Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Long-term persistence of seroprotection against measles following measles-mumps-rubella vaccination administered before and after pediatric liver transplantation.

Liver transplantation (LT) recipients are susceptible to infections, including measles. Concerns about the safety and efficacy of live-attenuated vaccines, such as the measles-mumps-rubella (MMR) vaccine, have led to hesitancy among providers in administering them to immunocompromised patients. This 9-year interventional study assessed seroprotection against measles following MMR vaccination in pediatric LT recipients. Of 119 participants enrolled, 60 (50%) were seroprotected against measles after transplantation. Among the 59 nonseroprotected participants, 56 fulfilled safety criteria and received MMR vaccination with a seroprotection rate of 90% (95% confidence interval [CI], 73%-98%) after a first dose, 95% (95% CI, 85%-99%) after primary vaccination with 1 to 3 doses, comparable to nonimmunocompromized populations. However, measles antibodies declined over time, suggesting the need for regular monitoring, and booster doses. Half of the vaccinees (26/53, 49%) subsequently lost seroprotection. Among them, 23 received additional doses of MMR, with a high seroconversion rate. At their last follow-up (median, 6.1 years; interquartile range, 3.0-8.1 after inclusion), 63% (95% CI, 49%-75%) of all vaccinees were seroprotected against measles. In conclusion, MMR vaccination in pediatric LT recipients offers seroprotection against measles, but long-term immunity should be monitored closely.

Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

OBJECTIVES: Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. DESIGN: Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. RESULTS: Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). CONCLUSIONS: The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

Inappropriate prescribing contributes to high antibiotic exposure in young children in Australia.

BACKGROUND: Antibiotic exposure increases antimicrobial resistance and has also been associated with long-term harms, including allergies, inflammatory diseases and weight gain. We assessed antibiotic exposure in the first 2 years of life in Australian children, the factors influencing this and its appropriateness. METHODS: Data from 1201 participants in the MIS BAIR randomized controlled trial were used. Multivariable logistic regression was used to identify factors associated with antibiotic exposure. RESULTS: At 1 and 2 years of age, exposure to at least one course of antibiotics was 43% and 67%, with the highest first antibiotic prescription rate between 9 and 18 months. Amoxicillin was the most frequently used antibiotic (59%), followed by cefalexin (7%). The most common diagnoses for which antibiotics were prescribed were respiratory tract infections from 0 to 6 months of age and otitis media from 6 to 12 months. Factors associated with antibiotic exposure from 0 to 12 months of age were delivery by Caesarean section (adjusted odd-ratio (aOR) 1.5, 95%CI 1.1-1.9), birth in winter (aOR 1.7, 95%CI 1.2-2.4), maternal antibiotic exposure during the last trimester of pregnancy (aOR 1.6, 95%CI 1.1-2.3), cessation of breastfeeding by 6 months of age (aOR 1.5, 95%CI 1.1-2.0) and day-care attendance (aOR 1.4, 95%CI 1.1-1.8). Based on parent-reported questionnaires, 27% of infants were treated in the first year of life for conditions unlikely to need antibiotic treatment. CONCLUSION: At least two-thirds of children were prescribed antibiotics in the first 2 years of life, and more than a quarter of these exposures may have been unnecessary.

Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Amoxicillin vs. placebo to reduce symptoms in children with group A streptococcal pharyngitis: a randomized, multicenter, double-blind, non-inferiority trial.

