Specifieke Polysacharide Antistof Deficiëntie: Optimalisatie van diagnostiek en hints wijzend op een rol van invariante Natural Killer T cellen

Streptococcus pneumoniae is a leading cause of life threatening infections like meningitis, pneumonia and septicaemia and the main pathogen involved in otitis and bronchitis. Pneumococcal capsular polysaccharides are the most important virulence factor of S. pneumoniae. Anti-polysaccharide antibodies have shown to be crucial for opsonisation and effective phagocytosis of S. pneumoniae, thereby providing protection against early phase disease. Patients with polysaccharide antibody deficiency (PsAD) suffer from recurrent upper and lower respiratory tract infections due to a deficient antibody response to capsular polysaccharides. This defect can present isolated (Specific Antibody Deficiency or SAD) or in the context of a broader immunodeficiency. Correct diagnosis is crucial to initiate appropriate treatment like immunoglobulin replacement therapy or prophylactic antibiotics, preventing irreversible organ damage (hearing loss, bronchiectasis). PsAD is diagnosed by measuring anti-polysaccharide IgG prior to and after Pneumococcal Polysaccharide Vaccine (PPV), but this method faces many challenges. The gold standard is a laborious and expensive WHO standardized ELISA. Guidelines to define a normal response remain controversial. Furthermore, standard vaccination of children with protein-conjugated pneumococcal polysaccharides (PCV) induces a T dependent antibody response, and is likely to influence the magnitude and nature of the antibody response to PPV. Finally, reports on hyporesponsiveness to subsequent vaccinations with polysaccharide vaccines raise concerns on the potential harmful effect of immunizing immunocompromised patients with PPV. Our first aim was to facilitate and improve diagnosis of PsAD. In Chapter 1, we demonstrated the need for alternatives methods to detect PsAD by showing that previous vaccination with PCV influences the response to PCV-PPV shared serotypes but also to non-PCV serotypes. Allohemagglutinins (AHA), antibodies to A and B polysaccharides on erythrocytes, are mentioned in many immunology reviews and textbooks as an alternative method to detect PsAD. Only a few dated studies described normal values of AHA and research on the diagnostic value of AHA to detect SAD was lacking. We conducted a retrospective study in 180 patients, and found low sensitivity and specificity of AHA to detect PsAD and no correlation of low AHA with low PPV response (Chapter 2). More importantly, low AHA did not associate with clinical signs of PsAD like recurrent lower respiratory tract infections and bronchiectasis. In Chapter 3, we aimed to investigate Typhim Vi vaccine as an alternative for PPV to diagnose PsAD. Typhim Vi vaccine contains Vi capsular polysaccharides from Salmonella typhi, a new or ‘neo-antigen’ for most European individuals, facilitating interpretation of the response. Hundred healthy volunteers were vaccinated with Typhim Vi and Pneumovax vaccine. We established normal values for post-vaccination IgG and fold increase of antibody titres pre- to post-vaccination after Typhim Vi vaccination. We confirmed that AAAAI criteria for PsAD cannot be applied to bead-based assay results for PPV response. Instead we propose serotype-specific 5th percentile cut-off values for post-vaccination IgG and fold increase post PPV measured by bead-based assay. Finally, we also assessed AHA in these 100 healthy subject and demonstrated a large spread of AHA, with fifth percentile cut-offs much lower than the currently used thresholds, again questioning the clinical value of low AHA. A follow-up study in 100 patients with suspected humoral immunodeficiency is currently recruiting participants to validate our findings in a patient population. Despite the importance of antibodies to capsular polysaccharides in the protection against pneumococcal disease, the mechanisms inducing a class switched IgG response to polysaccharides are still poorly understood. A number of ‘second signals’ required for an IgG response to polysaccharides have been identified and Primary Immunodeficiencies (PIDs) affecting one of the ‘second signal’ pathways are associated with PsAD (e.g. MyD88 and IRAK4 deficiency causing abnormal TLR signalling). However, in most patients with isolated PsAD (thus SAD) and in many patients with PID, a cause has not yet been found. The second aim of this thesis, was to investigate the role of invariant Natural Killer T (iNKT) cells in the pneumococcal polysaccharide antibody response in humans. iNKT cells are a specialized subset of T cells that use their restricted set of T cell receptors to recognize self and foreign lipids presented by CD1d on B cells and antigen presenting cells. Whilst the involvement of iNKT cells in the innate and adaptive response to S. pneumoniae in mice has clearly been demonstrated, the evidence in humans is scarce. We described the association of absent iNKT cells and pneumococcal infections in two siblings from consanguineous parents. Pneumococcal polysaccharide response was completely abolished. Based on the clinical presentation, a very rare calcium release activated calcium channelopathy due to STIM1 mutation was suspected and confirmed by genetic and functional testing (Chapter 4). This report was the first to describe prolonged survival in STIM1 deficiency, and auto-inflammatory manifestations other than auto-immune cytopenia namely severe colitis and psoriasis. In the last chapter (Chapter 5), we describe an unusual presentation of autosomal dominant hyper IgE syndrome with normal IgE, normal polysaccharide antibody response and normal iNKT cell numbers. Low iNKT cells in patients with PsAD and increased susceptibility of patients with low iNKT to S. pneumoniae infections hint towards a role of iNKT cells in the generation of polysaccharide antibody response. However, further studies are needed to elucidate the exact role of iNKT cells in T independent responses and to reveal the pathways involved. Multiple second signals are required for a fully functional polysaccharide response. The future identification of underlying genetic defects in patients with PsAD by next generation sequencing will hopefully shed a light on redundant and non-redundant signals for the polysaccharide antibody response.status: publishe

