Japanese Cedar Pollinosis Research Articles

Sublingual Immunotherapy in Pediatric Patients with Japanese Cedar Pollinosis in 2021

Sublingual Immunotherapy in Pediatric Patients with Japanese Cedar Pollinosis in 2021

Early Intervention with Fluticasone Furoate for Nasal Symptoms and Sleep Disturbance in Patients with Japanese Cedar Pollinosis

Early Intervention with Fluticasone Furoate for Nasal Symptoms and Sleep Disturbance in Patients with Japanese Cedar Pollinosis

Polymorphisms in Cha o 1 and Cha o 2, major allergens of Japanese cypress (Chamaecyparis obtusa) pollen from a restricted region in Japan.

Japanese cedar pollinosis is a major seasonal allergy in Japan, and Japanese cypress pollinosis is a growing concern because the cypress pollen season follows the cedar pollen season and cross-reactivity among allergens occurs between these closely related species. Allergens purified from pollen under unspecified collecting conditions can potentially heterogenous allergens profiles and batch to batch variability, and amino acid sequence variants in allergens possibly exist among trees. Polymorphisms have not been investigated for the cypress pollen major allergens, Cha o 1 and Cha o 2. Our aim was to examine the homogeneity of allergen amino acid sequences. DNA sequences of Cha o 1 and Cha o 2 from pollen collected from Chiba and Ibaraki prefectures and from needles of 47 plus trees located at seed orchards in Chiba Prefecture were examined by amplicon sequencing and amino acid substitutions were deduced. Sequence analysis of the pollen samples revealed that eight and seven residues of Cha o 2 were polymorphic, respectively. Thirteen residues in Cha o 2, including those residues identified in pollen, were deduced to be polymorphic for the plus trees. Cha o 2 expressed by the 47 plus trees included amino acid differences when compared with that of isoallergen Cha o 2.0101. No substitution was deduced in Cha o 1 for pollen taken from the two prefectures. One conservative amino acid substitution was deduced in Cha o 1 for the plus trees. Of the 47 plus trees examined, 38 were deduced to express only the isoallergen Cha o 1.0101 isoform, whereas eight trees were heterozygous and a single tree was homozygous for the non-synonymous mutation, which indicates relative uniformity of Cha o 1. Cha o 2 was found to be a heterogeneous allergen which suggests that studies using pollen from different trees may not give the same results.

Mapping naso-ocular symptom scores to EQ-5D-5L utility values in Japanese cedar pollinosis

BackgroundThe total naso-ocular symptom score (TSS) is widely used as an endpoint to evaluate the severity of seasonal allergic rhinitis. However, it is not a generic preference-based measure. We sought to develop an algorithm for mapping between the TSS and health utility in Japanese cedar pollinosis (JCP). We also performed a cost-utility analysis of sublingual immunotherapy (SLIT) for JCP by using this algorithm. MethodsPatients with JCP filled out the TSS questionnaire and EQ-5D-5L simultaneously during the pollen season in 2019 and in 2020. We estimated a direct utility mapping model by regressing responses to individual TSS questions directly onto utility. The incremental cost-effectiveness ratio (ICER) of active SLIT to a placebo was determined by examining the drug expense and the estimated quality-adjusted life year (QALY) using a dataset from a double-blind placebo-controlled clinical trial. ResultsA total of 238 records were included for analysis. The estimated utility decreased with increasing severity of rhinitis. Patients with comorbid asthma showed lower utility. A negative and significant correlation was seen between the TSS and utility in both 2019 and 2020. The estimated equations were: Y(utility) = −0.0161∗X(TSS) + 1.005 in non-asthmatic JCP patients. The ICER of active SLIT to the placebo was estimated to be 4,049,720 and 6,011,218 JPY/QALY in the first and second year, respectively. ConclusionsIt is possible to reasonably predict utility from the total naso-ocular symptom score by using regression models. In the estimated algorithm, pre-seasonal SLIT for JCP is cost-effective.

