Occupational Rhinitis : Diagnosis and Health-related Quality of Life

Occupational rhinitis is mainly caused by work environment and not by stimuli encountered outside the workplace. It differs from rhinitis that is worsened by, but not mainly caused by, workplace exposures. Occupational rhinitis can develop in response to allergens, inhaled irritants, or corrosive gases. The thesis evaluated the use of challenge tests in occupational rhinitis diagnostics, studied the long-term health-related quality of life among allergic occupational rhinitis patients, and the allergens of wheat grain among occupational respiratory allergy patients. The diagnosed occupational rhinitis was mainly allergic rhinitis, which was caused by occupational agents, most commonly flours and animal allergens. The non-IgE-mediated rhinitis reactions were less frequent and caused more often asthma than rhinitis. Both nasal challenges and inhalation challenges were found to be safe tests. The inhalation challenge tests had considerably resource-intensive methodology. However, the evaluation of nasal symptoms and signs together with bronchial reactions saved time and expense compared with the organization of multiple individual challenges. The scoring criteria used matched well with the weighted amount of discharge ≥ 0.2 g and in most cases gave comparable results. The challenge tests are valuable tools when there is uncertainty whether the patient's exposure should be reduced or discontinued. It was found that continuing exposure decreases health-related quality of life among patients with allergic occupational rhinitis despite of rhinitis medications, still approximately ten years after the diagnosis. Health-related quality of life among occupational rhinitis patients without any longer occupational exposure was mainly similar than that of the healthy controls. This highlights the importance of the reduction and cessation of occupational exposure. To achieve this, 17% of occupational rhinitis patients had been re-educated. Alpha-amylase inhibitors, lipid transfer protein 2G, thaumatin -like protein, and peroxidase I were found to be relevant allergens in Finnish patients with occupational respiratory wheat allergy. Of these allergens, thaumatin-like protein and lipid transfer protein 2G were found as new allergens associated with baker's rhinitis and asthma. The knowledge of the new clinically relevant proteins can be used in the future in the development of better standardized diagnostic preparations.

Prevalence and determinants of respiratory symptoms, asthma, chronic bronchitis and allergic sensitization in Helsinki : A comparison between Finland, Sweden and Estonia. The FinEsS studies - Helsinki I

Objectives: To assess the prevalence and risk factor profiles of respiratory symptoms, asthma and chronic bronchitis in Helsinki, and to compare these results with those for Sweden and Estonia. Other important aims were to evaluate the prevalence and determinants of type 1 sensitization in Helsinki. Materials and methods: This presentation is a part of a large epidemiological study in Finland, Estonia and Sweden (FinEsS). The first part of the study consisted of a postal questionnaire in 1995-1996 distributed to subjects in eight study centres. The study population in each centre was a population-based random sample designed to be representative of the general population. The original study sample in Helsinki consisted of 8000 subjects aged 20-69 years, 6062 (76%) of whom participated. Comparisons between countries were based on a narrower age group, 20-64 years, since 64 years was the upper age limit used in the original study in Estonia. Thus, altogether 58 661 subjects aged 20-64 years were invited to participate in Finland, Sweden and Estonia, and 44 483 (76%) did so. The second part of the study was a clinical study with a structured interview, lung function measurements and skin-prick tests with 15 common allergens. This thesis reports only the results of the prick tests in Helsinki. Of the 1200 subjects invited to participate in Helsinki, 643 (54%) consented. Skin-prick tests were performed on subjects ≤ 60 years of age; thus, a total of 498 tests were done. Results: In Helsinki, the prevalence of physician-diagnosed asthma was 6.6% and of physician-diagnosed chronic bronchitis 3.7% among subjects aged 20-69 years. Comparison of the results between Finland, Sweden and Estonia in subjects 20-64 years of age revealed the highest prevalence of physician-diagnosed asthma in Sweden, 7.8%, while the prevalence in Finland was 5.9% and in Estonia 2.0% (p<0.001). The prevalence of physician-diagnosed asthma among those aged 20-29 years was 7.9% in Stockholm, 6.3% in Helsinki and 2.8% in Tallinn. Asthma-related symptoms were most common in Estonia, and among those with typical asthma symptoms the diagnosis of asthma was least likely in Estonia. Physician-diagnosed chronic bronchitis was reported to be 10.7% in Estonia, 3.1% in Sweden and 2.9% in Finland among subjects aged 20-64 years (p<0.001). Among those aged 20-29 years, 7.6% in Tallinn reported physician-diagnosed chronic bronchitis, while the prevalence estimates were 1.4% in Stockholm and 1.3% in Helsinki. The prevalence of smoking was similar for women in all three countries, around 30%, but large differences in smoking habits were present among men; 60% of Estonian, 39% of Finnish and 28% of Swedish men smoked. Skin-prick tests in Helsinki revealed a high prevalence of sensitization, 46.9%. For subjects aged 26-39 years, the prevalence was highest, 56.8%, and 23.7% were sensitized to at least four allergens. The most common sensitizing allergen was the dog. Sensitization to multiple allergens was associated with a high prevalence of asthma and allergic rhinitis. Conclusions: Compared with earlier Finnish studies, a higher prevalence of asthma and a lower prevalence of chronic bronchitis were found in Helsinki. The prevalence of physician-diagnosed chronic bronchitis was low in Helsinki, with only one-fifth of subjects fulfilling the symptom criteria for chronic bronchitis reporting having a diagnosis of chronic bronchitis. The prevalences of asthma and chronic bronchitis were similar in Finland and Sweden, but in Estonia physician-diagnosed asthma was less common and physician-diagnosed chronic bronchitis more common, particularly among young subjects. Further analyses revealed that the diagnosis of asthma was favoured in Finland and Sweden, while the diagnosis of chronic bronchitis was more likely in Estonia for subjects with the same symptoms. Allergic sensitization was common in Helsinki. Our findings of multiple sensitization also speak in favour of evaluating the degree of sensitization when assessing allergies.

