Central nervous system manifestations of LRBA deficiency: case report of two siblings and literature review.

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature. CASE PRESENTATIONS: The younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla.  His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions. CONCLUSIONS: Neurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Hereditary angioedema (HAE) in Belgium: results from a national survey.

Background: Hereditary angioedema (HAE) is a rare heritable disorder that is characterized by recurrent, circumscribed, nonpitting, nonpruritic, often painful subepithelial swellings of sudden unpredictable onset that generally fade during 48-72 h. Epidemiological data of hereditary angioedema patients in Belgium is lacking. Methods: We set up a nation-wide, multicentric study involving the 8 Belgian hospitals known to follow-up patients with Type I and II HAE. All Belgium HAE patients were asked to fill out questionnaires that mainly covered demographic data, family history, and detailed information about diagnosis, treatment and burden of their Type I and II HAE. Results: 112 patients with type I or type II HAE could be included. Median delay between first symptoms and diagnosis was 7 years. 51% of patients had experienced pharyngeal or tongue swelling and 78% had experienced abdominal symptoms, both known to cause an important reduction in quality of life. 60% of symptomatic patients reported to receive long term prophylactic treatment. Human plasma-derived C1-esterase inhibitor concentrate was used by 56.3% of patients. 16.7% and 27.1% of patients used a 17-α-alkylated androgen and tranexamic acid as long term prophylactic therapy. Conclusions: We present the first nation-wide epidemiological study regarding HAE in Belgium. Our data show that the morbidity of HAE is not to be underestimated. Knowledge and dissemination of this data is critical in raising awareness, encouraging development of therapies and optimising nationwide management.

Clinical practice of hereditary angioedema in Belgium: opportunities for optimized care.

INTRODUCTION: Hereditary angioedema (HAE) is a rare disorder characterized by unpredictable painful and potentially life-threatening swelling episodes. The international WAO/EAACI guideline on the diagnosis and management of HAE was recently updated and provides up-to-date guidance for the management of. In this paper, we assessed to what extent the Belgian clinical practice was aligned with the revised guideline, and whether there were opportunities to optimise Belgian clinical practice in HAE. METHODS: We compared the updated international guideline for HAE with information we acquired on Belgian clinical practice, a Belgian patient registry and expert opinion analysis. The Belgian patient registry was developed with the involvement of eight Belgian reference centers for HAE patients. Eight Belgian experts, physicians in the participating centers, included patients in the patient registry and participated in the expert opinion analysis. RESULTS: The main action points to further optimise the Belgian clinical practice of HAE are Work towards total disease control and normalize patients' life by considering the use of new and innovative long-term prophylactic treatment options; (2) inform C1-INH-HAE patients about new long-term prophylactic therapies; (3) assure the availability of on-demand therapy for all C1-INH-HAE patients; (4) implement a more universally used assessment including multiple aspects of the disease (e.g. quality of life assessment) in daily clinical practice; and (5) continue and expand an existing patient registry to assure continued data availability on C1-INH-HAE in Belgium. CONCLUSIONS: In light of the updated WAO/EAACI guideline, five action points were identified and several other suggestions were made to optimise the Belgian clinical practice in C1-INH-HAE.

SARS-CoV-2-related Multisystem Inflammatory Syndrome in Adult complicated by myocarditis and cardiogenic shock.

Multisystem Inflammatory Syndrome in Adult (MIS-A) is a rare COVID-19 complication, presenting as fever with laboratory evidence of inflammation, severe illness requiring hospitalization and multisystem organ involvement. We report on a 25-year-old man presenting with fever, rash, abdominal pain, diarrhoea and vomiting following prior asymptomatic COVID-19 infection. He developed refractory shock and type 1 respiratory insufficiency requiring mechanical ventilation. Diagnostic testing revealed significant inflammation, anemia, thrombocytopenia, acute kidney injury, hepatosplenomegaly, colitis, lymphadenopathy and myocarditis necessitating inotropy. Ventilatory, vasopressor and inotropic support was weaned following pulse corticosteroids and intravenous immunoglobulins. Heart failure therapy was started. Short-term follow-up shows resolution of inflammation and cardiac dysfunction.

A case of disseminated tuberculosis during a twin pregnancy following in vitro fertilization.

