Vaccination proposal for patients on onasemnogene abeparvovec therapy.

The approval of disease-modifying treatment in spinal muscular atrophy made the condition less severe. The course of the disease changed, but some new concerns occurred with the different new therapies. The side effects of onasemnogene aboparvovec therapy can raise differential diagnostic challenges and necessitate immune therapy, leading to immunosuppression affecting response to vaccines. We provide a pretherapy screening proposal from an infectological point of view separately for newborns treated presymptomatically and children diagnosed with symptoms at any age. Furthermore, we summarise the guidelines on the vaccination before, during, and after immune therapy (steroids) in onasemnogene aboparvovec-treated patients.

[Reducing the risk of infections in hereditary and acquired complement deficiencies.] / Infekciók kockázatának csökkentése veleszületett és szerzett komplementdefektusokban.

Hereditary complement deficiencies are relatively rare worldwide, they account for about 1-10% of primary immunodeficiencies. Acquired complement deficiencies are more prevalent and with the more frequent use of complement inhibitor therapy, the incidence of patients with iatrogenic complement deficiency is increasing. Alike in the inherited forms, patients have a high risk of severe and life-threatening infections caused by encapsulated bacteria (sepsis, meningitis). The most frequent pathogens are Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae. C5 and C3 complement inhibitor therapies are available in Hungary, which are mostly indicated in the treatment of paroxysmal nocturnal hemoglobinuria, myasthenia gravis, neuromyelitis optica and atypical haemolytic uremic syndrome. It is of utmost importance to prevent severe, potentially life-threatening bacterial infections in this group of patients. Nevertheless, there is no Hungarian guidance to decrease the risk of infections, preventive measures are incomplete and not standardized posing potential risk of infections for these patients, so far. In this review, we aim to summarize the international clinical practices and guidance on the infection prevention in complement deficient patients. This recommendation might be a source of an evidence-based Hungarian guideline regarding vaccination and antibiotic prophylaxis in this specifically vulnerable group of patients. Orv Hetil. 2023; 164(25): 971-980.

Specific Antibody and the T-Cell Response Elicited by BNT162b2 Boosting After Two ChAdOx1 nCoV-19 in Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID) patients have markedly decreased immune response to vaccinations. In this study we evaluated humoral and T cell-mediated responses against severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) with additional flow cytometric changes in CVID patients receiving booster vaccination with BNT162b2 after two ChAdOx1 nCoV-19. The BNT162b2 vaccine raised the anti-spike protein S immunoglobulin G over the cut-off value from 70% to 83% in CVID, anti-neutralizing antibody had been raised over a cut-off value from 70% to 80% but levels after boosting were significantly less in both tests than in healthy controls (*p=0.02; **p=0.009 respectively). Anti-SARS-CoV-2 immunoglobulin A became less positive in CVID after boosting, but the difference was not significant. The cumulative interferon-γ positive T cell response by ELISpot was over the cut-off value in 53% of the tested individuals and raised to 83% after boosting. This and flow cytometric control of cumulative CD4+ and CD8+ virus-specific T cell absolute counts in CVID were also statistically not different from healthy individuals after boosting. Additional flow cytometric measures for CD45+ lymphocytes, CD3+, and CD19+ cells have not shown significant differences from controls except for lower CD4+T cell counts at both time points (**p=0.003; **p=0.002), in parallel CD4+ virus-specific T-cell ratio was significantly lower in CVID patients at the first time point (*p: 0.03). After boosting, in more than 33% of both CVID patients and also in their healthy controls we detected a decrease in absolute CD45+, CD3+, CD3+CD4+, and CD3+CD8+, CD19+, and CD16+56+ cell counts. CD16+CD56+ cell counts were significantly lower compared to controls before and after boosting (*p=0.02, *p=0.02). CVID patients receiving immunosuppressive therapy throughout the previous year or autologous stem cell transplantation two years before vaccination had worse responses in anti-spike, anti-neutralizing antibody, CD3+CD4+T, CD19+ B, and natural killer cell counts than the whole CVID group. Vaccinations had few side effects. Based on these data, CVID patients receiving booster vaccination with BNT162b2 after two ChadOx1 can effectively elevate the levels of protection against COVID-19 infection, but the duration of the immune response together with COVID-19 morbidity data needs further investigation among these patients.