P9‐11: Japanese cedar pollen sublingual immunotherapy for asthma patients with Japanese cedar pollinosis provided stability of symptoms of asthma in the off‐season

P9‐11: Japanese cedar pollen sublingual immunotherapy for asthma patients with Japanese cedar pollinosis provided stability of symptoms of asthma in the off‐season

Relationship among total tear IgE, specific serum IgE, and total serum IgE levels in patients with pollen-induced allergic conjunctivitis

BackgroundRecently, the number of patients with pollinosis, particularly Japanese cedar pollinosis, has markedly increased. We previously reported about local allergic conjunctivitis, which is a phenotype of allergic conjunctivitis (AC). AC cases are often sensitized by various antigens. This study aimed to investigate the relationship among total tear IgE (t-tIgE), specific serum IgE (s-sIgE), and total serum IgE (t-sIgE) levels in patients with pollen-induced AC.MethodsIn 2019, 1372 patients were clinically diagnosed with AC at the Yamana Eye Clinic using t-tIgE, t-sIgE, and s-sIgE tests against 39 allergens. Among the pollen-induced AC patients who underwent allergen testing, 99 tested positives for s-sIgE against pollen. The subjects comprised 33 (33.3%) male and 66 (66.7%) female individuals aged 9–86 years.ResultsThe t-tIgE test was positive in 68 (68.7%) patients and negative in 31 (31.3%) patients. In the t-sIgE test, 45 (45.5%) patients had t-sIgE levels above the reference value of 170 IU/mL. The higher the total score of the positive class value of each pollen-specific IgE (pollen-sIgE) antibody, the higher the positive rate of t-tIgE (p < 0.001). Of 32 patients in whom food-specific IgE (food-sIgE) was detected, 81.3% of the pollen-sIgE-positive and food-sIgE-positive cases were also positive for t-sIgE and t-tIgE. However, significant difference was not found between the total score of food-sIgE of the t-tIgE positive group and negative group.ConclusionsPollen-induced AC is caused by pollen sensitization of the conjunctiva. Food-induced AC might be induced by the different pathological mechanism involved in pollen-induced AC.

Reduced anaphylactic potential of denatured pullulan-conjugated Cry j 1

Japanese Cedar (JC) pollinosis is the most common seasonal allergic rhinitis in Japan. Throughout the JC pollen season, patients suffer from the allergic symptoms, resulting in a reduction of quality of life. Allergy immunotherapy (AIT) is an established treatment option for a wide range of allergens that unlike symptomatic treatments (e.g. antihistamines) may provide sustained immune tolerance. However, AIT, especially subcutaneous immunotherapy (SCIT) has a fatal anaphylaxis risk due to the use of crude allergen extracts. Consequently, development of allergen derivatives with substantially reduced anaphylactic potential is desirable.An allergen derivative that showed reduced IgE-binding and anaphylactic potential was developed through conjugation of native Cry j 1 (n Cry j 1), a major JC allergen, to the polysaccharide pullulan followed by chemical but non-covalent denaturation. The resulting Cry j 1 allergen derivative, Dn p-Cry j 1, showed reduced IgE-binding and IgE-mediated effector cell activation in vitro using an ELISA competition assay and a mast cell activation model (EXiLE). Reduced anaphylactic potential of Dn p-Cry j 1 in vivo was demonstrated using the rat passive cutaneous anaphylaxis (PCA) assay. The difference in anaphylactic potential of Dn p-Cry j 1 compared to n Cry j 1 in wild-type rats was of the same magnitude as the difference seen in the anaphylaxis reactions obtained with n Cry j 1 in wild-type rats and mast-cell deficient rats, indicating a dramatic reduction in anaphylactic potential of Dn p-Cry j 1. These results indicate that Dn p-Cry j 1 is a promising candidate for next-generation JC AIT.