The efficacy of antibiotic therapy for group A streptococcus (GAS) pharyngitis is debated. The role of antibiotics in preventing complications seems limited, with the main potential benefit being symptom duration reduction. Our study aimed to evaluate whether a placebo is non-inferior to amoxicillin in reducing fever duration. We randomized 88 children between 3 and 15 years of age presenting with acute symptoms of pharyngitis and a positive rapid antigen detection test for GAS to receive 6-day treatment with either placebo (n = 46) or amoxicillin (n = 42). The primary outcome was the difference in fever duration, with a non-inferiority threshold set at 12 h. The secondary outcomes included pain intensity and complications of streptococcal pharyngitis. The mean difference in fever duration between the amoxicillin and placebo groups was 2.0 h (95% CI, - 8.3 to 12.3) in the per-protocol analysis and 2.8 h (95% CI, - 6.5 to 12.2) in the intention-to-treat analysis. Treatment failure was observed in six participants in the placebo group and two in the amoxicillin group (relative risk, 2.15; 95% CI, 0.44-10.57). All patients were identified early and recovered well. There was no clinically relevant difference in pain intensity between groups over the 7 days following randomization, with the largest difference of 0.5 (95% CI, - 0.62-1.80) observed on day 3. CONCLUSION: Placebo appears to be non-inferior to amoxicillin in reducing fever duration. Pain intensity and risk of complications were similar between the two groups. These findings support the restrictive antibiotic treatment for streptococcal pharyngitis. WHAT IS KNOWN: • Group A streptococcus pharyngitis is a common reason for prescribing antibiotics in pediatric care. • In high-income countries, while antibiotic treatment has not been effective in preventing non-suppurative complications, the primary justification for their use remains the reduction of symptoms. WHAT IS NEW: • Our results suggest that antibiotics have a limited impact on the duration of fever and the intensity of pain in children with streptococcal pharyngitis. • Considering that suppurative complications can be promptly treated if they arise, we recommend a more judicious approach to antibiotic prescriptions. TRIAL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) # NCT03264911 on 15.08.2017.

Interpreting the Results of Trials of BCG Vaccination for Protection Against COVID-19.

BCG vaccination has beneficial off-target ("nonspecific") effects on nonmycobacterial infections. On this premise, trials set out to investigate whether BCG provides off-target protection against coronavirus disease 2019 (COVID-19). A literature search identified 11 randomized "BCG COVID-19" trials, with conflicting results. These trials and the differences in their study design are discussed using the PICOT (participants, intervention, control, outcome, and timing) framework to highlight the factors that likely explain their inconsistent findings. These include participant age, sex and comorbid conditions, BCG vaccination strain and dose, outcome measure and duration of follow-up. Understanding how to control these factors to best exploit BCG's off-target effects will be important in designing future trials and intervention strategies.

Incidence and predisposing factors for flucloxacillin-related hepatotoxicity in children.

BACKGROUND: Flucloxacillin-induced hepatotoxicity is well established in adults. However, there are few paediatric studies of flucloxacillin-induced hepatotoxicity despite this drug being among the most commonly prescribed in children. We aimed to determine the incidence of flucloxacillin-induced hepatotoxicity in children receiving IV therapy as well as identify risk factors for this adverse drug reaction. METHODS: We undertook a 2 year retrospective audit of children aged 0-18 years admitted to the Royal Children's Hospital (March 2019 to March 2021) who had liver function tests determined before and after receiving IV flucloxacillin for at least 24 hours duration. Causality was assessed using the Roussel Uclaf Causality Assessment Method and Naranjo criteria. RESULTS: Overall, the incidence of hepatotoxicity was 66/393 (17%). The median age of children with hepatotoxicity was 1.1 years (IQR 0.3-11.9), 43 (65%) received two or more concomitant hepatotoxic medications and 23 (35%) were receiving total parenteral nutrition. The median timing of onset of hepatotoxicity after commencement of flucloxacillin was 4 days (range 2-7). Severe hepatotoxicity (Common Terminology Criteria for Adverse Events grade 3 or above) occurred in 9/66 (14%) for bilirubin, 13/66 (20%) for ALT and 10/66 (15%) for GGT. Predisposing factors for hepatotoxicity were increasing age (OR 1.06 per additional year, 95% CI 1.01-1.10, P = 0.02), with adolescents aged 12-18 years having the highest risk (OR 5.10, 95% CI 2.02-12.85, P = 0.001), and two or more concomitant hepatotoxic medications (OR 2.51, 95% CI 1.02-6.18, P = 0.05). The median time to resolution of hepatotoxicity after cessation of flucloxacillin was 5 days (range 2-10). CONCLUSIONS: In children, older patients and those receiving two or more concomitant hepatotoxic medications are at greater risk of flucloxacillin-induced hepatotoxicity.

Bacillus Calmette-Guérin Skin Reaction Predicts Enhanced Mycobacteria-Specific T-Cell Responses in Infants: A Post Hoc Analysis of a Randomized Controlled Trial.

