Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Persisting chemosensory dysfunction in COVID-19 - a cross-sectional population-based survey.

BACKGROUND: Chemosensory dysfunction (CD) has been reported as a common symptom of SARS-CoV-2 infection, but it is not well understood whether and for how long changes of smell, taste and chemesthesis persist in infected individuals. METHODOLOGY: Unselected adult residents of the German federal state of Schleswig-Holstein with Polymerase Chain Reaction (PCR)-test-confirmed SARS-CoV-2 infection were invited to participate in this large cross-sectional study. Data on the medical history and subjective chemosensory function of participants were obtained through questionnaires and visual analogue scales (VAS). Olfactory function (OF) was objectified with the Sniffin Sticks test (SST), including threshold (T), discrimination (D) and identification (I) test as well as summarized TDI score, and compared to that in healthy controls. Gustatory function (GF) was evaluated with the suprathreshold taste strips (TS) test, and trigeminal function was tested with an ampoule containing ammonia. RESULTS: Between November 2020 and June 2021, 667 infected individuals (mean age: 48.2 years) were examined 9.1 months, on average, after positive PCR testing. Of these, 45.6% had persisting subjective olfactory dysfunction (OD), 36.2% had subjective gustatory dysfunction (GD). Tested OD, tested GD and impaired trigeminal function were observed in 34.6%, 7.3% and 1.8% of participants, respectively. The mean TDI score of participants was significantly lower compared to healthy subjects. Significant associations were observed between subjective OD and GD, and between tested OD and GD. CONCLUSION: Nine months after SARS-CoV-2 infection, OD prevalence is significantly increased among infected members of the general population. Therefore, OD should be included in the list of symptoms collectively defining Long-COVID.

Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP).

PURPOSE: Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. METHODS: The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. RESULTS: As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once. CONCLUSION: NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00023742).

Occurrence and determinants of parental psychosocial stress and mental health disorders in parents and their children in early childhood: rationale, objectives, and design of the population-based SKKIPPI cohort study.

PURPOSE: The postnatal period is a vulnerable time for parents and children but epidemiological and health care utilisation data for Germany on parental mental health during early childhood is scarce. This protocol describes the rationale, aim and study design of a population-based cohort study to assess the occurrence and determinants of psychosocial stress and mental health disorders, as well as the use and cost of health care and social services in early childhood. METHODS: As part of the collaborative SKKIPPI project, we will contact a random sample of 30,000 infants listed in the residents' registration offices of three German towns and we expect to include 6,000 mother-child pairs. Both parents are invited to fill out an online screening questionnaire. Mothers with indications of psychosocial stress will be interviewed to assess mental health disorders, regulatory problems of their children, as well as health care and social services utilisation, with a follow-up assessment after 6 months. RESULTS: After description of sociodemographic and health data, we will analyse occurrences, patterns, and potential determinants (maternal age, social status, household factors, migration status etc.) of psychosocial stress and mental health disorders in the mothers and their children in early childhood. CONCLUSIONS: Our study will identify potential risk and protective factors for postnatal mental health and health care utilization of psychosocially burdened families. This will help to improve prevention and treatment strategies to strengthen the parent-child relationship, to reduce persisting vulnerability of children, and to improve health care and social services. TRIAL REGISTRATION: The study has been registered in the German Clinical Trial Registry on February 8th 2019 (DRKS-ID: DRKS00016653).

[Cohort studies in child and adolescent psychiatry]. / Kohortenstudien in der Kinder- und Jugendpsychiatrie.