SARS-CoV-2 infection and its prevention in pediatric autoimmune diseases / SARS-CoV-2-fertozés és annak megelozése gyermekkori krónikus szisztémás autoimmun betegségekben.

Összefoglaló. A krónikus autoimmun betegségben szenvedokben a súlyos COVID-19 kialakulásának kockázata magasabb, a SARS-CoV-2-fertozés pedig a krónikus alapbetegség progressziójához, fellángolásához vezethet. A COVID-19 elkerülésének legbiztonságosabb, legköltséghatékonyabb módszere a vakcináció, illetve az emellett alkalmazott higiénés szabályok betartása, a megfelelo maszk viselése. A hiedelemmel ellentétben önmagában az autoimmun megbetegedés nem jelent oltási ellenjavallatot, sot a rizikóállapot miatt ezek a betegek az elsok között oltandók. A COVID-19 elleni vakcina alkalmazásának egyetlen egyértelmu kontraindikációja az anamnézisben szereplo súlyos allergiás reakció (anafilaxia) a vakcina valamelyik alkotórészével szemben. A betegek olthatóságát többek között befolyásolja az aktuális betegségaktivitás és az alkalmazott kezelés. Az immunizáció idejét a legbiztonságosabban a gondozó orvos tervezheti meg. Az autoimmun betegek immunizációja során észlelheto oltási reakciók és szövodmények incidenciája megegyezik az egészséges populációban is tapasztalt elofordulási gyakorisággal. Orv Hetil. 2022; 163(11): 414-423. Summary. The risk of developing severe COVID-19 is higher in patients with autoimmune diseases, and SARS-CoV-2 infection can lead to progression and exacerbation of the underlying chronic disease. The safest and most cost-effective way to avoid COVID-19 is to be vaccinated, to follow the hygiene rules and to wear an appropriate mask. Contrary to belief, autoimmune disease alone is not a contraindication to vaccination and, in fact, patients should be among the first to be vaccinated because of the risk. The only clear contraindication to the use of COVID-19 vaccine is a history of severe allergic reaction (anaphylaxis) to any of the components of the vaccine. Indication of vaccination migh be influenced by, among other things, the current disease activity and the treatment applied. The timing of immunization can be the most safely planned by the attending physician. The incidence of vaccination reactions and complications during immunization in autoimmune patients is similar to that seen in the healthy population. Orv Hetil. 2022; 163(11): 414-423.

Coupling of N-tosylhydrazones with tetrazoles: synthesis of 2-ß-D-glycopyranosylmethyl-5-substituted-2H-tetrazole type glycomimetics.

Coupling reactions of O-peracylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) with tetrazoles were studied under metal-free conditions using thermic or microwave activation in the presence of different bases. The reactions proved highly regioselective and gave the corresponding, up-to-now unknown 2-ß-d-glycopyranosylmethyl-2H-tetrazoles in 7-67% yields. The method can be applied to get new types of disaccharide mimetics, 5-glycosyl-2-glycopyranosylmethyl-2H-tetrazoles, as well. Galectin binding studies with C-(ß-d-galactopyranosyl)formaldehyde tosylhydrazone and 2-(ß-d-galactopyranosylmethyl)-5-phenyl-2H-tetrazole revealed no significant inhibition of any of these lectins.

16q24.3 Microduplication in a Patient With Developmental Delay, Intellectual Disability, Short Stature, and Nonspecific Dysmorphic Features: Case Report and Review of the Literature.

