagnosis in children yielded contrasting results, probably due to different inclusion/exclusion criteria. METHODS: We systematically searched PubMed, EMBASE and Cochrane databases and calculated pooled estimates of sensitivities and specificities of QuantiFERON-TB Gold In Tube (QFT-G-IT), T-SPOT.TB, and tuberculin skin test (TST). Several sub-analysis were performed: stratification by background (low income vs. high income countries); including only microbiological confirmed TB cases; including only studies performing a simultaneous three-way comparison of the three tests, and including immunocompromised children. RESULTS: Overall, 31 studies (6183 children) for QFT-G-IT, 14 studies (2518 children) for T-SPOT.TB and 34 studies (6439 children) for TST were included in the analyses. In high income countries QFT-G-IT sensitivity was 0.79 (95%IC: 0.75-0.82) considering all the studies, 0.78 (95%CI:0.70-0.84) including only studies performing a simultaneous three-way comparison and 0.86 (95%IC 0.81-0.90) considering only microbiologically confirmed studies. In the same analyses T-SPOT.TB sensitivity was 0.67 (95%IC 0.62-0.73); 0.76 (95%CI: 0.68 to 0.83); and 0.79 (95%IC 0.69-0.87), respectively. In low income countries QFT-G-IT pooled sensitivity was significantly lower: 0.57 (95%IC:0.52-0.61), considering all the studies, and 0.66 (95%IC 0.55-0.76) considering only microbiologically confirmed cases; while T-SPOT.TB sensitivity was 0.61 (95%IC 0.57-0.65) overall, but reached 0.80 (95%IC 0.73-0.86) in microbiologically confirmed cases. In microbiologically confirmed cases TST sensitivity was similar: 0.86 (95%IC 0.79-0.91) in high income countries, and 0.74 (95%IC 0.68-0.80) in low income countries. Higher IGRAs specificity with respect to TST was observed in high income countries (97-98% vs. 92%) but not in low income countries (85-93% vs. 90%). CONCLUSIONS: Both IGRAs showed no better performance than TST in low income countries.

Hospitalization rates of complicated pneumococcal community-acquired pneumonia is increasing in Tuscan children.

To provide epidemiological data on community-acquired pneumonia (CAP) and complicated CAP, a retrospective study was conducted on a partially vaccinated paediatric population. Data from children hospitalized for CAP in Tuscan hospitals between January 1st, 1999 and December 31st, 2009 were analysed. A total of 5,450 children with CAP were hospitalized. Annual hospitalization rates for CAP did not change significantly over the study period (X2 for trend= 0.652; p=0.419). The total annual hospitalization rate for pneumococcal CAP varied according to age (28.04 per 100,000 children aged less than 5 years, 10.06 per 100,000 children aged 6-12 years and 0.98 per 100,000 children aged greater than13years). Hospitalization rates for pneumococcal CAP increased from12.84 (95 percent CI:7.35-18.34) in 2001 to 45.4 (95 percent CI:35.93-54.90) per 100,000 children aged less than 5 years in 2009 (p less than 0.0001). In addition, a significant increase of hospitalization rates for complicated CAP (from 6.07 in 1999 to 13.66 in 2009 per 100,000 children; P less than 0.0001) and pneumococcal complicated CAP (from 0.19 in 1999 to 3.41 in 2009 per 100,000 children) over the study period were highlighted. Our epidemiological data confirm the decision to introduce the PCV13 vaccine, to satisfy the need to prevent a wider group of pneumococcal serotypes.

Treating paediatric community-acquired pneumonia in the era of antimicrobial resistance.

UNLABELLED: Increasing levels of paediatric community-acquired pneumonia (CAP), caused by drug-resistant bacteria and antimicrobial resistance, vary with age and countries and, in some cases, serotypes. When empirical first-line treatment administration fails, paediatricians should consider second-line treatments based on the prevalence of local resistance. A more judicious use of antimicrobial agents is also required. CONCLUSION: Knowledge of local epidemiology and an appropriate use of antimicrobial drugs are necessary to treat CAP in this era of antimicrobial resistance.

Vaccines and autoimmunity.

Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases.

[How to interpret the results of immunological tests for the diagnosis of tuberculosis in child].

New available immunologic tests for tuberculosis (TB) diagnosis are Interferon-gamma release assay (IGRA). In adults these tests showed a higher specificity than tuberculin skin test (TST) but their superior sensitivity compared to TST sensitivity has not been proved yet. In children, interpretation of results remains disputed, especially in those <5 years. Hereby we report the most recent literature data for use and interpretation of IGRA is results in children.