Disease-Modifying Effect of Japanese Cedar Pollen Sublingual Immunotherapy Tablets

Japanese cedar (JC) pollinosis is a common allergic rhinitis in Japan. JC pollen sublingual immunotherapy (SLIT) tablets are licensed for the treatment of JC pollinosis. To assess the disease-modifying effects of JC pollen SLIT tablets over 5 years (2014-2019), comprising a 3-year treatment period and 2-year follow-up. A total of 1042 patients with JC pollinosis (aged 5-64 years) were included in the study. An optimal dose-finding study was performed in the first 15 months, after which 240 patients in the placebo (P) group and 236 patients in the optimalactive dose (A) group (5000 Japanese allergy units) were re-randomized to receive P or A for an additional 18 months (designated AA, AP, PA, and PP groups). Clinical efficacy was evaluated by the total nasal symptom and medication score (TNSMS) during the peak symptom period of each JC pollen season over 3 years of treatment and 2 years of observation after treatment cessation. The AA, AP, and PA groups exhibited significantly reduced TNSMS; however, the largest relative reduction was seen in the AA group both during the treatment period (third season, 46.3% vs PP, P < .001) and during the 2-year follow-up period (fourth and fifth seasons, 45.3% and 34.0% vs PP, respectively; P < .001). The most common adverse drug reactions were mild reactions at the administration site. JC pollen SLIT tablets show sustained clinical efficacy during 3 years of treatment and sustained disease-modifying effects for at least 2 years after treatment cessation.

Serum Concentrations of Antigen-Specific IgG4 in Patients with Japanese Cedar Pollinosis

Purpose: To elucidate the usefulness of Japanese cedar pollen (JCP)-specific antigen-specific immunoglobulin (IgG) 4 as a biomarker for predicting the efficacy of sublingual immunotherapy for cedar pollen-induced allergic rhinitis. Methods: We divided a total of 105 cases with Japanese cedar pollinosis into three groups: “SLIT Successful,” SLIT Unsatisfactory,” and “SCIT” groups. The SLIT group patients were treated with JCP Droplet (Torii Pharmaceutical Co. Ltd., Tokyo, Japan) for one year from 2015 and were divided into two groups, the SLIT Successful group or the SLIT Unsatisfactory group. The SLIT Successful group (n = 16) were subjects treated by SLIT only, who were able to experience control of their naso-ocular symptoms without the need for antiallergic rescue agents during the peak season of atmospheric pollen. The SLIT Unsatisfactory group (n = 76) comprised subjects treated with SLIT only, who did not respond successfully, and were administered with rescue agents to control their naso-ocular symptoms. The SCIT group had been treated with standardized JCP extract (Torii Pharmaceutical Co., Ltd., Tokyo, Japan) for three years from 2012, and were also able to experience control of their symptoms during the peak pollen season without the need for antiallergic rescue agents. We determined the serum level of JCP-specific immunoglobulin E (IgE), IgG, and IgG4 used in the 3gAllergy-specific IgE assay (3gAllergy). The serum levels of periostin and SCCA2 were measured using established ELISA procedures (clones SS18A and SS17B; Shino-Test, Japan) following the manufacturer’s instructions. We then made ROC curves for each group and assessed which index was best able to predict the efficacy of sublingual immunotherapy. Results: Serum JCP-specific IgE was significantly lower in the SCIT group than in the SLIT Successful group and the SLIT Unsatisfactory group (p &lt; 0.05). Serum JCP-specific IgG was significantly higher in the SCIT group and the SLIT Successful group than in the SLIT Unsatisfactory group (p &lt; 0.05). Serum JCP-specific IgG4 was also significantly higher in the SCIT group and the SLIT Successful group than in the SLIT Unsatisfactory group (p &lt; 0.05). There was no significant difference among serum levels of periostin in the SCIT group, the SLIT Successful group, or the SLIT Unsatisfactory group. There was also no significant difference in SCCA2 among the three groups. In terms of ROC curves, a serum JCP-specific IgG4 value greater than 989.5 UA/mL showed the best sensitivity (93.3%) and specificity (94.7%) (p &lt; 0.05) among other parameters. Conclusions: The serum JCP-specific IgG4 level is significantly correlated with the clinical efficacy of SLIT. Serum JCP-specific IgG4 cutoff levels greater than 989.5 UA/mL were correlated with an effective clinical response to SLIT, with a sensitivity of 93.3% and a specificity of 94.7%.