BACKGROUND: Longitudinal cohort studies with early start and life span perspectives are increasingly recognized as being crucial to uncover developmental trajectories as well as risk and resilience factors of psychiatric disorders. OBJECTIVE: The importance of longitudinal studies is presented and the main findings of the Mannheim study of children at risk (MARS), the adolescent brain cognitive development (ABCD), the pediatric and adolescent health survey (Kinder- und Jugendgesundheitssurvey, KiGGS) and the AIMS longitudinal European autism project (LEAP) cohort studies are described. MATERIAL AND METHODS: A literature search was carried out in MEDLINE. RESULTS: The MARS followed participants with psychosocial and organic risks over more than 30 years starting from birth and showed the importance of early risk factors (prenatal period up to early childhood) for neuropsychosocial development. The ABCD cohort study (start 9-10 years old) underlined the developmental significance of early socioemotional and prenatal risks as well as toxin exposure. The KiGGS cohort followed children and adolescents from age 0-17 years up to the ages of 10-28 years. Main findings underline the importance of the socioeconomic status and gender-specific effects with respect to sensitive periods for the onset and trajectories of psychiatric disorders. The AIMS cohort followed patients with and without autism spectrum disorders aged between 6 and 30 years and first results revealed small effects regarding group differences. Further, cohort studies starting prenatally along with deep phenotyping are warranted to uncover the complex etiology of mental disorders. CONCLUSION: Existing cohort studies on early mental development have shown specific focal points. To identify general and specific risk and resilience factors for psychiatric disorders and to model trajectories, there is a need for multimodal integration of data sets.

Efficacy of Parent-Infant-Psychotherapy with mothers with postpartum mental disorder: study protocol of the randomized controlled trial as part of the SKKIPPI project.

BACKGROUND: After the birth of a child, many mothers and fathers experience postpartum mental disorders like depression, anxiety, obsessive-compulsive disorder, stress or other illnesses. This endangers the establishment of a secure attachment between the children and their primary caregivers. Early problems in parent-child interaction can have adverse long-term effects on the family and the child's well-being. In order to prevent a transgenerational transmission of mental disorders, it is necessary to evaluate psychotherapeutic interventions that target psychologically burdened parents of infants or toddlers. The aim of this trial is to investigate the efficacy of Parent-Infant-Psychotherapy (PIP) for mothers with postpartum mental disorder and their infants (0-12 months). METHODS/DESIGN: In this open, randomized controlled intervention trial 180 mother-infant-dyads will be included and randomly allocated to 12 sessions of PIP or care as usual. The interventions take place either in inpatient adult psychiatric departments or in outpatient settings with home visits. The primary outcome is the change in maternal sensitivity assessed by the Sensitivity subscale of the Emotional Availability Scale (EAS) through videotaped dyadic play-interactions after 6 weeks. Secondary outcomes are maternal psychopathology, stress, parental reflective functioning, infant development and attachment after 6 weeks and 12 months. In addition, maternal attachment (AAI) and reflective functioning (AAI) will be analyzed as potential moderators, and resource usage in the German health system as well as associated costs will be evaluated. DISCUSSION: There is increasing demand for well-controlled studies on psychotherapeutic interventions in the postpartum period that do not only focus on particular risk groups. This randomized controlled trial (RCT) represents one of the first studies to investigate the efficacy of PIP in inpatient psychiatric departments and outpatient care centers in Germany. The results will fill knowledge gaps on the factors contributing to symptom reduction in postpartum mental disorders and improvements in mother-child relationships and help in developing preventive and therapeutic strategies for the fragmented German health care system. TRIAL REGISTRATION: German Register for Clinical Trials, ID: DRKS00016353.

[Empirical health services research in emergency and acute medicine : Preliminary results of concomitant monitoring of patient recruitment and sample quality]. / Empirische Versorgungsforschung in der Notfall- und Akutmedizin : Erste Ergebnisse eines begleitenden Monitorings zur Patientenrekrutierung und Stichprobenqualität.

