Adequate immune responses to vaccines after chemotherapy for leukaemia diagnosed in childhood.

AIM: The survival rate after treatment for childhood leukaemia has greatly improved, but could result in protracted immune deficiency. This study examined the immune status of children after chemotherapy and evaluated their responses to immunisation. METHODS: Subjects who had completed their treatment for acute lymphoblastic leukaemia at The Children's Hospital Reykjavík, Iceland, during 2011-2020 had blood drawn and were then immunised for influenza in October 2021. Blood was drawn again 4 weeks later and their humoral and cellular responses were measured with a haemagglutination inhibition assay and lymphocyte stimulation test. Antibodies to other immunisations were also evaluated. RESULTS: We studied 18 patients (10 male) who had completed their treatment at 3.7-20.3 years of age (mean 9.1), 11-84 months (mean 36.9) before enrolment. Conventional immunological evaluation did not reveal notable abnormalities. The responses to several childhood vaccinations, including the pneumococcal conjugate vaccination, were adequate in most patients. Humoral responses to the influenza vaccine confirmed adequate reactions in all but one patient. Considerable variations were observed in the lymphocyte stimulations tests. CONCLUSION: Most patients reacted adequately to immunisation, especially against annual influenza and Streptococcus pneumoniae, reiterating the usefulness of vaccinations. The most appropriate timing for vaccination after treatment still needs to be determined.

Normal neonatal TREC and KREC levels in early onset juvenile idiopathic arthritis.

OBJECTIVE: Dysregulated central tolerance predisposes to autoimmune diseases. Reduced thymic output as well as compromised central B cell tolerance checkpoints have been proposed in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate neonatal levels of T-cell receptor excision circles (TRECs) and kappa-deleting element excision circles (KRECs), as markers of T- and B-cell output at birth, in patients with early onset JIA. METHODS: TRECs and KRECs were quantitated by multiplex qPCR from dried blood spots (DBS), collected 2-5 days after birth, in 156 children with early onset JIA and in 312 matched controls. RESULTS: When analysed from neonatal dried blood spots, the median TREC level was 78 (IQR 55-113) in JIA cases and 88 (IQR 57-117) copies/well in controls. The median KREC level was 51 (IQR 35-69) and 53 (IQR 35-74) copies/well, in JIA cases and controls, respectively. Stratification by sex and age at disease onset did not reveal any difference in the levels of TRECs and KRECs. CONCLUSION: T- and B-cell output at birth, as measured by TREC and KREC levels in neonatal dried blood spots, does not differ in children with early onset JIA compared to controls.

Longitudinal asthma and allergy study showed that childhood symptoms frequently persisted into adulthood.

AIMS: The prevalence of allergic diseases is high and increasing in many countries. The aim of this study was to describe the prevalence of allergic diseases and changes in clinical expression in a birth cohort followed for three decades. METHODS: We followed Icelandic citizens born in 1987 for allergic diseases when they were 2, 4, 8, 15, 21 and 29 years of age. These were diagnosed using standardised questionnaires, physical examinations and skin-prick tests. RESULTS: Just under half (46%) of the 112 who took part at 29 years of age had one or more allergic diseases, usually mild. Eczema was confirmed in 14% and was highest at the age of 2 years (31%). The prevalence of asthma was 23% and was highest at the age of 4 years (28%). Allergic rhinitis affected 30% at 29 years of age but was not found before the age of 2 years. In addition, 34% had a positive skin-prick test at 29 years of age. CONCLUSION: The results show that 46% of Icelandic adults diagnosed with allergic diseases during childhood still had symptoms at the age of 29, usually mild, developing from eczema in infancy to asthma and allergic rhinitis in adulthood.

Keratinocytes secrete multiple inflammatory and immune biomarkers, which are regulated by LL-37, in a psoriasis mimicking microenvironment.

Psoriasis is an autoimmune disease driven by a Th17 response linked to the antimicrobial peptide (AMP) LL-37 that has been connected to the induction and chronicity of psoriasis. We show that keratinocytes secrete various immune biomarkers with a direct link to psoriasis immunopathogenesis. Under pro-inflammatory microenvironmental conditions, LL-37 was found to regulate keratinocyte secretion of various immune biomarkers (eg C-X-C motif chemokine ligand (CXCL)8 and interleukin (IL)-1ß) and alter extracellular signal-regulated kinase (ERK)1/2 signalling. However, during neutral conditions LL-37 induced a different pattern of keratinocyte immune biomarker secretion (eg vascular endothelial growth factor, CXCL8 and IL-6). Thus, an interesting pattern emerged regarding the immunomodulatory effects of LL-37 on keratinocytes; in general, expression of immune biomarkers that were upregulated in a Th1-like microenvironment was downregulated in the presence of LL-37. In contrast, LL-37 reinforced the Th17 response. In active psoriatic skin lesions, LL-37 expression was found to be significantly upregulated, which was also evident from the unique diffuse epidermic expression pattern not found in healthy skin. Finally, successful phototherapy of psoriasis patients converted this LL-37 inflammatory psoriatic skin pattern into a more localized basal layer expression as found in healthy controls. Thus, these findings demonstrate that LL-37 has a significant role in skin immune homeostasis and that its interplay with keratinocytes may have a more direct role in the immunopathogenesis of psoriasis than previously thought.