Rationale: Scar formation following bacillus Calmette-Guérin (BCG) vaccination has been associated with lower all-cause mortality; the relation between scar and mycobacteria-specific protection against tuberculosis is debated. Objectives: To evaluate the association between BCG skin reaction and mycobacteria-specific immune responses. Methods: A post hoc analysis was done among 214 infants in Australia randomized to vaccination with one of three BCG vaccine strains (BCG-Denmark, BCG-Japan, or BCG-Russia) given at birth or BCG-Denmark given at 2 months of age. Measurements and Main Results: BCG skin reaction size and characteristics 10 weeks after vaccination were related to the in vitro mycobacteria-specific immune responses measured in stimulated whole blood. The size and characteristics of the skin reaction correlated positively with in vitro immune responses, even after adjusting for BCG vaccine strain and age at vaccination. Specifically, the reaction size and characteristics correlated with the proportion of mycobacteria-specific polyfunctional CD4+ T cells after stimulation with BCG and PPD and, to a lesser extent, after stimulation with Mycobacterium tuberculosis or Mycobacterium ulcerans. A similar correlation was observed with concentrations of IFN-γ, IL-2, tumor necrosis factor, and IL-13 in the supernatant after stimulation with BCG, PPD, and M. tuberculosis and to some degree for the proportions of mycobacteria-specific polyfunctional CD8+ T cells and CD107+ cytotoxic cells. Conclusions: BCG skin reaction correlated with the magnitude of mycobacteria-specific T-cell responses. As T-cell responses play a key role in defense against mycobacteria, the relationship between BCG scar formation and protection against tuberculosis should be revisited. This may also extend to the need for BCG revaccination in scar-negative individuals.Clinical trial registered with www.australianclinicaltrials.gov.au/clinical-trial-registries (ACTRN12608000227392).

Prevention of infant eczema by neonatal Bacillus Calmette-Guérin vaccination: The MIS BAIR randomized controlled trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off-target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. METHODS: Randomized controlled trial with 1272 infants allocated to receive BCG-Denmark or no BCG at birth. The primary outcome was the 12-month incidence of eczema based on 3-monthly questionnaires. Eczema was also assessed at a 12-month clinic visit. ClinicalTrial.gov: NCT01906853. RESULTS: The 12-month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) -4.3%, 95% CI -9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12-month visit (aRD -3.5%, 95% CI -8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD -3.3, 95% CI -9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD -3.0%, 95% CI -8.8% to 2.7%). In 344 high-risk infants (two atopic parents), the 12-month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD -11.5%, 95% CI -21.9% to -1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). CONCLUSION: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high-risk infants. A single dose of BCG-Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents.

Impact of antibiotic allergy labels on patient outcomes in a tertiary paediatric hospital.

AIMS: Antibiotic allergies are reported in 5-15% of children. This study aimed to evaluate the impact of common ß-lactam antibiotic allergy labels (AALs) on hospital treatment, focusing on length of stay and appropriateness of antibiotic prescribing. METHODS: This was a retrospective cohort study over 21 months at the Royal Children's Hospital Melbourne, Australia. A subset of children with the most common ß-lactam allergies, and who required admission for intravenous antibiotics over a 12-month period, was analysed for appropriateness of prescribing. Non-allergic patients were matched to evaluate associations between AALs and hospital treatment. RESULTS: There were 98 912 children admitted over the study period, of whom 938 (1%) had at least one AAL on first admission. Of all encounters, 5145 (2.5%) were for children with AALs. The most common AALs were to amoxicillin and amoxicillin-clavulanic acid combinations (40.8%), cefalexin (14.4%) and trimethoprim-sulfamethoxazole (9.7%). For the subset, there were 66 admissions for children who required intravenous antibiotics. Documentation was adequate for 27% of AALs. Inappropriate prescribing occurred in almost half (47%). Hospital stay was longer for children with AALs (median 4.7 days; IQR 2.3-9.2) compared to non-allergic controls (median 3.9 days; IQR 1.9-6.8; P = .02). Children with AALs were more likely to receive restricted antibiotics (aOR 3.03; 95% CI, 1.45-6.30; P = .003). CONCLUSION: This is the first study to demonstrate high rates of inappropriate prescribing in children with AALs. Children with AALs were significantly more likely to receive restricted antibiotics and had a longer length of stay compared with non-allergic controls.

Does bacillus Calmette-Guérin vaccine prevent herpes simplex virus recurrences? A systematic review.