Physical activity and its correlates in people with cystic fibrosis: a systematic review

Cystic fibrosis (CF) is a life-shortening genetic disease, affecting multiple life domains including physical activity (PA). Although higher PA levels are associated with multiple health benefits, little insight exists on the PA level of people with CF (PwCF) compared to healthy peers. Evidence on the influencing factors (i.e. correlates) of PA in this clinical population is scarce, but essential to fully understand their PA behaviour. Therefore, the present review aims to provide an overview of the PA level of PwCF compared to healthy peers, and the correlates of PA in PwCF. A systematic search of three databases resulted in 46 included studies. Analysis of 16 studies showed that the CF population is equally active compared to healthy peers, but there is a trend towards less high-intensity PA in youths with CF. Furthermore, PA is positively associated with quality of life, lung function, (maximal) exercise capacity, bone mineral density and quadriceps force. Also, PA was lower on weekdays compared to weekend days and lower when experiencing pulmonary exacerbations. More high-quality research is required in PwCF, particularly longitudinal studies that further explore the correlates of PA, with PA investigated as a primary outcome and measured objectively

Physical activity and its correlates in patients with Cystic Fibrosis: a systematic review

Regular physical activity (PA) is associated with multiple health benefits, yet little insight exists on PA levels of patients with CF (PwCF). This systematic review aimed to compare PA levels of PwCF (youth and adults) to healthy peers, and explore the influencing factors (i.e. correlates) of PA in these patients.Medline (PubMed), Web of Science and PsychArticles were systematically searched for eligible literature and 46 studies were included, describing 2351 PwCF.PwCF are~as active as their~healthy peers, although CF youth tend to be less active at higher PA intensities. In addition, both groups do not meet PA guidelines set by the World Health Organization (WHO)[Bull,F.C.et al. Br J Sports Med 2020;54:1451-1462]. PA is positively associated with quality of life, lung function, exercise capacity, bone mineral density and quadriceps force, and negatively with weekday and respiratory exacerbations (table). No associations were found with age, pancreatic insufficiency, or colonisation with bacteria.PwCF and healthy peers are equally active, but do not meet WHO guidelines. Several PA correlates that were widely investigated in the healthy population remain undetermined (e.g. sex) or unknown (e.g. behavioural factors, parental support, access to green space) in PwCF. However, these correlates could form excellent target points to improve PA. More high-quality research is needed to further unravel the PA behaviour of PwCF.FootnotesCite this article as Eur Respir J 2022; 60: Suppl. 66, 700.This article was presented at the 2022 ERS International Congress, in session {\textquotedblleft}-{\textquotedblright}.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only)

Identification of two new gain-of-function STAT1 mutations in the DNA-binding domain

status: publishe

The burden and surveillance of RSV disease in young children in Belgium-expert opinion

Infections with respiratory syncytial virus (RSV) can cause severe disease. In young children, RSV is the most common cause of lower respiratory tract illness and life-threatening infections most commonly occur in the first years of life. In adults, elderly and immunocompromised people are most vulnerable. Recently there has been an acceleration in the development of candidate RSV vaccines, monoclonal antibodies and therapeutics which are expected to become available in Europe within the next 2–10 years. Understanding the true burden of childhood RSV disease will become very important to support public health authorities and policy makers in the assessment of new therapeutic opportunities against RSV disease. A systematic literature search was performed to map local data on the burden of RSV disease and to evaluate available RSV surveillance systems. A group of 9 paediatric infectious diseases specialists participated in an expert panel. The purpose of this meeting was to evaluate and map the burden associated with RSV infection in children, including patient pathways and the epidemiological patterns of virus circulation in Belgium. Sources of information on the burden of RSV disease in Belgium are very limited. For the outpatient setting, it is estimated that 5–10% of young patients seen in primary care are referred to the hospital. Around 3500 children between 0 and 12 months of age are hospitalized for RSV-bronchiolitis every year and represent the majority of all hospitalizations. The current Belgian RSV surveillance system was evaluated and found to be insufficient. Knowledge gaps are highlighted and future perspectives and priorities offered. Conclusion: The Belgian population-based RSV surveillance should be improved, and a hospital-led reporting system should be put in place to enable the evaluation of the true burden of RSV disease in Belgium and to improve disease management in the future

Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses

Over the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination program. This may impact on the diagnosis of polysaccharide antibody deficiency by measurement of anti-polysaccharide IgG after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T-dependent, more pronounced memory response. The antibody response to PPV was retrospectively studied in patients referred for suspected humoral immunodeficiency. The study population was divided in 4 subgroups based on age (2-5 years old versus ≥10 years old) and time tested (1998-2005 versus 2010-2012). Only 2-5 year-old children tested in 2010-2012 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV-PPV shared serotypes 4 and 18C than the un-primed groups. To a lesser extent, this was also found for non-PCV serotype 9N, but not for non-PCV-serotypes 19A and 8. Furthermore, PCV-priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes but can also influence antibody response to some non-PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced. This article is protected by copyright. All rights reserved.status: publishe

AD Hyper-IgE Syndrome Due to a Novel Loss-of-Function Mutation in STAT3: a Diagnostic Pursuit Won by Clinical Acuity

status: publishe