Long-term oral administration of transgenic rice containing cedar pollen T-cell epitopes potentially improves medication- and allergy-related quality-of-life scores.

Background: We previously developed a transgenic rice that contains seven linked human predominant T-cell epitopes (7Crp) derived from Japanese cedar (JC) pollen allergens Cry j 1 and Cry j 2. Oral administration of 80 g of transgenic rice for 20 weeks suppressed allergen-specific T-cell proliferation in participants with JC pollinosis, but their clinical symptoms did not improve. Objective: We examined the clinical efficacy of low-dose (5 g and 20 g) intake of the transgenic rice administered for two successive seasons. Methods: In this randomized, double-blind, placebo controlled study, transgenic rice seeds (5 g or 20 g) were orally administered to the participants for 24 weeks in each of two successive JC pollen seasons. We analyzed T-cell proliferation and cytokine expression, and monitored symptom and medication scores during the pollen season. Quality of life (QOL) was evaluated by using the Japanese Allergic Rhinitis Quality of Life Standard Questionnaire (JRQLQ). Results: Specific T-cell proliferation after stimulation with 7Crp, Cry j 1, and Cry j 2 was significantly suppressed in the second JC pollen season. No significant differences were found among the three groups (5 g, 20 g, and placebo) with regard to clinical symptoms or medication scores in the first season. However, the medication scores and face scale for overall condition of JRQLQ improved in the 5-g transgenic rice group in the second season, although careful re-examination with a large sample size is necessary to confirm the results. Conclusion: Low-dose oral administration of transgenic rice that contains 7Crp significantly reduced allergen-specific T-cell responses and improved medication scores during the second season of administration. Thus, oral intake of the transgenic rice has the potential to induce immune tolerance to JC pollen allergens when administered for at least two successive seasons.

Next-Generation Allergen-Specific Immunotherapy for Japanese Cedar Pollinosis Using Molecular Approaches.

Japanese cedar (JC) pollinosis is the most major IgE-mediated type I allergic disease in Japan. Allergen-specific immunotherapy is the only curative treatment for allergic diseases. Subcutaneous immunotherapy and sublingual immunotherapy have been introduced in Japan for JC pollinosis, but do not avoid some adverse side effects, because the natural allergens used as tolerogens cross-link with specific IgE types on mast cells and basophils. To make immunotherapy for JC pollinosis safer, more effective and convenient, rice-based oral allergy vaccines using hybrid peptides composed of multiple T-cell epitopes or recombinant deconstructed hypoallergenic derivatives derived from major allergens — Cry j 1 and Cry j 2 — have been developed and their efficacy and safety evaluated by oral administration of transgenic rice seeds. Furthermore, recombinant modified JC allergens conjugated with various immunomodulatory molecules and DNA-based vaccines have been created and their efficacy assessed.

Practical Study of Immunotherapy in Patients with Japanese Cedar Pollinosis Using a Questionnaire. Comparison between Sublingual Immunotherapy and Subcutaneous Immunotherapy in the Third Season

Practical Study of Immunotherapy in Patients with Japanese Cedar Pollinosis Using a Questionnaire. Comparison between Sublingual Immunotherapy and Subcutaneous Immunotherapy in the Third Season

Intranasal levels of lead as an exacerbation factor for allergic rhinitis in humans and mice