We describe the case of a seven-year-old female patient who presented in our service with severe developmental delay, intellectual disability, facial dysmorphism, and femur fracture, observed in the context of very low bone mineral density. Array-based single nucleotide polymorphism (SNP array) analysis identified a 113 kb duplication involving the morbid OMIM genes: ANKRD11 (exon1), RPL13, and PGN genes. ANKRD11 deletions are frequently described in association with KBG syndrome, the duplications being less frequent (one case described before). The exome sequencing was negative for pathogenic variants or of uncertain significance in genes possibly associated with this phenotype. The patient presented subtle signs of KBG syndrome. It is known that the phenotype of KBG syndrome has a wide clinical spectrum, this syndrome being often underdiagnosed due to overlapping features with other conditions, also characterized by multiple congenital anomalies and intellectual disability. The particularity of this case is represented by the very low bone mineral density in a patient with 16q24.3 duplication. ANKRD11 haploinsufficiency is known to be associated with skeletal involvement, such as short stature, or delayed bone age. An effect on bone density has been observed only in experimental studies on mice with induced missense mutations in the ANKRD11 gene. This CNV also involved the duplication of the very conserved RPL13 gene, which could have a role for the skeletal phenotype of this patient, knowing the high level of gene expression in bone tissue and also the association with spondyloepimetaphyseal dysplasia Isidor Toutain type, in case of splicing mutations.

Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: Multicenter, retrospective data collection.

PURPOSE: To collect retrospective data of patients with Juvenile Idiopathic Arthritis (JIA) and other rheumatic diseases who received live attenuated booster measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMR/V) during treatment with immunosuppressive therapy. RESULTS: Data from 13 pediatric rheumatology centers in 10 countries, including 234 patients, were collected. Mean age at diagnosis was 5 ± 2.7 years, 67% were girls. Among them, 211 (90.2%) had JIA and 110 (47%) were in remission on medication. Disease activity was low in 37%, high in 8%, and moderate in 8%. One hundred-twenty-four received MMR/V booster while on methotrexate (MTX); 3 reported local mild adverse events (AE). Among 62 on MTX + biologics and 9 patients who received a combination of 2 disease modifying antirheumatic drugs (DMARDs), 9 reported mild AE. Among 39 on biologics, 1 reported fever one day after booster vaccination. No vaccine-related infection of measles, rubella, mumps or varicella was reported, none of the patients developed disease flare, including those with high disease activity. CONCLUSIONS: In this retrospective study, live-attenuated MMR/V booster vaccines were safe for children with rheumatic diseases, on immunosuppressive therapies. This strengthens the Paediatric Rheumatology European Society (PReS) recommendation that vaccination with live attenuated vaccines in patients on immunosuppressive therapies can be considered individually, weighing the benefit of vaccination against the risk of inducing infection through vaccination. These data provide the basis for a prospective data collection study, planned by the PReS vaccination study group.

[Hungarian recommendation for the immunization of health-care personnel against hepatitis B virus]. / Állásfoglalás az egészségügyi dolgozók hepatitis B-vírus-fertozéssel szembeni immunizációjáról.

More than 200 million HBV surface antigen (HBsAg) positive, hepatitis B virus (HBV) carriers live worldwide. Health-care personnel have increasing risk for aquiring the HBV infection. An effective vaccine is available against the infection, however, a certain proportion of the vaccinated patients do not respond to the vaccine depending on certain factors. Therefore, vaccine-induced immunity (anti-HBs) should be tested at health-care workers. For nonresponders, there are other vaccination strategies to try to achieve protection. This recommendation also provides a guidance for postexposure prophylaxis following occupational exposures against HBV infection. This is the first Hungarian recommendation about this topic. Orv Hetil. 2019; 160(41): 1607-1616.

[Prevention of invasive meningococcal infection, recognition and first treatment of the disease in primary care]. / Az invazív meningococcusfertozés megelozése, felismerése és elso, területi ellátása.