BACKGROUND: Up until now, research data on the implementation of empirical health services research in emergency departments in Germany are scarce. STUDY AIM: A monitoring instrument applied in a multicenter prospective cohort study in emergency departments (EDs) is described and discussed regarding requirements for the control and supervision of data collection. MATERIALS AND METHODS: Patients with cardiac diseases, respiratory tract infections, and hip fractures were recruited in eight EDs located in a central district of Berlin. Enrolment figures and nonresponder reasons were analyzed through descriptive statistics. Potential sample bias was examined in terms of response rates as well as the distribution of age and sex in the group of participants and nonresponders. Qualitative content analysis was applied to data from routine supervisory and feedback meetings with study nurses. RESULTS: Within the first 8 months of data collection, 61.1% of the aimed 1104 patients were recruited. Most frequently stated nonresponder reasons were the dense work and care processes in EDs (41.9%) and patients' disease burden (24.7%). Moreover, qualitative results revealed problems with identifying potentially eligible participants and difficulties because of missing research infrastructure in study centers. The response rate of 50.7% and approximately equal distribution of age and sex in participants and nonresponders do not indicate sample biases. DISCUSSION: The monitoring instrument has proven to be suited for empirical research in EDs and revealed optimization potential. We recommend using qualitative and quantitative data systematically.

Polymer-based ammonium-limited fed-batch cultivation in shake flasks improves lipid productivity of the microalga Chlorella vulgaris.

The aim of this work was to study ammonium-limited fed-batch conditions in heterotrophic C. vulgaris shake flask cultivations. Therefore, an innovative polymer-based ammonium release technique (polymer beads) was developed. Using these beads in shake flasks, C. vulgaris cultivations resulted in simultaneous growth and lipid accumulation. Lipid productivity was increased by 43% compared to batch cultivations. Furthermore, by online monitoring of the metabolic activity (RAMOS technique), unlimited growth and depletion of nutrients could be identified. A previously unknown sulfur limitation was detected in the applied Bold's Basal Medium. Combining the ammonium release beads with the RAMOS technique proved to be an efficient method for microalgae process development.

Polymer-based controlled-release fed-batch microtiter plate - diminishing the gap between early process development and production conditions.

BACKGROUND: Fed-batch conditions are advantageous for industrial cultivations as they avoid unfavorable phenomena appearing in batch cultivations. Those are for example the formation of overflow metabolites, catabolite repression, oxygen limitation or inhibition due to elevated osmotic concentrations. For both, the early bioprocess development and the optimization of existing bioprocesses, small-scale reaction vessels are applied to ensure high throughput, low costs and prompt results. However, most conventional small-scale procedures work in batch operation mode, which stands in contrast to fed-batch conditions in large-scale bioprocesses. Extensive expenditure for installations and operation accompany almost all cultivation systems in the market allowing fed-batch conditions in small-scale. An alternative, more cost efficient enzymatic glucose release system is strongly influenced by environmental conditions. To overcome these issues, this study investigates a polymer-based fed-batch system for controlled substrate release in microtiter plates. RESULTS: Immobilizing a solid silicone matrix with embedded glucose crystals at the bottom of each well of a microtiter plate is a suitable technique for implementing fed-batch conditions in microtiter plates. The results showed that the glucose release rate depends on the osmotic concentration, the pH and the temperature of the medium. Moreover, the applied nitrogen source proved to influence the glucose release rate. A new developed mathematical tool predicts the glucose release for various media conditions. The two model organisms E. coli and H. polymorpha were cultivated in the fed-batch microtiter plate to investigate the general applicability for microbial systems. Online monitoring of the oxygen transfer rate and offline analysis of substrate, product, biomass and pH confirmed that fed-batch conditions are comparable to large-scale cultivations. Furthermore, due to fed-batch conditions in microtiter plates, product formation could be enhanced by the factor 245 compared to batch cultivations. CONCLUSIONS: The polymer-based fed-batch microtiter plate represents a sophisticated and cost efficient system to mimic typical industrial fed-batch conditions in small-scale. Thus, a more reliable strain screening and early process development can be performed. A systematical scale-down with low expenditure of work, time and money is possible.

Daily allergic multimorbidity in rhinitis using mobile technology: A novel concept of the MASK study.