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (ß = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

[First case of COVID-19 treated with tocilizumab in Iceland]. / Fyrsta meðferð með tocilizumab við COVID-19 hérlendis - sjúkratilfelli

A gentleman in his early fifties became ill with flu-like symptoms after vacationing abroad and was diagnosed with COVID-19 after returning to Iceland. A few days later he was admitted to the University Hospital, Landspitali, due to worsening respiratory symptoms and severe fatigue. A computed tomography scan of lthe lungs showed diffuse bilateral consolidations and ground glass changes. He developed respiratory failure and was transferred to the intensive care unit where he received further treatment, including tocilizumab (IL-6 receptor inhibitor). He subsequently showed clinical improvement and did not require endotracheal intubation.

Ara h 1 and Ara h 6 Sensitization Causes Clinical Peanut Allergy in Ara h 2-Negative Individuals.

BACKGROUND: Of the major peanut allergens, sensitivity to Ara h 2 has the highest prediction for clinical allergy. In this study, we evaluated sensitization to peanut components in Iceland and related Ara h 2-negative sensitization to clinical allergy. METHODS: Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Bet v 1 IgEs were measured (ImmunoCAP) in 220 peanut IgE (Pn-IgE)-positive serum samples. Ara h 2 IgE-negative individuals were invited to an open peanut challenge and evaluated for Ara h 6 and 9 sensitization (ISAC microarray). RESULTS: The Ara h 2 IgE-negative group (52.3%, 115/220) was older (p = 0.04) and more likely to have a history of pollen allergy than the Ara h 2-positive group (p < 0.001). Of the Ara h 2-negative participants, 24.3% were already consuming peanuts and 38.3% were unavailable. Of the 43 who underwent an open peanut challenge, 79% were negative, 14% were positive, and 7% were inconclusive. Those who reacted to peanuts had a higher Ara h 1 IgE than that of the tolerant participants, and 3 were positive to Ara h 6 IgE, and 2 of those subjects were monosensitized. Ara h 8 may have caused a positive reaction, while Ara h 9 did not. CONCLUSIONS: Half of the peanut-sensitized individuals in Iceland were not sensitized to the major allergen Ara h 2. Ara h 1, Ara h 3, and Ara h 6 sensitizations resulted in a positive open peanut challenge and they are therefore clinically important for individuals with a peanut allergy in Iceland.

Frequency and distribution of FCN2 and FCN3 functional variants among MBL2 genotypes.

The six types of pattern recognition molecules (PRMs) that initiate complement via the lectin pathway (LP) comprise collectins and ficolins. The importance of having various PRMs to initiate the LP is currently unclear. Mannan-binding lectin (MBL) is a collectin member of the LP PRMs. MBL deficiency is common with mild clinical consequence. Thus, the lack of MBL may be compensated for by the other PRMs. We hypothesized that variants FCN2 + 6424 and FCN3 + 1637delC that cause gene-dose-dependent reduction in ficolin-2 and ficolin-3 levels, respectively, may be rare in MBL-deficient individuals due to the importance of compensation within the LP. The aim of this study was to investigate the distribution and frequency of these variants among MBL2 genotypes in healthy subjects. The allele frequency of FCN2 + 6424 and FCN3 + 1637delC was 0.099 and 0.015, respectively, in the cohort (n = 498). The frequency of FCN2 + 6424 tended to be lower among MBL-deficient subjects (n = 53) than among MBL-sufficient subjects (n = 445) (0.047 versus 0.106, P = 0.057). In addition, individuals who were homozygous for FCN2 + 6424 were sufficient MBL producers. The frequency of FCN3 + 1637delC did not differ between the groups. The frequency of FCN2 + 6424 was similar in FCN3 + 1637delC carriers (n = 15) versus wild type (n = 498). Furthermore, subjects that were heterozygote carriers of both FCN2 + 6424 and FCN3 + 1637delC were sufficient MBL producers. In conclusion, FCN2 + 6424 carriers with MBL deficiency tend to be rare among healthy individuals. MBL-deficient individuals with additional LP PRM defects may be at risk to morbidity.