Neisseria meningitidis, the meningococcus, is a Gram-negative diplococcal bacterium that is only found naturally in humans. The meningococcus is part of the normal microbiota of the human nasopharynx and is commonly carried in healthy individuals. In some cases systemic invasion occurs, which can lead to meningitis and/or septicemia. Invasive disease caused by Neisseria meningitidis is potentially devastating, with a high case fatality rate and high rates of significant sequelae among survivors after septicaemia or meningitis. Between 2006-2015 every year between 34 and 70 were the numbers of the registered invasive disease because of Neisseria meningitis, the morbidity rate was 0.2-0.7°/0000. Half of the diseases (50.7%) were caused by B serotype N. meningitidis, 23.2% were C serotype. In this article the authors summarise what you must do and must not do as primary care physician when suddenly meeting a young patients suspected of having meningococcus infection.

Surveillance of pneumococcal diseases in Central and Eastern Europe.

Pneumococcal infection is a major cause of morbidity and mortality worldwide. The burden of disease associated with S. pneumoniae is largely preventable through routine vaccination. Pneumococcal conjugate vaccines (e.g. PCV7, PCV13) provide protection from invasive pneumococcal disease as well as non-invasive infection (pneumonia, acute otitis media), and decrease vaccine-type nasopharyngeal colonisation, thus reducing transmission to unvaccinated individuals. PCVs have also been shown to reduce the incidence of antibiotic-resistant pneumococcal disease. Surveillance for pneumococcal disease is important to understand local epidemiology, serotype distribution and antibiotic resistance rates. Surveillance systems also help to inform policy development, including vaccine recommendations, and monitor the impact of pneumococcal vaccination. National pneumococcal surveillance systems exist in a number of countries in Central and Eastern Europe (such as Croatia, Czech Republic, Hungary, Poland, Romania and Slovakia), and some have introduced PCVs (Czech Republic, Hungary, Kazakhstan, Russia, Slovakia and Turkey). Those countries without established programs (such as Kazakhstan, Russia and Ukraine) may be able to learn from the experiences of those with national surveillance systems. The serotype distributions and impact of PCV13 on pediatric pneumococcal diseases are relatively similar in different parts of the world, suggesting that approaches to vaccination used elsewhere are also likely to be effective in Central and Eastern Europe. This article briefly reviews the epidemiology of pneumococcal disease, presents the latest surveillance data from Central and Eastern Europe, and discusses any similarities and differences in these data as well the potential implications for vaccination policies in the region.

Varicella vaccine without human serum albumin versus licensed varicella vaccine in children during the second year of life: a randomized, double-blind, non-inferiority trial.

BACKGROUND: GSK's varicella vaccine contains human serum albumin (HSA) which is used to stabilize the virus and prevent immunogens from adhering to the injection vial walls. However, because HSA is derived from human blood, there is a theoretical risk that it might contain infectious agents which could be unsafe for humans. Given this concern, a study was undertaken to compare the immunogenicity and safety of a new formulation without HSA with the currently licensed varicella vaccine in the Czech Republic and Hungary. METHODS: Healthy children aged 11-21 months received two doses of the varicella vaccine either with or without HSA. Antibody titres against varicella-zoster virus (anti-VZV) were measured 42 days after each dose, using an immunofluorescence assay (IFA, cut-off = 4dilution(-1)) and enzyme linked immunosorbent assay (ELISA, cut-off = 25 mIU/ml). Solicited local symptoms were recorded during a 4-day post-vaccination follow-up period; solicited general and unsolicited symptoms were recorded during a 43-day post-vaccination follow-up period and serious adverse event (SAEs) were recorded throughout the study. RESULTS: Of 244 children (mean age = 15.2 months [SD = 3.2]) vaccinated in the study, 233 (vaccine without HSA N = 117; vaccine containing HSA N = 116) formed the according-to-protocol immunogenicity cohort. Observed seroconversion/seroresponse rates were >98 and 100 %, 42 days after doses 1 and 2, respectively. The rates were within the same range in both groups, irrespective of the testing assay. The varicella vaccine without HSA was non-inferior to the licensed vaccine in terms of anti-VZV antibody Geometric Mean Titre/Concentration ratio (1.12 [95 % CI:0.86-1.46] by IFA; 1.12 [95 % CI:0.93-1.33] by ELISA) approximately six weeks after the first dose of the 2-dose vaccination course. The incidence of solicited and unsolicited symptoms was similar after both vaccines; low-grade fever was numerically higher after the first dose of the varicella vaccine without HSA. Seven SAEs were reported, none of which were fatal or considered to be vaccine-related. CONCLUSIONS: The first dose of a new varicella vaccine without HSA was immunologically non-inferior to the licensed varicella vaccine. After two doses, both vaccines had acceptable safety profiles in children aged 11-21 months in the Czech Republic and Hungary. TRIAL REGISTRATION: NCT00568334 , registered on 5 December 2007 ( www.clinicaltrials.gov ).