Tacrolimus ointment for long-term treatment of atopic dermatitis

Atopic dermatitis (AD) or atopic eczema is characterised by a superficial skin inflammation with an overall Th2 cell dominance and impaired function of the epidermal barrier. Patients also are at an increased risk for asthma and allergic rhinitis. Treatment with tacrolimus ointment inhibits T cell activation and blocks the production of several inflammatory cytokines in the skin, without suppressing collagen synthesis. The aims of this thesis were to determine: (1) long-term efficacy, safety, and effects on cell-mediated immunity and serum IgE levels in patients with moderate-to-severe AD treated for 1 year with tacrolimus ointment or a corticosteroid regimen, (2) the 10-year outcome of eczema, respiratory symptoms, and serum IgE levels in AD patients initially treated long-term with tacrolimus ointment, and (3) pharmacokinetics and long-term safety and efficacy of 0.03% tacrolimus ointment in infants under age 2 with AD. Cell-mediated immunity, reflecting Th1 cell reactivity, was measured by recall antigens and was at baseline lower in patients with AD compared to healthy controls. Treatment with either 0.1% tacrolimus ointment or a corticosteroid regimen for one year enhanced recall antigen reactivity. Transepidermal water loss (TEWL), an indicator of skin barrier function, decreased at months 6 and 12 in both tacrolimus- and corticosteroid-treated patients; TEWL for the head and neck was significantly lower in tacrolimus-treated patients. Patients in the 10-year open follow-up study showed a decrease in affected body surface area from a baseline 19.0% to a 10-year 1.6% and those with bronchial hyper-responsiveness at baseline showed an increase in the provocative dose of inhaled histamine producing a 15% decrease in FEV1, indicating less hyper-responsiveness. Respiratory symptoms (asthma and rhinitis) reported by the patient decreased in those with active symptoms at baseline. A good treatment response after one year of tacrolimus treatment predicted a good treatment response throughout the 10-year follow-up and a decrease in total serum IgE levels at the 10-year follow-up visit. The 2-week pharmacokinetic and the long-term study with 0.03% tacrolimus ointment showed good and continuous improvement of AD in the infants. Tacrolimus blood levels were throughout the study low and treatment well tolerated. This thesis underlines the importance of effective long-term topical treatment of AD. When the active skin inflammation decreases, cell-mediated immunity of the skin improves and a secondary marker for Th2 cell reactivity, total serum IgE, decreases. Respiratory symptoms seem to improve when the eczema area decreases. All these effects can be attributed to improvement of skin barrier function. One potential method to prevent a progression from AD to asthma and allergic rhinitis may be avoidance of early sensitisation through the skin, so early treatment of AD in infants is crucial. Long-term treatment with 0.03% tacrolimus ointment was effective and safe in infants over age 3 months.

Topical tacrolimus in atopic dermatitis : Effects of long-term treatment on skin and respiratory symptoms

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.

