Intralymphatic immunotherapy with birch and grass pollen extracts. A randomized double-blind placebo-controlled clinical trial.

INTRODUCTION: There is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis. METHODS: Thirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALK-Abelló) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA. RESULTS: There were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-γ levels increased only in the actively treated group. CONCLUSION: In this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen.

INTRODUCTION: There is a need for a fast, efficient and safe way to induce tolerance in patients with severe allergic rhinitis. Intralymphatic immune therapy has been shown to be effective. METHODS: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analysed by flow cytometry and Luminex. RESULTS: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment with one or two allergens. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased 3 years after treatment. CONCLUSIONS: Intralymphatic immunotherapy with one or two allergens in patients with grass and birch pollen allergy was safe, effective and may be associated with bystander immune modulatory responses. CLINICAL TRIAL REGISTRATION: EudraCT (2013-004726-28).

Fatigue Is Common in Immunoglobulin G Subclass Deficiency and Correlates With Inflammatory Response and Need for Immunoglobulin Replacement Therapy.

Purpose: Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT. Method: Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion. Results: QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1. Conclusion: Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.

Correction to: A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases.

An amendment to this paper has been published and can be accessed via the original article.

A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases.

BACKGROUND: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. METHODS: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. RESULTS: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. CONCLUSIONS: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.

Fcγ-receptor polymorphisms associated with clinical symptoms in patients with immunoglobulin G subclass deficiency.

BACKGROUND: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some FcγR polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the FcγR-profile differs between individuals with IgGsd and a control population. METHODS: Single nucleotide polymorphisms (SNPs) of FcγRIIa, FcγRIIIa and FcγRIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing. RESULTS: In the IgGsd-group, homozygous frequency for FcγRIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical FcγRIIc-ORF (p = .03) and classical FcγRIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding FcγRIIIa. CONCLUSION: The gene for classical FcγRIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical FcγRIIc-ORF as well as low-binding capacity receptor FcγRIIa-R/R131 were more frequent. Further studies on the FcγR polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

Discovering aspects of health-experiences of a web-based health diary among adults with primary immunodeficiency.

AIM: Advances in technology generate new opportunities to develop e-health tools to help individuals in self-management by assessing symptoms of illness and its relation to treatments. Self-management is central when living with primary immunodeficiency diseases. The aim was to explore the experiences of people living with primary immunodeficiency, who used a pilot version of the web-based health diary. DESIGN: Explorative design. METHODS: In total, 16 participants (median age 59) attended one of three focus groups. Inductive content analysis was used. RESULTS: The participants could be encouraged to discover aspects of their health by contributing to documentation which could support the health concept. A greater understanding about their own health and communicating with healthcare professionals during encounters was expressed. The web-based health diary is a helpful tool to discover aspects of health that affects the individuals' life situation and assists the self-management of a long-term condition such as immunodeficiency.

Health-related quality of life in relation to disease activity in adults with hereditary angioedema in Sweden.

BACKGROUND: Health-related quality of life (HR-QoL) is impaired in patients with hereditary angioedema (HAE) but has not yet been satisfactorily described. OBJECTIVE: To study HR-QoL in patients with HAE by combining different HR-QoL instruments with disease activity assessment. METHODS: All adults in the Swedish HAE registry were invited to take part in this questionnaire study, which used the generic HR-QoL instruments, EuroQol 5 Dimensions 5 Level (EQ-5D-5L) and the RAND Corporation Short Form 36 (RAND-36), the disease-specific Angioedema Quality of Life instrument (AE-QoL), the recently introduced Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication. RESULTS: Sixty-four of 133 adults (26 men, 38 women) between 18 and 91 years old responded. The most affected HR-QoL dimensions in the EQ-5D-5L were pain/discomfort and anxiety/depression; in the RAND-36, energy/fatigue, general health, pain; and, in the AE-QoL, fears/shame and fatigue/mood. Women had lower HR-QoL in the RAND-36 for general health and energy/fatigue (p < 0.05). Patients who reported any AAS of >0 had significantly impaired HR-QoL. There were significant associations (p < 0.05) between the AAS and EQ-5D-5L, between the AAS and all dimensions of the RAND-36 except physical function, and between the AAS and AE-QoL in all dimensions. Nine of 36 patients who reported sick leave during the previous 4 weeks had significantly impaired HR-QoL in all the instruments (p < 0.05). There was no significant difference in HR-QoL in the patients with and the patients without prophylactic medication, except for the nutrition dimension of the AE-QoL (p < 0.05). CONCLUSION: Comprehensive information is obtained by combining different HR-QoL instruments. Pain, anxiety/depression, and fatigue/mood are important aspects of HAE but the AE-QoL disregards pain. HR-QoL was not significantly affected by prophylaxis. Increased disease activity was associated with impaired HR-QoL, which justifies more active disease management.