A woman presented with cough, fever, and dyspnea during a twin pregnancy following a 13th in vitro fertilization procedure. Ultimately, she was diagnosed with miliary tuberculosis and tuberculostatic treatment was initiated, complicated by drug-induced hepatotoxicity. In retrospect, previous pelvic tuberculosis had likely been overlooked. This case report highlights the need to recognize tuberculosis as a cause of infertility even in low-incidence countries and emphasizes that the peripartum period is a major risk factor for drug-induced liver injury.

Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation.

Hyperinflammatory syndromes are life-threatening disorders caused by overzealous immune cell activation and cytokine release, often resulting from defects in negative feedback mechanisms. In the quintessential hyperinflammatory syndrome familial hemophagocytic lymphohistiocytosis (HLH), inborn errors of cytotoxicity result in effector cell accumulation, immune dysregulation and, if untreated, tissue damage and death. Here, we describe a human case with a homozygous nonsense R688* RC3H1 mutation suffering from hyperinflammation, presenting as relapsing HLH. RC3H1 encodes Roquin-1, a posttranscriptional repressor of immune-regulatory proteins such as ICOS, OX40 and TNF. Comparing the R688* variant with the murine M199R variant reveals a phenotypic resemblance, both in immune cell activation, hypercytokinemia and disease development. Mechanistically, R688* Roquin-1 fails to localize to P-bodies and interact with the CCR4-NOT deadenylation complex, impeding mRNA decay and dysregulating cytokine production. The results from this unique case suggest that impaired Roquin-1 function provokes hyperinflammation by a failure to quench immune activation.

Screening protocols to monitor respiratory status in primary immunodeficiency disease: findings from a European survey and subclinical infection working group.

Many patients with primary immunodeficiency (PID) who have antibody deficiency develop progressive lung disease due to underlying subclinical infection and inflammation. To understand how these patients are monitored we conducted a retrospective survey based on patient records of 13 PID centres across Europe, regarding the care of 1061 adult and 178 paediatric patients with PID on immunoglobulin (Ig) G replacement. The most common diagnosis was common variable immunodeficiency in adults (75%) and hypogammaglobulinaemia in children (39%). The frequency of clinic visits varied both within and between centres: every 1-12 months for adult patients and every 3-6 months for paediatric patients. Patients diagnosed with lung diseases were more likely to receive pharmaceutical therapies and received a wider range of therapies than patients without lung disease. Variation existed between centres in the frequency with which some clinical and laboratory monitoring tests are performed, including exercise tests, laboratory testing for IgG subclass levels and specific antibodies, and lung function tests such as spirometry. Some tests were carried out more frequently in adults than in children, probably due to difficulties conducting these tests in younger children. The percentage of patients seen regularly by a chest physician, or who had microbiology tests performed following chest and sinus exacerbations, also varied widely between centres. Our survey revealed a great deal of variation across Europe in how frequently patients with PID visit the clinic and how frequently some monitoring tests are carried out. These results highlight the urgent need for consensus guidelines on how to monitor lung complications in PID patients.

Achromobacter xylosoxidans induced bronchiolitis obliterans in cystic fibrosis.

We report a 12-year-old boy with progressive bronchiolitis obliterans caused by Achromobacter xylosoxidans (Ax) colonization after liver transplantation, resulting in a steep decline in lung function.

Genetic variations in toll-like receptor pathway and lung function decline in Cystic fibrosis patients.

The toll-like receptor (TLR) family maintains pulmonary homeostasis by pathogen recognition, clearance and regulation of inflammation. Genes affecting inflammation response play a key role in modifying Cystic fibrosis (CF) lung disease severity. We assessed the impact of single nucleotide polymorphisms (SNPs) of TLR genes (TLR1 to TLR10, CD14, lipopolyssacharide-binding protein (LBP)) on lung function in CF patients. Each SNP was tested for time-dependent effect on FEV1, using six genetic models. In addition, we investigated associations between SNP genotypes and extreme subject specific slopes of FEV1 decline. Variant alleles of polymorphisms of TLR2 rs1898830, rs5743708, and rs3804100 demonstrated a consistent association with lung disease severity (p = 0.008, p = 0.006 and p = 0.029 respectively). Patients homozygous for variant C allele of TLR5 polymorphism rs5744174 are more frequently associated with extreme fast FEV1 decline (OR: 20 (95% Confidence Interval:1.85-216.18)). Patients homozygous AA for TLR1 polymorphism rs5743551 are more frequently associated with faster decline of FEV1 compared to heterozygous genotype (OR:7.33 (95% CI:1.63-33.11). Our findings indicate that variations in TLR1, TLR2 and TLR5 genes may influence CF lung function decline. Further functional analysis is required to provide new insights into the pathogenesis of TLRs in CF lung disease severity.