Air pollutants are suspected to affect pathological conditions of allergic rhinitis (AR). After detecting Pb (375 μg/kg) in Japanese cedar pollen, the effects of intranasal exposure to Pb on symptoms of AR were investigated. Pollen counts, subjective symptoms, and Pb levels in nasal epithelial lining fluid (ELF) were investigated in 44 patients with Japanese cedar pollinosis and 57 controls from preseason to season. Effects of intranasal exposure to Pb on symptoms were confirmed by using a mouse model of AR. Pb levels in ELF from patients were >40% higher than those in ELF from control subjects during the pollen season but not before the pollen season. Pb level in ELF was positively associated with pollen counts for the latest 4 days before visiting a hospital as well as scores of subjective symptoms. Intranasal exposure to Pb exacerbated symptoms in allergic mice, suggesting Pb as an exacerbation factor. Pb levels in ELF and nasal mucosa in Pb-exposed allergic mice were higher than those in Pb-exposed nonallergic mice, despite intranasally challenging the same amount of Pb. Because the increased Pb level in the nasal mucosa of Pb-exposed allergic mice was decreased after washing the nasal cavity, Pb on the surface of but not inside the nasal mucosa may have been a source of increased Pb level in ELF of allergic mice. Increased nasal Pb level partially derived from pollen could exacerbate subjective symptoms of AR, indicating Pb as a novel hazardous air pollutant for AR.

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis

ObjectiveJapanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed. MethodsThis study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients’ nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices. ResultsFrom the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment. ConclusionThe efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.

Effects of sublingual immunotherapy on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis

ObjectiveJapanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis (AR) in Japan. AR reduces the quality of life not only because of nasal symptoms but also because of sleep disturbance. In the present study, we investigated the effects of sublingual immunotherapy (SLIT) with a standardized JC pollen extract on nasal symptoms and AR-related sleep disturbance in patients with JC pollinosis. MethodsIn the present non-randomized controlled study, we assigned thirty-one patients with JC pollinosis who received SLIT into the SLIT group, and another thirty-eight patients with JC pollinosis who visited our hospital without treatment into the untreated group. We evaluated nasal symptoms and sleep disturbance using the classification of the severity of AR symptoms and the Athens Insomnia Scale, respectively. ResultsThe nasal symptom scores and the Athens Insomnia Scale scores of patients in the SLIT group were both significantly lower than those of patients in the untreated group. There was a significant correlation between total nasal symptom scores and the Athens Insomnia Scale scores. ConclusionsThese findings suggested that SLIT with JC pollen extract suppressed nasal symptoms in patients with JC pollinosis, leading to improvements in AR-related sleep disturbance and daytime troubles with daily life.

Anti-inflammatory roles of interleukin-35 in the pathogenesis of Japanese cedar pollinosis.

BackgroundInterleukin (IL)-35 has been recently identified as an anti-inflammatory cytokine in allergic inflammation. However, its biological role in the pathogenesis of allergic rhinitis has not been fully elucidated.ObjectiveThe purpose of this study was to investigate the anti-inflammatory activity of IL-35 in the pathogenesis of allergic rhinitis in patients with Japanese cedar pollinosis (JCP).MethodsPeripheral blood mononuclear cells were collected from healthy controls and JCP patients during the off-season for pollen. Peripheral blood mononuclear cells were incubated with Cry j 1, a major allergen of Japanese cedar pollen and production of IL-5, IL-13, and IL-35 were measured by enzyme-linked immunosorbent assay. Th2 (CD4+ST2+) cells and group 2 innate lymphoid cells were isolated from peripheral blood mononuclear cells of JCP patients, and the inhibitory effects of IL-35 on cell differentiation, proliferation and mRNA expression of IL-5, IL-13, and GATA3 were examined. B cells were also isolated and the effects of IL-35 on total IgE production were examined.ResultsCry j 1-induced production of IL-5 and IL-13 was significantly increased in peripheral blood mononuclear cells from JCP patients, whereas Cry j 1-induced IL-35 production was significantly decreased compared with healthy controls. IL-35 significantly inhibited Th2 cell differentiation, group 2 innate lymphoid cell proliferation, and mRNA expression of IL-5, IL-13, and GATA3 in Th2 cells and group 2 innate lymphoid cells. IL-35 also inhibited IgE production from B cells.ConclusionIL-35 is an important anti-inflammatory cytokine in JCP, and its biological roles include the downregulation of Th2 cells and group 2 innate lymphoid cells, and the inhibition of IgE production from B cells. These findings demonstrate that IL-35 may have the potential to exert anti-allergic effects for the treatment of allergic rhinitis.