Psoriasis treatment: faster and long-standing results after bathing in geothermal seawater. A randomized trial of three UVB phototherapy regimens.

BACKGROUND: The combination of seawater baths and narrowband ultraviolet B (NB-UVB) is a known treatment for psoriasis. This study evaluates two treatment regimens that combine bathing in geothermal seawater and NB-UVB therapy in comparison with NB-UVB monotherapy. METHODS: Sixty-eight psoriasis patients were randomly assigned to outpatient bathing in geothermal seawater combined with NB-UVB therapy three times a week, intensive daily treatment involving bathing in geothermal seawater combined with NB-UVB therapy, or NB-UVB therapy alone three times a week; treatment period was 6 weeks. Disease severity [Psoriasis Area Severity Index (PASI) and Lattice System Physician's Global Assessment scores], quality of life (Dermatology Life Quality Index) and histological changes were evaluated before, during and after treatment. The primary end point was the proportion of patients who achieved PASI 75 at 6 weeks. RESULTS: At 6 weeks, the percentage of patients who achieved PASI 75 and PASI 90 was significantly greater for both regimens, bathing in geothermal seawater three times a week (68.1% and 18.2%, respectively) and intensive treatment with geothermal seawater (73.1% and 42.3%, respectively) than for NB-UVB monotherapy (16.7% and 0%, respectively) (P < 0.05 in all comparisons). Clinical improvement was paralleled by improvement in quality of life and histological score and a reduction in NB-UVB doses. CONCLUSION: Bathing in geothermal seawater combined with NB-UVB therapy in psoriasis induces faster clinical and histological improvement, produces longer remission time and permits lower NB-UVB doses than UVB therapy alone.

Obesity in adolescents does not influence early immune responses to influenza vaccination.

BACKGROUND: Obesity has been linked to reduced vaccine responses against tetanus, hepatitis B and influenza. Data on the influence of paediatric obesity on influenza vaccine response is still lacking and this study aims to fill the gap. METHODS: A total of 30 children with obesity and 30 children with normal weight, aged 12-18 years, were recruited. Participants were vaccinated with a tetravalent influenza vaccine. Blood was collected prior to the vaccination and again four weeks later. The humoral response was assessed with haemagglutinin inhibition assay. The cellular response was assessed with T-cell stimulation assays measuring TNF-α, IFN-γ, IL-2 and IL-13. RESULTS: Of the 29/30 from the study group and 30/30 from the control group finished both visits. Seroconversion occurred for > 90% of participants in both groups for the A/H1N1, A/H3N2 and B/Victoria strains, but the B/Yamagata strain had lower seroconversion rates (93% in the study group and 80% in the control group). 97-100% of participants from both groups had adequate serological responses following vaccination. Cellular responses were similar between the two groups post-vaccination. CONCLUSIONS: Early humoral and cellular immune responses to influenza vaccinations are similar among adolescents with obesity and normal weight.

A long-term follow-up of allergic diseases in Iceland.

INTRODUCTION: Allergic disorders are an increasing health problem in many countries, in particular among children. We have evaluated the prevalence and manifestations of allergy in a cohort of young Icelanders for more than two decades. Variations in the epidemiology and clinical expression of allergy in different communities may help to identify etiological factors contributing to these disorders. METHODS: A cohort of 179 children has been monitored for allergic manifestations for two decades, at the ages of two, four, eight, and 15 years, and most recently at the age of 21 years involving 120 of the participants. RESULTS: Cumulative prevalences of 40%, 45%, and 29% have been observed, respectively, for rhinoconjunctivitis, eczema, and asthma during the study period. None had developed rhinoconjunctivitis at the age of about 2 years, but the point prevalence gradually increased to 33% at the age of 21 years. Conversely, the prevalence of eczema was 31% at the age of 2 years, but gradually declined to 8% at the age of 21 years. The prevalence of asthma peaked at 28% at the age of 4 years, but declined thereafter and has remained stable at about 13% from the age of eight to 21 years. DISCUSSION: The prevalence of allergic diseases is high in Iceland among children and young individuals. Asthma and atopic eczema are very common in childhood, but decreases with age while the prevalence of rhinoconjunctivitis increases markedly. The very high and increasing prevalence of rhinoconjunctivitis among 15- to 21-year-old individuals is noteworthy.

[Lyme disease in Iceland - Epidemiology from 2011 to 2015].