Polymorphisms in the lectin pathway genes as a possible cause of early chronic Pseudomonas aeruginosa colonization in cystic fibrosis patients.

Genes of innate immunity may be involved in early onset of chronic Pa (Pseudomonas aeruginosa) colonization (cPaC) in cystic fibrosis (CF) patients. We studied 19 single nucleotide polymorphisms (SNPs) in 5 genes coding for proteins of the lectin complement pathway: MBL2 (Mannose binding lectin 2), MASP 1, 2, 3 (MBL-associated serine Protease) and FCN 1, 2 (Ficolin) gene in 96 CF patients. Association survival analysis using different genetic models was performed looking for an association between SNPs and age at onset of cPaC. CF patients who are MBL deficient are earlier chronic Pa colonized compared to MBL sufficient patients. Also patients with MBL2 genotype YO/YO, YO/XA, XA/XA, YA/YO and YA/XA are earlier chronic Pa colonized. CF patients heterozygous or homozygous for mutant alleles of two linked SNPs in the FCN1 gene (rs2989727 and rs1071583) are earlier colonized with Pa. Similarly, earlier onset of Pa colonization is seen in CF patients heterozygous for linked SNPs of FCN2 gene (rs7865453 and rs7851696) and MASP3 gene (rs7851696). Variants in MBL2, FCN1, FCN2 and MASP3 genes are significantly associated with earlier onset of chronic P. aeruginosa colonization.

Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms.

In children with persistent respiratory symptoms despite regular anti-asthma inhalation treatment, diagnostic investigations to exclude underlying disease are warranted. 124 children were prospectively enrolled, and 24-h oesophageal pH measurement and fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) were performed. BAL fluid (BALF) was processed for neutrophil counting and bacterial culture. Inflammation of the respiratory mucosa was assessed. A structural abnormality of the central airways was found in 47% of subjects (40% females). In 19% of subjects, neither anatomical anomalies nor inflamed respiratory mucosa were observed, whereas in 64%, definite macroscopic mucosal inflammation was observed. Inflammation of the respiratory mucosa was associated with a significantly higher percentage of neutrophils in the BALF: median (interquartile range) 48 (14-82)% compared with 7 (0-16)% (p<0.025). A positive BALF culture was found in 62% of the infants with mucosal inflammation compared with 25% in the group without inflammation (p<0.016). 56% of the BALF samples were positive for bacterial culture. In children with persistent respiratory symptoms, nearly half have anatomical anomalies of the central airways. In 62% of the children with mucosal inflammation, a positive BAL culture and a significantly higher percentage of BALF neutrophils were detected.

Recommended indications for the administration of polyclonal immunoglobulin preparations.

The following recommendations, which aim at standardising and rationalising the clinical indications for administering polyclonal immunoglobulins in Belgium, were drawn up by a working group of the Superior Health Council. To this end, the Superior Health Council organised an expert meeting devoted to"Guidelines for the use of immunoglobulins". The experts discussed the indications for immunoglobulin use, the'ideal'immunoglobulin preparation, its mechanisms of action, the practical issues involved in administering immunoglobulins and their potential side effects. The recommendations formulated by the experts were validated by the Superior Health Council working group with the purpose of harmonising immunoglobulin use in Belgium

A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian Susceptibility to Mycobacterial Diseases in European descendants.

Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany; 1 from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12Rbeta1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12Rbeta1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established.

Epidemiology of Pseudomonas aeruginosa in a cystic fibrosis rehabilitation centre.