Recurrent infections with herpes simplex virus (HSV) in the orofacial (cold sores), ocular or genital region are common and sometimes disabling, calling for an effective preventive intervention. The bacillus Calmette-Guérin (BCG) vaccine has beneficial off-target effects that might impact recurrence of HSV infections. In this systematic review, Medline, EMBASE, and PubMed were searched in June 2020; 16 articles were deemed relevant comprising eight animal and eight human studies (301 patients). In animals, BCG administration led to a 1.9 to 5.5-fold increase in survival rate following HSV challenge (vaginal, corneal, or intraperitoneal inoculation). This beneficial effect was influenced by the dose of BCG (higher better), mode of administration (intradermal better than intraperitoneal), and the interval between vaccination and viral challenge (at least 6 days required). In nonrandomized human studies (that failed to control for a placebo effect), BCG vaccination appeared beneficial in 78% of adults with recurrent herpes genitalis or labialis, with 37% being recurrence-free for an extended period, 41% experiencing less frequent or severe episodes, and only 22% reporting no change. This clinical benefit is consistent with the findings of immunological sub-studies. In the two studies restricted to recurrent herpes labialis, 94% appeared to benefit from BCG. The one randomized controlled trial used an intervention in the control group that has immunomodulatory effects thus limiting interpretation. In conclusion, BCG vaccine is a potential, safe, affordable and readily available candidate intervention to decrease the high burden of disease associated with HSV infection and recurrences, but properly controlled randomized trials are required.

Immunogenicity and safety of routine vaccines in children and adolescents with rheumatic diseases on immunosuppressive treatment - a systematic review.

The immunogenicity of vaccines in children with juvenile autoimmune rheumatic diseases (JARDs) can be reduced, there are additional safety concerns around vaccination, and there is a potential for worsening in disease activity. In this systematic review, we summarise studies that investigated the immunogenicity and safety of routine vaccines in children and adolescents with JARD on immunosuppressive treatment. We identified 37 studies investigating 2571 children and adolescents with JARD on immunosuppressive treatment and 4895 control children. Of the 56 geometric mean antibody titres measured, 19 (34%) were lower, six (11%) higher, and 31 (55%) similar; of the 39 seroprotection rates measured, 10 (26%) were lower, two (5%) higher, and 27 (69%) similar; and of the 27 seroconversion rates measured, nine (33%) were lower, two (8%) higher, and 16 (59%) similar in children with JARD on immunosuppressive treatment compared with control children. However, many of the studies were underpowered, and not designed to show non-inferiority between children with JARD and controls. Subgroup analysis for different types of immunosuppressive treatments was not feasible, as most studies did not report results by treatment. Severe adverse events were reported in 38 children (33 with juvenile idiopathic arthritis, four with systemic lupus erythematosus, and one in a healthy child); most of them were likely not related to the vaccination (e.g. elective hospitalisation or surgery). A worsening in disease activity was reported in 44 (2%) children with JARD; again, many of them were likely not related to the vaccination. There were no safety concerns with live attenuated vaccines; however, only few studies reported results for this. CONCLUSION: Vaccination in children with JARD on immunosuppressive treatment is safe and should be promoted, especially since these children are at increased risk for infection. The importance for the completion of vaccination schedules should be stressed. Strategies to compensate for the lower vaccine responses, which are found in approximately one-third of these children, include measuring antibody levels to determine the optimal timing for the administration of additional booster doses. WHAT IS KNOWN: • Children with juvenile autoimmune rheumatic diseases (JARDs) are at higher risk for infections, due to their underlying disease and their immunosuppressive treatment. • In children with JARD, the immunogenicity of vaccines might be reduced, and concerns about safety or the potential for worsening in disease activity after vaccination exist. WHAT IS NEW: • Our systematic review shows that vaccines in children with JARDs on immunosuppressive treatment are safe and immunogenic. • There are several limitations of the currently published studies, including random timing of measuring vaccine responses and age differences between children with JARD and control groups. Many of the studies were underpowered, and not designed to show non-inferiority between children with JARD and controls.