BACKGROUND: Multimorbidity in allergic airway diseases is well known, but no data exist about the daily dynamics of symptoms and their impact on work. To better understand this, we aimed to assess the presence and control of daily allergic multimorbidity (asthma, conjunctivitis, rhinitis) and its impact on work productivity using a mobile technology, the Allergy Diary. METHODS: We undertook a 1-year prospective observational study in which 4 210 users and 32 585 days were monitored in 19 countries. Five visual analogue scales (VAS) assessed the daily burden of the disease (i.e., global evaluation, nose, eyes, asthma and work). Visual analogue scale levels <20/100 were categorized as "Low" burden and VAS levels ≥50/100 as "High" burden. RESULTS: Visual analogue scales global measured levels assessing the global control of the allergic disease were significantly associated with allergic multimorbidity. Eight hypothesis-driven patterns were defined based on "Low" and "High" VAS levels. There were <0.2% days of Rhinitis Low and Asthma High or Conjunctivitis High patterns. There were 5.9% days with a Rhinitis High-Asthma Low pattern. There were 1.7% days with a Rhinitis High-Asthma High-Conjunctivitis Low pattern. A novel Rhinitis High-Asthma High-Conjunctivitis High pattern was identified in 2.9% days and had the greatest impact on uncontrolled VAS global measured and impaired work productivity. Work productivity was significantly correlated with VAS global measured levels. CONCLUSIONS: In a novel approach examining daily symptoms with mobile technology, we found considerable intra-individual variability of allergic multimorbidity including a previously unrecognized extreme pattern of uncontrolled multimorbidity.

Treatment of allergic rhinitis using mobile technology with real-world data: The MASK observational pilot study.

BACKGROUND: Large observational implementation studies are needed to triangulate the findings from randomized control trials as they reflect "real-world" everyday practice. In a pilot study, we attempted to provide additional and complementary insights on the real-life treatment of allergic rhinitis (AR) using mobile technology. METHODS: A mobile phone app (Allergy Diary, freely available in Google Play and Apple App stores) collects the data of daily visual analog scales (VAS) for (i) overall allergic symptoms, (ii) nasal, ocular, and asthma symptoms, (iii) work, as well as (iv) medication use using a treatment scroll list including all medications (prescribed and over the counter (OTC)) for rhinitis customized for 15 countries. RESULTS: A total of 2871 users filled in 17 091 days of VAS in 2015 and 2016. Medications were reported for 9634 days. The assessment of days appeared to be more informative than the course of the treatment as, in real life, patients do not necessarily use treatment on a daily basis; rather, they appear to increase treatment use with the loss of symptom control. The Allergy Diary allowed differentiation between treatments within or between classes (intranasal corticosteroid use containing medications and oral H1-antihistamines). The control of days differed between no [best control], single, or multiple treatments (worst control). CONCLUSIONS: This study confirms the usefulness of the Allergy Diary in accessing and assessing everyday use and practice in AR. This pilot observational study uses a very simple assessment (VAS) on a mobile phone, shows novel findings, and generates new hypotheses.

Fish oil in infancy protects against food allergy in Iceland-Results from a birth cohort study.

BACKGROUND: Consumption of oily fish or fish oil during pregnancy, lactation and infancy has been linked to a reduction in the development of allergic diseases in childhood. METHODS: In an observational study, Icelandic children (n = 1304) were prospectively followed from birth to 2.5 years with detailed questionnaires administered at birth and at 1 and 2 years of age, including questions about fish oil supplementation. Children with suspected food allergy were invited for physical examinations, allergic sensitization tests, and a double-blind, placebo-controlled food challenge if the allergy testing or clinical history indicated food allergy. The study investigated the development of sensitization to food and confirmed food allergy according to age and frequency of postnatal fish oil supplementation using proportional hazards modelling. RESULTS: The incidence of diagnosed food sensitization was significantly lower in children who received regular fish oil supplementation (relative risk: 0.51, 95% confidence interval: 0.32-0.82). The incidence of challenge-confirmed food allergy was also reduced, although not statistically significant (0.57, 0.30-1.12). Children who began to receive fish oil in their first half year of life were significantly more protected than those who began later (P = .045 for sensitization, P = .018 for allergy). Indicators of allergy severity decreased with increased fish oil consumption (P = .013). Adjusting for parent education and allergic family history did not change the results. CONCLUSION: Postnatal fish oil consumption is associated with decreased food sensitization and food allergies in infants and may provide an intervention strategy for allergy prevention.