Probiotics and prebiotics in the primary prevention of allergic diseases

The rapid increase in allergic diseases in developed, high-income countries during recent decades is attributed to several changes in the environment such as urbanization and improved hygiene. This relative lack of microbial stimulation is connected to a delay in maturation of the infantile immune system and seems to predispose especially genetically prone infants to allergic diseases. Probiotics, which are live ingestible health-promoting microbes, may compensate for the lack of microbial stimulation of the developing gut immune system and may thus be beneficial in prevention of allergies. Prebiotics, which are indigestible nutrients by us, promote the growth and activity of a number of bacterial strains considered beneficial for the gut. In a large cohort of 1 223 infants at hereditary risk for allergies we studied in a double-blind placebo-controlled manner whether probiotics administered in early life prevent allergic diseases from developing. We also evaluated their safety and their effects on common childhood infections, vaccine antibody responses, and intestinal immune markers. Pregnant mothers used a mixture of four probiotic bacteria or a placebo, from their 36th week of gestation. Their infants received the same probiotics plus prebiotic galacto-oligosaccharides for 6 months. The 2-year follow-up consisted of clinical examinations and allergy tests, fecal and blood sampling, and regular questionnaires. Among the 925 infants participating in the 2-year follow-up the cumulative incidence of any allergic disease (food allergy, eczema, asthma, rhinitis) was comparable in the probiotic (32%) and the placebo (35%) group. However, eczema, which was the most common manifestation (88%) of all allergic diseases, occurred less frequently in the probiotic (26%) than in the placebo group (32%). The preventive effect was more pronounced against atopic (IgE-associated) eczema which, of all atopic diseases, accounted for 92%. The relative risk reduction of eczema was 26% and of atopic eczema 34%. To prevent one case of eczema, the number of mother-infant pairs needed to treat was 16. Probiotic treatment was safe without any undesirable outcome for neonatal morbidity, feeding-related behavior, serious adverse events, growth, or for vaccine-induced antibody responses. Fewer infants in the probiotic than in the placebo group received antibiotics during their first 6 months of life and thereafter to age 2 years suffered from fewer respiratory tract infections. As a novel finding, we discovered that high fecal immunoglobulin A (IgA) concentrations at age 6 months associated with reduced risk for atopic (IgE-associated) diseases by age 2 years. In conclusion, although feeding probiotics to high-risk newborn infants showed no preventive effect on the cumulative incidence of any allergic diseases by age 2, they apparently prevented eczema. This probiotic effect was more pronounced among IgE-sensitized infants. The treatment was safe and seemed to stimulate maturation of the immune system as indicated by increased resistance to respiratory infections and improved vaccine antibody responses.

Dietary aspects of cow's milk allergy in young children

Cow s milk allergy (CMA) affects about 2-6% of infants and young children. Environmental factors during early life are suggested to play a role in the development of allergic diseases. One of these factors is likely to be maternal diet during pregnancy and lactation. The association between maternal diet and development of CMA in offspring is not well known, but diet could contain factors that facilitate development of tolerance. After an established food allergy, another issue is gaining tolerance towards an antigen that causes symptoms. The strictness of the elimination depends on the individual level of tolerance. This study aimed at validating a questionnaire used to inquire about food allergies in children, at researching associations between maternal diet during pregnancy and lactation and subsequent development of cow s milk allergy in the offspring, and at evaluating the degree of adherence to a therapeutic elimination diet of children with CMA and factors associated with the adherence and age of recovery. These research questions were addressed in a prospective birth cohort born between 1997 and 2004 at the Tampere and Oulu University Hospitals. Altogether 6753 children of the Diabetes Prediction and Prevention (DIPP) Nutrition cohort were investigated. Questionnaires regarding allergic diseases are often used in studies without validation. High-quality valid tools are therefore needed. Two validation studies were conducted here: one by comparing parentally reported food allergies with information gathered from patient records of 1122 children, and the other one by comparing parentally reported CMA with information in the reimbursement records of special infant formulae in the registers of the Social Insurance Institution for 6753 children. Both of these studies showed that the questionnaire works well and is a valid tool for measuring food allergies in children. In the first validation study, Cohen s kappa values were within 0.71-0.88 for CMA, 0.74-0.82 for cereal allergy, and 0.66-0.86 for any reported food allergy. In the second validation study, the kappa value was 0.79, sensitivity 0.958, and specificity 0.965 for reported and diagnosed CMA. To investigate the associations between maternal diet during pregnancy and lactation and CMA in offspring, 6288 children were studied. Maternal diet during pregnancy (8th month) and lactation (3rd month) was assessed by a validated, 181-item semi-quantitative food frequency questionnaire (FFQ), and as an endpoint register-based information on diagnosed CMA was obtained from the Social Insurance Institution and complemented with parental reports of CMA in their children. The associations between maternal food consumption and CMA in offspring were analyzed by logistic regression comparing the highest and lowest quarters with two middle quarters of consumption and adjusted for several potential confounding factors. High maternal intake of milk products (OR 0.56, 95% CI 0.37-0.86 p = 0.002) was associated with a lower risk of CMA in offspring. When stratified according to maternal allergic rhinitis or asthma, a protective association of high use of milk products with CMA was seen in children of allergy-free mothers (OR 0.30, 95% CI 0.13 - 0.69, p < 0.001), but not in children of allergic mothers. Moreover, low maternal consumption of fish during pregnancy was associated with a higher risk of CMA in children of mothers with allergic rhinitis or asthma (OR 1.47, 95% CI 0.96 - 2.27 for the lowest quarter, p = 0.043). In children of nonallergic mothers, this association was not seen. Maternal diet during lactation was not associated with CMA in offspring, apart from an inverse association between citrus and kiwi fruit consumption and CMA. These results imply that maternal diet during pregnancy may contain factors protective against CMA in offspring, more so than maternal diet during lactation. These results need to be confirmed in other studies before giving recommendations to the public. To evaluate the degree of adherence to a therapeutic elimination diet in children with diagnosed CMA, food records of 267 children were studied. Subsequent food records were examined to assess the age at reintroduction of milk products to the child s diet. Nine of ten families adhered to the elimination diet of the child with extreme accuracy. Older and monosensitized children had more often small amounts of cow s milk protein in their diet (p < 0.001 for both). Adherence to the diet was not related to any other sociodemographic factor studied or to the age at reintroduction of milk products to the diet. Low intakes of vitamin D, calcium, and riboflavin are of concern in children following a cow s milk-free diet. In summary, we found that the questionnaires used in the DIPP study are valid in investigating CMA in young children; that there are associations between maternal diet during pregnancy and lactation and the development of CMA in offspring; and that the therapeutic elimination diet in children with diagnosed CMA is rigorously adhered to.