Pseudomonas aeruginosa is the leading pathogen in cystic fibrosis (CF) lungs. Since there is great concern about clonal spread in CF centres, this study examined the P. aeruginosa genotypes of colonised residents of a CF rehabilitation centre. The isolates from the sputum of 76 P. aeruginosa-colonised patients were genotyped by fluorescent amplified fragment length polymorphism on arrival and departure. A total of 71 different P. aeruginosa genotypes were identified from 749 isolates. Forty-nine patients had one genotype, 20 had two genotypes and seven had three. Forty-four patients had one or more genotypes in common with other patients (i.e. cluster types). Thirty-two patients were colonised by a single genotype not shared by any other patient. Thirty-eight of the 44 patients with a cluster type already carried their cluster type strain(s) on arrival. Patient-to-patient transmission could not be excluded for eight patients. For five of these, this infection was transient. None of the environmental P. aeruginosa isolates had a genotype similar to the patients' genotypes. In summary, most patients were colonised by only one or two P. aeruginosa genotypes and the risk of persistent patient-to-patient transmission was low during the study period (4%). Most patients with a cluster-type strain carried this strain on arrival, indicating that transmission could have happened in the past. No environmental contamination could be established.

Asphyxiating tracheal bronchogenic cyst.

We report on a 7-month old infant with severe respiratory distress secondary to a paratracheal bronchogenic cyst. Respiratory relief was achieved by transtracheal puncture of the cyst. Surgical removal of the cyst was performed 1 week later because of radiological evidence of reaccumulation of fluid.

Factors influencing long term persistence of sinus rhythm after a first electrical cardioversion for atrial fibrillation.

It is conventionally thought that electrical cardioversion in patients with atrial fibrillation (AF) of longstanding duration or with a large left atrial diameter, only seldom results in long term success. Recurrence is common, although antiarrhythmic drugs often effectively decrease the number and duration of recurrent AF episodes. We analysed clinical, functional and pharmacological variables which could possibly influence the long term outcome after a first electrical cardioversion for AF in a retrospective study on 85 patients. Univariate and multivariate analysis was used to identify factors predicting maintenance of sinus rhythm at 100 days, and absence of recurrence during the entire follow-up. In univariate analysis, the only significant predictor for maintenance of sinus rhythm at 100 days was the duration of the preceding AF episode. Multivariate analysis with persistence of sinus rhythm at 100 days as endpoint confirmed this as a prognostic factor (p < 0.03), but sotalol treatment also contributed to maintenance of sinus rhythm (p < 0.05). When considering the entire observation period, class III antiarrhythmic drugs, i.e. sotalol and amiodarone, were useful in preventing recurrence (p < 0.01 and < 0.02). High age (above 75 years) was a predictor of recurrence. In conclusion, class III antiarrhythmic drugs, the duration of atrial fibrillation and high age were the most important determinants of long term outcome, while echocardiographic parameters and the presence of heart disease played no role.

Changes in the QT interval and its adaptation to rate, assessed with continuous electrocardiographic recordings in patients with ventricular fibrillation, as compared to normal individuals without arrhythmias.

Various QT interval variables and heart rate variability parameters were studied in six patients with ventricular fibrillation but without heart disease and compared with findings in 21 normal persons. QT and QT dispersion (QTd) were measured from conventional 12 lead ECGs: for dynamic QT analysis, QT intervals were automatically measured to the end of the T wave (QTe) on a 24 h ECG recording. The adaptation of the QT interval to changes in heart rate was expressed as the slope of the linear regression lines relating QTc to the RR interval (Sc). The complete 24 h ECG recording and four 6 h segments were studied (morning, day, evening, and night). Ventricular fibrillation patients had slightly prolonged QTmax intervals on the 12 lead ECG, QT dispersion was longer in ventricular fibrillation patients than in normal persons (88 +/- 29 ms vs 59 +/- 26 ms. P < 0.05), and on the 24 h ECG recording, normal persons and ventricular fibrillation patients had a comparable RR. In addition, parameters for long-term (SD, standard deviation of normal RR intervals) and short-term (RMSSD, the root-mean-square successive differences of normal RR intervals heart rate variability were not different. Automatic measurement of the QT interval and the QTc/RR slopes was possible over 24 h and in the 6 h intervals in a large majority of patients (25/27 and 88/108 readings). The mean 24 h QT and the mean 6 h QT interval were comparable in normal subjects and ventricular fibrillation patients except for the day segment. The 24 h Se was significantly lower in ventricular fibrillation patients, compared to normal individuals. Furthermore, Se in the morning and night segment was also significantly lower in ventricular fibrillation patients (both P < 0.05). In conclusion, patients with ventricular fibrillation but without underlying structural heart disease have normal heart rate variability parameters. However, abnormal repolarization behaviour, characterized by an increased QTd and a depressed adaptation of QT to variations in RR (especially during the night and the morning), is present. These findings may help to understand and treat arrhythmias in this patient group.