Antibody and cell-mediated immune response to whole virion and split virion influenza vaccine in patients with inflammatory bowel disease on maintenance immunosuppressive and biological therapy.

OBJECTIVE: Influenza vaccination is recommended for inflammatory bowel disease (IBD) patients on immunosuppressive therapy. The objective was to evaluate the antibody and cell-mediated immune response to the split and whole virion influenza vaccine in patients with IBD treated with anti-TNF-α and immunosuppressive therapy. PATIENTS AND METHODS: One hundred and fifty-six immunocompromised IBD patients were vaccinated. Fifty-three patients (control group) refused vaccination. Split virion vaccine and whole virion vaccine were used. Serum samples were obtained for pre- and postimmunization antibody titers to influenza vaccine (A/California/7/2009 [H1N1], A/Victoria/361/2011 [H3N2], B/Wisconsin/1/2010-like B/Hubei-Wujiagang/158/2009). Cell-mediated response was evaluated using an interferon (INF)-γ, interleukine (IL)-2 and tumor necrosis factor (TNF)-α ELISA. RESULTS: Postimmunization titers of both influenza subtypes increased significantly after the administration of split virion vaccines compared to the controls and to those who received whole virion vaccine. The antibody titers of Influenza B also increased significantly in patients immunized with split vaccine and treated with anti-TNF-α therapy. After influenza vaccination, the level of serum IL-2 significantly decreased. No serious side effects developed occurred after influenza vaccination, and the influenza-like symptoms did not differ significantly between vaccinated versus control patients. The relapse of the disease was observed in only 10% of the patients and was more common in vaccinated than in control subjects. CONCLUSION: Split virion vaccines seem to be more effective than whole virion vaccines. Measuring the antibody responses is worthwhile in patients treated with immunosuppressants to determine the efficacy of influenza vaccination.

Visual and neurologic deterioration in otogenic lateral sinus thrombosis: 15 year experience.

OBJECTIVES: Otogenic lateral sinus thrombosis is a rare complication of acute otitis media whose clinical presentation has changed with the early use of antibiotics. The aim of this study was to analyze the changing clinical signs, vaccination status, therapeutic management and outcome of these patients. METHODS: Retrospective chart review of 10 children treated with otogenic lateral sinus thrombosis in a tertiary level teaching hospital in Budapest, Hungary, from January 1998 till August 2013. RESULTS: Patients were divided into Early and Late presenting groups. In the Early presenting group, sepsis developed within one week after the onset of acute otitis media. At admission otological symptoms were predominant. The Late presenting group experienced acute otitis media several weeks prior to presentation and in this group neurologic symptoms dominated the clinical picture at admission. All patients received antibiotics. Eight of them were also treated with low molecular weight heparin. All children underwent cortical mastoidectomy. After surgery, the clinical signs of elevated intracranial pressure transiently worsened. This manifested as progression of papilledema in seven children, causing severe visual disturbance in two cases. After medical treatment and serial lumbar punctures all patients except one recovered. This child has permanent visual acuity failure of 0.5D unilaterally. At one year follow up complete and partial recanalization were noted in five and two patients, respectively. CONCLUSIONS: After mastoidectomy the signs of elevated intracranial pressure can transiently worsen, papilledema can progress. Daily bedside monitoring of visual acuity and regular ophthalmoscopy with neurologic examination is recommended during hospitalization. Close follow up is advised up to one year. When the dominant sinus is occluded, the clinical scenario is more protracted and severe.