Snoring and sleep apnea in children

Snoring is a primary and major clinical symptom of upper airway obstruction during sleep. Sleep-disordered breathing ranges from primary snoring to significant partial upper airway obstruction, and obstructive sleep apnea. Adult snoring and obstructive sleep apnea have been extensively studied, whereas less is known about these disorders in children. Snoring and more severe obstructive sleep apnea have been shown to have a harmful effect on the neurobehavioral development of children, but the mechanisms of this effect remains unknown. Furthermore, the correlation of this effect to objective sleep study parameters remains poor. This study evaluated the prevalence of snoring in preschool-aged children in Finland. Host and environmental risk factors, and neurobehavioral and neurocognitive symptoms of children suffering from snoring or obstructive sleep apnea were also investigated. The feasibility of acoustic rhinometry in young children was assessed. The prevalence and risk factors of snoring (I) were evaluated by a questionnaire. The random sample included 2100 children aged 1-6 years living in Helsinki. All 3- to 6-year-old children whose parents reported their child to snore always, often, or sometimes were categorized as snorers, and invited to participate to the clinical study (II-IV). Non-snoring children whose parents were willing to participate in the clinical study were invited to serve as controls. Children underwent a clinical ear-nose-throat examination. Emotional, behavioral, and cognitive performances were evaluated by Child Behavioral Checklist (CBCL), Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) and NEPSY-A Developmental Neuropsychological Assessment (NEPSY). Nasal volume was measured by acoustic rhinometry, and nasal resistance by rhinomanometry. Lateral and posteroanterior cephalometry were performed. A standard overnight ambulatory polysomnography was performed in the home environment. Twenty-six healthy children were tested in order to assess the feasibility of acoustic rhinometry in young children (V). Snoring was common in children; 6.3% of children snored always or often, whereas 81.3% snored never or occasionally. No differences were apparent between snorers and non-snorers regarding age, or gender. Pediatric snoring was associated with recurrent upper respiratory infections, otitis media, and allergic rhinitis. Exposure to parental tobacco smoke, especially maternal smoking, was more common among snorers. Rhinitis was more common among children who exposured to tobacco smoke. Overnight polysomnography (PSG) was performed on 87 children; 74% showed no signs of significant upper airway obstruction during sleep. Three children had obstructive apnea/hypopnea index (OAHI) greater than 5/h. Age, gender, or a previous adenoidectomy or tonsillectomy did not correlate with OAHI, whereas tonsillar size did correlate with OAHI. Relative body weight and obesity correlated with none of the PSG parameters. In cephalometry, no clear differences or correlations were found in PSG parameters or between snorers and non-snorers. No correlations were observed between acoustic rhinometry, rhinomanometry, and PSG parameters. Psychiatric symptoms were more frequent in the snoring group than in the nonsnoring group. In particular, anxious and depressed symptoms were more prevalent in the snoring group. Snoring children frequently scored lower in language functions. However, PSG parameters correlated poorly with neurocognitive test results in these children. This study and previous studies indicate that snoring without episodes of obstructive apnea or SpO2 desaturations may cause impairment in behavioral and neurocognitive functions. The mechanism of action remains unknown. Exposure to parental tobacco smoke is more common among snorers than non-snorers, emphasizing the importance of a smoke-free environment. Children tolerated acoustic rhinometry measurements well.