[Insect venom allergy ­ the diagnosis can be difficult to make but good treatment is available]. / Insektsgiftallergi - diagnostiken kan vara svår men bra behandling finns.

Bee and wasp stings can cause allergic reactions. Although the local reactions are more frequent, anaphylaxis due to insect stings can be potentially fatal. Rapid recognition of anaphylaxis is therefore critical and reactions should immediately be treated with i.m. adrenaline. Patients having experienced anaphylaxis should be referred to an allergist for diagnostic evaluation and possible venom-immunotherapy (VIT). The clinical history is essential in diagnosis of venom allergy as the test results are not always reliable. Diagnostic testing with venom components might be beneficial in appropriate patients. The analysis of serum tryptase from the acute episode can be crucial. Mastocytosis is associated in about 8 percent of patients with severe anaphylaxis from insect stings and should be considered in the differential diagnosis. VIT is indicated for patients with a history of anaphylaxis and is effective in preventing future anaphylaxis from Hymenoptera stings.

Swedish children with hereditary angioedema report good overall health and quality of life despite symptoms.

AIM: Few studies have been published on children with hereditary angioedema (HAE), an autosomal dominant disease caused by mutations on chromosome 11. This study explored various aspects of the disease in the Swedish paediatric population. METHODS: A retrospective questionnaire was sent to all 36 Swedish children known to have HAE, and a physician carried out follow-up telephone interviews. RESULTS: Most of the questionnaires were completed by the parents of 31 (86%) children with HAE, with or without their input, at a median age of nine years (range 1-17), and the physician also interviewed 29. HAE symptoms were experienced by 23 children, including abdominal attacks (96%), skin swelling (78%) and swelling in the mouth and/or upper airways (52%). Psychological stress was the most common trigger for abdominal attacks and trauma and sports triggered skin swelling. The majority (n = 19) had access to complement-1 esterase inhibitor concentrate at home. Current health and quality of life were generally rated as good, independent of whether the child had experienced HAE symptoms or not. CONCLUSION: Most children with HAE had experienced abdominal attacks and skin swelling, but their overall health and quality of life were generally perceived to be good.

Potential Involvement of Type I Interferon Signaling in Immunotherapy in Seasonal Allergic Rhinitis.

Specific immunotherapy (SIT) reverses the symptoms of seasonal allergic rhinitis (SAR) in most patients. Recent studies report type I interferons shifting the balance between type I T helper cell (Th1) and type II T helper cells (Th2) towards Th2 dominance by inhibiting the differentiation of naive T cells into Th1 cells. As SIT is thought to cause a shift towards Th1 dominance, we hypothesized that SIT would alter interferon type I signaling. To test this, allergen and diluent challenged CD4+ T cells from healthy controls and patients from different time points were analyzed. The initial experiments focused on signature genes of the pathway and found complex changes following immunotherapy, which were consistent with our hypothesis. As interferon signaling involves multiple genes, expression profiling studies were performed, showing altered expression of the pathway. These findings require validation in a larger group of patients in further studies.

Hereditary Angioedema in Swedish Adults: Report From the National Cohort.

Hereditary angioedema (HAE) is rare, disabling and sometimes life-threatening. The aim of this study is to describe its prevalence, symptomatology and treatment in Sweden. A total of 146 patients were identified; 110 adults and 36 children with HAE type I (n = 136) or II (n = 10), giving a minimal HAE prevalence of 1.54/100,000. All patients received a written questionnaire followed by a structured telephone interview. This report focuses on the 102 adults who responded. Females reported 19 attacks in the previous year vs. 9 for males (p < 0.01), and females reported 10 days of sick leave vs. 4 days for males (p < 0.05). For all treated acute attacks, plasma-derived C1-inhibitor concentrate (pdC1INH) (used in 27% of patients) had a good effect. For maintenance treatment, 43% used attenuated androgens and 8% used pdC1INH, which reduced their attack rate by more than 50%. In conclusion, the minimal HAE prevalence in Sweden was 1.54/100,000. HAE affected females more severely. Attenuated androgens and pdC1INH had a good effect on preventing attacks.

A validated gene regulatory network and GWAS identifies early regulators of T cell-associated diseases.