Comparison of the Total Number of Japanese Cedar Pollinosis Outpatients at an ENT Clinic in the Omura City in Nagasaki Prefecture in 2016 and 2019

Comparison of the Total Number of Japanese Cedar Pollinosis Outpatients at an ENT Clinic in the Omura City in Nagasaki Prefecture in 2016 and 2019

Validation of antihistamine treatments using a treatment-specific questionnaire for Japanese cedar pollinosis − Patient satisfaction and treatment efficacy −

Validation of antihistamine treatments using a treatment-specific questionnaire for Japanese cedar pollinosis − Patient satisfaction and treatment efficacy −

Predictors of adherence to sublingual immunotherapy for Japanese cedar pollinosis: a prospective analysis.

Sublingual immunotherapy (SLIT) often has low adherence rates. To provide effective support for SLIT continuation, we investigated potential predictors of SLIT adherence through a prospective analysis of patient characteristics. We excluded evaluation of treatment effect and symptoms during treatment, aiming instead to identify predictors of later dropout or insufficient adherence due to indolence or forgetfulness using only information obtained at initial examination. We provided patients with a questionnaire and monitored self-reported adherence once every 6 months. Cases of dropout for clear reasons were excluded, but cases of dropout or insufficient adherence to SLIT for indolence or forgetfulness were included. Fifty-three patients receiving SLIT were assessed. Nine patients dropped out after providing a clear reason. Thirty-four patients maintained good adherence. Seven patients continued SLIT but with insufficient adherence, while three patients discontinued SLIT for unclear reasons (indolence or forgetfulness) and these ten individuals were classified as the poor-adherence group. Univariate analysis and multivariate logistic regression analysis of the good-adherence and poor-adherence groups showed age to be a significant predictor of SLIT adherence. Based on analysis of a receiver operating characteristic curve, age < 40.5 years was selected as the optimal cutoff value for predicting poor adherence to SLIT. To prevent treatment SLIT discontinuation on account of indolence or forgetfulness, the necessity of longterm treatment continuity should be communicated clearly prior to commencing treatment, especially for patients under 40 years of age.

PRS36 IMPACT of Omalizumab on Paid and Unpaid Work Productivity Among Severe Japanese Cedar Pollinosis Patients

Japanese cedar pollinosis (JCP) is a form of seasonal allergic rhinitis that affects 38.8% of the Japanese population. Furthermore, associated symptoms among severe JCP patients lead to impairment of work (paid work), and activities of daily living (unpaid work). The current standard of care (SoC) for severe / the most severe types of JCP includes combination uses of second-generation antihistamines, nasal steroids and leukotriene receptor antagonists, occasionally use of nasal vasoconstrictor. Even with the SoC, symptoms may not be relieved in some patients with these types of JCP; therefore, omalizumab, a humanized monoclonal anti-immunoglobulin E (IgE) antibody, has been recently approved as a new treatment in Japan. In this study, we have estimated the impact of omalizumab on paid and unpaid work in this JCP population in Japan. The impact of omalizumab on paid and unpaid work productivity was retrospectively evaluated based on Work Productivity and Activity Impairment Questionnaire-Allergy Specific scores, obtained from a recent trial of omalizumab (NCT03369704) enrolling patients with severe JCP. The ‘human capital approach’ for paid work and the ‘replacement cost approach’ for unpaid work were implemented to monetize the benefit with wages: benefit quantified by using official Japanese statistics on employment and time use. These estimates were simulated in a static cohort model and sensitivity analysis conducted to account for model structural uncertainties. Nearly one-third of paid and unpaid work productivity losses can be avoided by omalizumab. Male patients accounted for the major share of ‘avoided’ paid work productivity losses; whereas, the ‘avoided’ unpaid work losses are substantially contributed by females. Omalizumab provides substantial benefits in terms of paid and unpaid work in patients with severe / the most severe JCP. Further, the results suggest that unpaid work is of importance when estimating productivity costs due to poor health.