Neonatal Bacille Calmette-Guérin Vaccination and Infections in the First Year of Life: The MIS BAIR Randomized Controlled Trial.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination has beneficial off-target effects that may include protecting against non-mycobacterial infectious diseases. We aimed to determine whether neonatal BCG vaccination reduces lower respiratory tract infections (LRTI) in infants in the Melbourne Infant Study: BCG for Allergy and Infection Reduction (MIS BAIR) trial. METHODS: In this investigator-blinded trial, neonates in Australia were randomized to receive BCG-Denmark vaccination or no BCG at birth. Episodes of LRTI were determined by symptoms reported in parent-completed, 3-month questionnaires over the first year of life. Data were analyzed by intention-to-treat using binary regression. RESULTS: A total of 1272 neonates were randomized to the BCG vaccination (n = 637) or control (n = 635) group. The proportion of participants with an episode of LRTI in the first year of life among BCG-vaccinated infants was 54.8% compared to 58.0% in the control group, resulting in a risk difference of -3.2 (95% confidence interval, -9.0 to 2.6) after multiple imputation. There was no interaction observed between the primary outcome and sex, maternal BCG, or the other prespecified effect modifiers. CONCLUSIONS: Based on the findings of this trial, there is insufficient evidence to support the use of neonatal BCG vaccination to prevent LRTI in the first year of life in high-income settings.

Risk of Vaccine-Preventable Infections in Swiss Adults with Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) have a higher risk of infection and are frequently not up to date with their immunizations. OBJECTIVES: This study aims to review vaccination status and evaluate whether age, disease type, or treatment regimen could predict the absence of seroprotection against selected vaccine-preventable infection in adults with IBD. METHODS: Cross-sectional study using questionnaire, immunization records review, and assessment of tetanus-specific, varicella-specific, and measles-specific immunoglobulin G concentrations. ClinicalTrials.gov: NCT01908283. RESULTS: Among the 306 adults assessed (median age 42.7 years old, 70% with Crohn's disease, 78% receiving immunosuppressive treatment), only 33% had an immunization record available. Absence of seroprotection against tetanus (6%) was associated with increasing age and absence of booster dose; absence of seroprotection against varicella (1%) or measles (3%) was exclusively observed in younger patients with Crohn's disease. There was no statistically significant difference in immunoglobulin concentrations among treatment groups. Although vaccinations are strongly recommended in IBD patients, the frequencies of participants with at least 1 dose of vaccine recorded were low for nearly all antigens: tetanus 94%, diphtheria 87%, pertussis 54%, poliovirus 22%, measles-mumps-rubella 47%, varicella-zoster 0%, Streptococcus pneumoniae 5%, Neisseria meningitidis 12%, hepatitis A 41%, hepatitis B 48%, human papillomavirus 5%, and tick-borne encephalitis 6%. CONCLUSIONS: Although many guidelines recommend the vaccination of IBD patients, disease prevention through immunization is still often overlooked, including in Switzerland, increasing their risk of vaccine-preventable diseases. Serological testing should be standardized to monitor patients' protection during follow-up as immunity may wane faster in this population.

Vaccination of immune compromised children-an overview for physicians.

Immune compromised children are threatened by a higher risk of infections; some of these are preventable by vaccination. Primary care physicians play a fundamental role in optimising vaccination status. In this narrative review, we present the evidence on vaccine safety and immunogenicity in immune compromised children and discuss in which conditions live-attenuated vaccines can possibly be used. Vaccination schedules differ in some of these conditions, including the use of vaccines with higher antigenic contents (e.g. high-dose hepatitis B vaccine), additional vaccine doses (e.g. 2-dose schedule meningococcal vaccine), more frequent booster doses (e.g. life-long pneumococcal vaccine booster), supplementary vaccines (e.g. meningococcal B vaccine) and use of vaccines beyond the age of usual recommendation (e.g. Haemophilus influenza type b vaccine after 5 years of age). Serological monitoring is a useful tool for customizing vaccination schedule in immune compromised children, confirming adequate vaccine response and documenting seroprotection (especially against measles and varicella). Finally, verification of vaccination status of all household members can prevent them being vector of transmission of an infection to the immune compromised children. Conclusion: Intensified information strategies are needed to improve trust, rectify perceived risks and improve vaccine acceptability; primary physicians can play a critical role in the latter. What is Known: • Physician's awareness is key to success, since it repeatedly correlates with higher vaccination rates What is New: • The vaccination status of immunocompromised children is rarely up-to-date • Knowing the latest vaccine recommendations is challenging, as they differ for each medical condition and change periodically • This review summarises the vaccine recommendations for children with compromised immune systems and highlights how paediatricians play a key role in coordinating their application.

Management and prevention of varicella and measles infections in pediatric solid organ transplant candidates and recipients: An IPTA survey of current practice.