Early regulators of disease may increase understanding of disease mechanisms and serve as markers for presymptomatic diagnosis and treatment. However, early regulators are difficult to identify because patients generally present after they are symptomatic. We hypothesized that early regulators of T cell-associated diseases could be found by identifying upstream transcription factors (TFs) in T cell differentiation and by prioritizing hub TFs that were enriched for disease-associated polymorphisms. A gene regulatory network (GRN) was constructed by time series profiling of the transcriptomes and methylomes of human CD4(+) T cells during in vitro differentiation into four helper T cell lineages, in combination with sequence-based TF binding predictions. The TFs GATA3, MAF, and MYB were identified as early regulators and validated by ChIP-seq (chromatin immunoprecipitation sequencing) and small interfering RNA knockdowns. Differential mRNA expression of the TFs and their targets in T cell-associated diseases supports their clinical relevance. To directly test if the TFs were altered early in disease, T cells from patients with two T cell-mediated diseases, multiple sclerosis and seasonal allergic rhinitis, were analyzed. Strikingly, the TFs were differentially expressed during asymptomatic stages of both diseases, whereas their targets showed altered expression during symptomatic stages. This analytical strategy to identify early regulators of disease by combining GRNs with genome-wide association studies may be generally applicable for functional and clinical studies of early disease development.

Does the frequency of respiratory tract infections help to identify humoral immunodeficiencies in a primary health-care cohort?

BACKGROUND: Primary immune deficiency (PID) due to humoral defects is associated with recurrent respiratory tract infections (RTIs). Reliable clinical warning signs of PID would facilitate early diagnosis and thereby reduce long-term complications. The aim of the present study was to evaluate the accuracy of the warning sign, 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years,' for detecting PID among adults in a primary health-care setting. METHODS: Fifty-three cases with 'four or more antibiotic-treated RTIs annually for 3 or more consecutive years' were selected from a Swedish primary health-care registry of RTIs. In addition, 66 age- and sex-matched controls were selected having a maximum of one antibiotic-treated RTI during the period covered by the study. Levels of immunoglobulin (Ig) IgG, IgA, IgM, IgG subclasses, and IgG antibodies against Haemophilus influenzae and Streptococcus pneumoniae as well as the inflammatory markers, C-reactive protein, interleukin (IL)-6 and IL-8 were determined. RESULTS: IgG subclass deficiencies (IgGsd) were found in 5/53 (9.4%) of the cases and in 7/66 (10.6%) controls. The most frequent deficiency was IgG3sd and this was found in three participants in the case group and seven in the control group. The mean level of IgG3 was lower in the control group (p = 0.02). The mean level of IL-8 was lower in the case group (p = 0.02). CONCLUSION: The results show that physicians working in primary health care cannot solely rely on the frequency of antibiotic-treated RTIs as a warning sign for the detection of common humoral immune deficiencies.

Quantifying the burden of disease and perceived health state in patients with hereditary angioedema in Sweden.

Hereditary angioedema (HAE) due to C1 inhibitor deficiency is a rare disease characterized by attacks of edema, known to impact quality of life (QoL). This study investigates the burden of HAE in Swedish patients, both children and adults. We used a retrospective registry study of Swedish patients with HAE, captured by the Sweha-Reg census. Data were collected using a paper-based survey. Patients completed EuroQoL 5 Dimensions 5 Levels (EQ5D-5L) questionnaires for both the attack-free state (EQ5D today), and the last HAE attack (EQ5D attack). Questions related to patient's age and sex and other variables, such as attack location and severity, were included to better understand the burden of HAE. EQ5D-5L values were estimated for the two HAE disease states. Patient-reported sick leave was also analyzed. A total of 103 responses were analyzed from 139 surveys (74% response rate). One hundred one reported an EQ5D today score (mean, 0.825) and 78 reported an EQ5D attack score (mean, 0.512) with significant differences between the two states (p < 0.0001). This difference was observed for both mild (p < 0.05), moderate (p < 0.0001), and severe attacks (p < 0.0001). Attack frequency had a negative effect on EQ5D today. Patients with >30 attacks a year had a significantly lower EQ5D today score than those with less frequent attacks. Of 74 participants, 33 (44.6%) had been absent from work or school during the latest attack and, of those with a severe attack, 81% had been absent. HAE has a significant impact on QoL both during and between attacks and on absenteeism during attacks.

Comprehensive profiling of peripheral immune cells and subsets in patients with intermittent allergic rhinitis compared to healthy controls and after treatment with glucocorticoids.

Intermittent allergic rhinitis (IAR) is a common allergic disease, which is associated with local infiltration of T cells, eosinophils, and basophils. However, changes of circulating inflammatory cells may reflect local and systemic allergic inflammation and potentially, also the response to treatment with glucocorticoids (GCs). In this study, we comprehensively profiled peripheral blood immune cells and subsets from 12 patients with IAR during the birch pollen season before and after GC treatment and nine healthy controls by flow cytometry. Orthogonal partial least squares discriminant analysis (OPLS-DA) identified that peripheral immune cells and subsets markedly separated symptomatic patients and controls. Eosinophils, basophils, and Th2 cells contributed most to the separation. However, there was no good separation between patients before and after GC treatment. Local allergic inflammation in the nasal mucosa is associated with increased circulating Th2 cells, eosinophils, and basophils. Local GC treatment has limited effects on circulating immune cells.

Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

HAE international home therapy consensus document.

Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks ('self or assisted administration') and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.