The Allergic Rhinitis and its Impact on Asthma (ARIA) score of allergic rhinitis using mobile technology correlates with quality of life: The MASK study.

Mobile technology has been used to appraise allergic rhinitis control, but more data are needed. To better assess the importance of mobile technologies in rhinitis control, the ARIA (Allergic Rhinitis and its Impact on Asthma) score ranging from 0 to 4 of the Allergy Diary was compared with EQ-5D (EuroQuol) and WPAI-AS (Work Productivity and Activity Impairment in allergy) in 1288 users in 18 countries. This study showed that quality-of-life data (EQ-5D visual analogue scale and WPA-IS Question 9) are similar in users without rhinitis and in those with mild rhinitis (scores 0-2). Users with a score of 3 or 4 had a significant impairment in quality-of-life questionnaires.

Evolution of the IgE and IgG repertoire to a comprehensive array of allergen molecules in the first decade of life.

BACKGROUND: In early childhood, the allergen-specific IgG repertoire is mainly directed to animal and vegetable food molecules and infrequently to airborne molecules. It is unknown whether this early pattern is maintained throughout childhood. OBJECTIVE: To investigate the evolution of IgG and IgE responses to a broad panel of allergenic molecules from birth to age 10 years. METHODS: We examined the sera collected between birth and age 10 years from participants in the German Multicentre Allergy Study, a birth cohort born in 1990. The IgE (cutoff ≥0.30 ISU) and IgG (cutoff ≥0.10 ISU) responses to 35 genuine allergenic molecules were measured with a multiplex microarray approach (ImmunoCAP ISAC™). RESULTS: IgE responses were mostly directed against a restricted group of airborne molecules, with a sequence and prevalence hierarchy (Phl p 1> Bet v 1> Fel d 1> Phl p 5> Der p 2> Der p 1) largely maintained over time. Conversely, the IgG repertoire was much broader, starting with animal foodborne, then spreading to vegetable foodborne and finally to airborne molecules. A strong and persistent IgG response to a given airborne molecule almost invariably preceded or accompanied an IgE response to that molecule. CONCLUSIONS: The evolution of IgG and IgE responses throughout childhood differs widely at population level. IgG responses are mostly directed to animal food allergens, while IgE responses are dominated by airborne allergens. However, a strong IgG response almost invariably precedes or accompanies the appearance of IgE to the same molecule in specifically sensitized subjects.

The sex-shift in single disease and multimorbid asthma and rhinitis during puberty - a study by MeDALL.

BACKGROUND: Cross-sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We examined the sex-specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data. METHODS: In six European population-based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero-allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta-analysis. FINDINGS: We included data from 19 013 participants from birth to age 14-20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%-confidence interval 0.73-0.86) and 0.86 (0.79-0.94), respectively (sex-puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63-0.81 and 0.81, 0.64-1.02, respectively (sex-puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female-male-OR 0.55, 0.46-0.64) and a considerable shift towards a sex-balanced prevalence after puberty onset (0.89, 0.74-1.04); sex-puberty interaction: P < .001. INTERPRETATION: The male predominance in prevalence before puberty and the "sex-shift" towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.

The work productivity and activity impairment allergic specific (WPAI-AS) questionnaire using mobile technology: the MASK study

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