Primary versus secondary failure after varicella vaccination: implications for interval between 2 doses.

BACKGROUND: Two-dose varicella vaccination is recommended for optimal control of varicella in populations with high (>90%) 1-dose coverage. Optimal timing of the second dose may depend on whether breakthrough varicella results from primary vaccine failure (no protective immunity after vaccination) or secondary vaccine failure (waning protective immunity). METHODS: Published literature (1995 to 2012) on vaccine failure after varicella vaccination cited in PubMed and other online sources was reviewed. RESULTS: Nineteen publications detailed 21 varicella outbreaks with breakthrough varicella rates ranging from 0% to 42%; the publications showed no consistent trend between breakthrough varicella rate and time since vaccination. CONCLUSIONS: Literature to date indicates a relatively high rate of primary vaccine failure and limited evidence of secondary vaccine failure among 1-dose varicella vaccine recipients, suggesting that a short interval between 2 doses might be preferable in countries considering implementation of universal varicella vaccination to reduce breakthrough varicella. However, any potential disruption to well-established vaccination schedules should be considered.

Cellular and serological changes in the peripheral blood of splenectomized and spleen autotransplanted mice.

BACKGROUND: Our department worked out a modified surgical form of spleen autotransplantation earlier, named "spleen apron method" introduced already into the clinical practice. Recently we tested the immunological changes in a group of patients autotransplanted with about 10-15% of their spleen, what was the at least always implantable amount after the severe splenic injuries. In the current work we aimed at measuring some cellular and serological changes in the peripheral blood of splenectomized and spleen autotransplanted inbred mice two and eight months after the operations in order to get more unambiguous results than that we could obtain in our patients with this technique. MATERIALS AND METHODS: We divided 96 two months old Balb/c female mice into eight groups (n = 12/group). The group of controls, sham operated, splenectomized and autotransplanted animals with two and eight months of survival time after the operations. During the autotransplantation we inserted the same amount of spleen, five slices, "chips," about 10-15% of total mass of spleen, into the greater omentum similarly as it was used in the patients. The concentration of serum proteins were measured by laser nephelometry. The lymphocyte subsets were analyzed by flow cytometry. RESULTS: We found that two months after the operations the number of CD 19+ B-cells increased in the splenectomized but decreased in the autotransplanted animals. Eight months after the operations the number of both CD3+ T and CD19+ B lymphocytes decreased both in the splenectomized and autotransplanted animals compared to the controls and sham operated mice. However, the numbers of T and B cells were slightly but not significantly higher in the autotransplanted than in the splenectomized mice. The serum level of IgM was also decreased in the splenectomized and autotransplanted mice at both time points, however, eight months after the operations the concentration of IgM was significantly higher in the autotransplanted group than in the splenectomized animals. CONCLUSION: The effects of autotransplanted "chips" were different at the various ages of the animals. Additionally, they showed some immunological benefit being quantitatively in accordance to the amount of the transplanted spleen. The elevated level of serum IgM what we found in the autotransplanted mice even with this amount of transplanted spleen eight months after the operations, however, might have the potentially greatest importance compared to splenectomy. These experiments can prove that the attempts for autotransplantation may have real perspectives but their efficacy depends on the amount of the successfully transplanted (saved) mass of spleen.