INTRODUCTION: Lyme disease is caused by an infection with Borrelia burgdorferi sensu latu (B. burgdorferi sl.) which is carried by Ixodes ticks. The disease has not been considered to be endemic in Iceland and no cases of Icelandic origin have been published. The epidemiology of Lyme disease in Iceland has never been studied. The objective of this study was to provide basic epidemiological information about Lyme disease in Iceland. MATERIAL AND METHODS: Included in the study were all pa--tients who had a measurement of serum antibodies against B. burgdorferi sl. or were diagnosed with Lyme disease (ICD-10, A69.2) at Landspítali University Hospital in Iceland from 2011-2015. Clinical data regarding these patients was retrospectively collected from medical records and the database of the Department of clinical microbiology at Landspítali University Hospital. RESULTS: 501 patient had a measurement of serum antibodies against B. burgdorferi sl. and 11 patients were clinically diag-nosed with Lyme disease during the study period. 33 patients fulfilled criteria for a confirmed diagnosis of Lyme disease. 32 (97%) patients had erythema migrans and one (3%) patient had neuroborreliosis. An average of 6.6 cases were diagnosed a year (two cases per 100,000 persons/year). All cases originated abroad. CONCLUSIONS: Lyme disease is rare in Iceland. On average around 6 to 7 cases are diagnosed every year, primarily localised infec-tions presenting as erythema migrans. None of the cases had a definitive Icelandic origin and the yearly number of cases has not been increasing.

Corrigendum to "A Clinical Decision Support System for the Diagnosis, Fracture Risks and Treatment of Osteoporosis".

[This corrects the article DOI: 10.1155/2015/189769.].

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 × 10-7, 4.3 × 10-9) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

A clinical decision support system for the diagnosis, fracture risks and treatment of osteoporosis.

Expanding medical knowledge increases the potential risk of medical errors in clinical practice. We present, OPAD, a clinical decision support system in the field of the medical care of osteoporosis. We utilize clinical information from international guidelines and experts in the field of osteoporosis. Physicians are provided with user interface to insert standard patient data, from which OPAD provides instant diagnostic comments, 10-year risk of fragility fracture, treatment options for the given case, and when to offer a follow-up DXA-evaluation. Thus, the medical decision making is standardized according to the best expert knowledge at any given time. OPAD was evaluated in a set of 308 randomly selected individuals. OPAD's ten-year fracture risk computation is nearly identical to FRAX (r = 0.988). In 58% of cases OPAD recommended DXA evaluation at the present time. Following a DXA measurement in all individuals, 71% of those that were recommended to have DXA at the present time received recommendation for further investigation or specific treatment by the OPAD. In only 5.9% of individuals in which DXA was not recommended, the result of the BMD measurement changed the recommendations given by OPAD.

[Inherited deficiency of the initiator molecules of the lectin-complement pathway]. / Arfgengur skortur í raesisameindum lektínferils komplímentvirkjunar.

The complement system is an important immune system. Its activation results in membranolytic elimination of microbes and opsonization. The classical, alternative and lectin pathways (LP) activate complement. Either mannan-binding lectin (MBL), ficolin-1, ficolin-2 or ficolin-3 initiate the LP through associated serine protease (MASP-2) after binding to microorganisms'surface carbohydrate patterns. Genetic polymorphisms behind MBL deficiency are rather common. Numerous studies indicate that MBL deficiency is a risk factor for invasive and recurrent infections, especially when other immune systems are immature, deficient or compromised. Research in ficolins is limited but last year ficolin-3 deficiency was described. This review focuses on these recently WHO defined immunodeficiencies.

[Allergen immunotherapy in Iceland 1977-2006]. / Arangur afnaemismedferdar á Islandi 1977-2006.

INTRODUCTION: The prevelance of allery and asthma has increased rapidly over the last 3 decades and is now estimated that 25-30% of population in Western industrialized countries show symptoms of allergy or asthma. The aim of this study was to reveal the success of allergen immunotherapy (AIT) in Landspitali from 1977-2006. MATERIAL AND METHODS: During the study period a total number of 289 individuals underwent immunotherapy in outpatient clinic of allergy and asthma in Landspítali. A total number of 169 individuals were contacted, of whom 128 (76%) accepted to participate in the study. The evaluation was based on medical records, standardized questionnaire and skin-prick tests. RESULTS: Patients were evaluated on the average of 20 years after finishing treatment. 118 (92%) patients were desensitized to grass pollen, to birch pollen (30%), cat dander (30%) and dust mite (28%). At the time of the study 67% reported to be asymptomatic or with greatly improved allergy symptoms. Males had better response to AIT than women (p=0.04). Participants with positive family history of allergy and/or asthma in first degree relatives also reported better response to AIT (p=0.02). Furthermore, AIT to grass pollen and dust mite seemed to be more effective than AIT to cat dander and birch (p=0.04). AIT was also shown to reduce asthma. CONCLUSION: AIT for 3-5 years provides significant beneficial effect of allergy and asthma symptoms in patients who undergo such therapy. Finally, it s findings support the notion that AIT may reduce the risk of new allergic manifestations.