BACKGROUND: Varicella and measles infections can be life-threatening after solid organ transplantation (SOT) but may be preventable with live-attenuated vaccines (LAV). METHODS: This survey conducted in January 2019 among subscribers of the International Pediatric Transplantation Association listserv aimed to explore the current strategies to prevent and manage both infections in the pediatric SOT population, including recommending LAV after SOT. RESULTS: The answers given by 95 pediatric SOT healthcare workers show that these strategies are not yet optimal and call for further education. In particular, 59% of respondents are unnecessarily waiting for a SOT candidate to be >1 year of age to start administrating LAV before SOT. Interestingly, most respondents are willing to administer LAV after SOT (57%), and a fifth (21%) are already doing so, off-label. The survey queried the precautions taken to improve safety evaluations after LAV, and identified knowledge gaps and practitioners' concerns. CONCLUSION: The results of this survey could be used as a starting point for education and promotion of the safe administration of LAV in carefully selected SOT recipients; in turn, this would increase available data that would contribute to the development of evidence-based guidelines by the transplant societies and ultimately prevent these infections after SOT.

Multimodal safety assessment of measles-mumps-rubella vaccination after pediatric liver transplantation.

Live-attenuated vaccines are currently contraindicated in solid-organ transplant recipients. However, the risk of vaccine-preventable infections is lifelong, and can be particularly severe after transplantation. In this prospective interventional national cohort study, 44 pediatric liver transplant recipients with measles IgG antibodies <150 IU/L (below seroprotection threshold) received measles-mumps-rubella vaccine (MMR) at a median of 6.3 years posttransplantation (interquartile range, 4.0 to 10.9). A maximum of two additional doses were administered in nonresponders or when seroprotection was lost. Vaccine responses occurred in 98% (95% confidence interval [CI], 88-100) of patients. Seroprotection at 1-, 2-, and 3-year follow-up reached 62% (95% CI, 45-78), 86% (95% CI, 70-95), and 89% (95% CI, 67-99), respectively. All patients responded appropriately to the booster dose(s). Vaccinations were well tolerated and no serious adverse event attributable to vaccination was identified during the 8-week follow-up period (or later), using a multimodal approach including standardized telephone interviews, diarized side effect reporting, and monitoring of vaccinal virus shedding. We conclude that live attenuated MMR vaccine can be administered in liver transplant recipients fulfilling specific eligibility criteria (>1 year posttransplantation, low immunosuppression, lymphocyte count ≥0.75 G/L), inducing seroprotection in most subjects. (Clinicaltrials.gov number NCT01770119).

High Immunogenicity of the Pneumococcal Conjugated Vaccine in Immunocompromised Adults With Inflammatory Bowel Disease.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are predisposed to pneumococcal infections due to their underlying disease and iatrogenic immunosuppression. Vaccination with the 13-valent pneumococcal conjugated vaccine (PCV13) is recommended, but with poor take-up and few data available. We performed an open-label, phase IV, multicenter study to evaluate the safety and immunogenicity of PCV13 in adults with IBD and to analyze the influence of immunomodulating treatments on anti-pneumococcal seroresponses. METHODS: We enrolled 306 patients with IBD from March 2014 through February 2016, with the following exclusion criteria: current IBD flare, pregnancy, pneumococcal immunization in the previous 5 years, and influenza immunization in the previous 4 weeks. PCV13 was administered intramuscularly. Serotype-specific vaccine responses were evaluated using an opsonophagocytic assay. Adverse events were monitored by diary cards and standardized phone interviews. RESULTS: The median seroprotection rate increased significantly from 43.9% (95% confidence interval [CI], 42.3-45.5) at inclusion to 90.4% (95% CI, 89.5-91.3%; P < 0.001) after vaccination. Patients receiving anti-tumor necrosis factor agents achieved a slightly lower seroprotection rate (from 44.5% [95% CI, 42.3%-46.8%] to 86.6% [95% CI, 84.9%-88.1%]) than patients treated with other types of immunosuppressive regimens (thiopurine, methotrexate, oral corticosteroids; from 44.7% [95% CI, 41.7%-47.7%] to 93.8% [95% CI, 92.1%-95.2%]) or nonimmunosuppressive treatment (5-aminosalicylate, topical corticosteroids, vedolizumab; from 41.3% [95% CI, 37.9%-44.8%] to 95.2% [95% CI, 93.4%-96.6%]). There were no safety issues. DISCUSSION: Overall, the administration of PCV13 was highly immunogenic and well tolerated, irrespective of the baseline treatment, and should be encouraged in all adults with IBD.