Interferon-γ release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a systematic review and meta-analysis.

Data regarding the use of interferon-gamma release assays (IGRAs) for tuberculosis diagnosis are accumulating. We systematically searched PubMed, EMBASE and Cochrane and performed pooled estimates of sensitivity and specificity of QuantiFERON-TB Gold In Tube (QFT-G-IT) and T-SPOT.TB compared to tuberculin skin test (TST). For studies assessing sensitivity, children had to have active tuberculosis. Specificity data were derived from children classified as non-infected. Eleven studies were included in the sensitivity analysis for TST, 10 for QFT-G-IT, and 9 for T-SPOT.TB. Eight studies were included in specificity analysis for TST, 8 for QFT-G-IT, and 7 for T-SPOT.TB. Pooled QFT-G-IT sensitivity was 0.79 (95% CI:0.70-0.89) pooled T-SPOT.TB sensitivity was 0.74 (95% CI:0.59-0.90) and pooled TST sensitivity was 0.82 (95% CI:0.72-0.93). Pooled QFT-G-IT and T-SPOT.TB specificities were 0.95 (95% CI:0.93- 0.97) and 0.96 (95% CI:0.93-1.00), respectively. Pooled TST specificity was significantly lower 0.83 (95% CI:0.74-0.92). IGRA performance in children showed no better sensitivity than TST, but higher specificity.

Interferon-γ release assays for the diagnosis of Mycobacterium tuberculosis infection in children: a literature review.

The role of interferon-gamma release assays (IGRAs) for immunologic diagnosis of tuberculosis in children is under debate. We carried out a narrative review on the studies on IGRAs in paediatric populations. A literature search was conducted using multiple keywords and standardized terminology in Medline, EMBASE and Cochrane databases, up to January 27th, 2011. Study quality was assessed using the MOOSE checklist and results of relevant studies were summarized. Sixty-seven paediatric studies (study population ranging from 14 to 5,244 children) were identified. Non-commercial ELISPOT assay (by means of ESAT-6 and CFP-10 antigens) had been carried out in 11 studies. QuantiFERON-TB Gold (QFT-G), QuantiFERON-TB Gold In-tube (QFT-G-IT), and T-SPOT.TB assays had been performed in 10, 44 and 18 studies, respectively. Most studies reported higher specificity of IGRA than tuberculin skin test (TST), but interpretation of the results is complicated by the fact that a gold standard for the diagnosis of latent TB is lacking. The reported sensitivity for active TB ranged from 51-93 percent for QFT-G/QFT-G-IT and 40-100 percent for ELISPOT assays, suggesting that a negative IGRA result may not exclude tuberculosis. Combining TST and IGRA results increased the diagnostic sensitivity. Rates of indeterminate results largely varied (0 to 35 percent). Most of the studies on young (less than 5 years) or immune-compromised children reported a proportion of indeterminate results exceeding 4 percent. Agreement among TST and IGRA, assessed by the k statistics, ranged from -0.03 to 0.87. Higher rates of discordance were reported in BCG-vaccinated than in non-BCG-vaccinated children. Studies on children less than 5 years and immunocompromised children reported conflicting results, as did studies on serial IGRA determinations. Despite the large amount of literature data, the role of IGRA in the pediatric population is still unclear, especially in young children. Combined use of TST/IGRA may increase diagnostic sensitivity but interpretation of discordant results remains a challenging issue.

Natural killer cell deficiencies in a consecutive series of children with herpetic encephalitis.

Natural killer (NK) cells play a fundamental role in innate and early phases of adaptive immunity against viral infections, both in humans and in animal models. To date, NK cell deficiencies in patients with severe herpetic infections have been reported in single cases, and their role as predisposing factor is still controversial. Five children affected by herpetic encephalitis were consecutively admitted to the Anna Meyer Children's Hospital in Florence (Italy) between 2003 and 2005. We therefore investigated the presence of NK cell deficiencies in a consecutive series of children with herpetic encephalitis. Five healthy children were included in the study as controls. Differential WBC counts, main Ig and IgE class serum analysis, cytofluorimetric analysis of circulating T, B and NK cells were performed on our study population. Sequencing of a selected region of CD16A gene transcript was carried out in two patients. All patients resulted to be affected by deficiencies related to NK cells in respect to controls. One patient was also affected by lymphopenia, while no other significant deficits of immunity were detected in the study population. To date, this is the first survey that demonstrates isolated NK cell deficiencies in a cohort of consecutive patients affected by severe herpes simplex infections. These findings suggest a role for NK cell deficiencies as a predisposing factor for increased susceptibility and severe course of disease in these patients.