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IntroductionThe previous data concerning the prevalence of idiopathic pulmonary fibrosis (IPF) and the frequency of antifibrotic drug use in Finland were based on research registries and medical records whereas nationwide data on the number of patients with IPF in specialised care and those on antifibrotic treatment have not been published.MethodsWe made an information request to the Finnish National Hospital Discharge Register (Hilmo) covering the whole population of Finland to find out the annual numbers of patients with IPF treated in specialised care in 2016–2021. The numbers of the patients initiating and using pirfenidone and nintedanib were requested from the Social Insurance Institution of Finland (Kela) for the same time period.ResultsThe estimated prevalence of IPF in specialised care was 36.0 per 100 000 in 2021, having increased since 2016. The number of antifibrotic drug users and their proportion of outpatients with IPF had also risen during the follow-up period. In 2021, 35% of the patients with IPF used pirfenidone or nintedanib. The number of inpatients treated in specialised care because of IPF had declined during 2016−2021.ConclusionsThe prevalence of IPF was higher than expected in Finnish specialised care and had increased during the 6-year follow-up time. The increase in the number of patients with IPF using antifibrotic drugs might have diminished the need for IPF-related hospitalisations.

Background: Patients with pulmonary aspergillomas occasionally undergo surgery but it is somewhat unclear who of these patients benefit from surgical treatment. Methods: We retrospectively evaluated all 22 patients that underwent surgery in Helsinki University Central Hospital between 2004 and 2017. We assessed their clinical backgrounds, anti-fungal medication, indication for surgery, complications, recurrent infections and survival. Results: Of the 22 patients, 14 male and 8 female, mean age 56, an underlying pulmonary disease was present in 20. On immunosuppressive medication were 8 (36%). Most received anti-fungal medication preoperatively (n=12) and/or postoperatively (n=17), 3 patients did not receive anti-fungal medication. Length of the medication periods were diverse. Main indication for surgery was haemoptysis. One in-hospital-death occurred, and other complications included prolonged air-leak, postoperative pneumonia, pneumothorax and pneumomediastinum. No Aspergillus empyema or pleurites occurred. Five-year survival was 54%. One in-hospital-death and one other death were the result of Aspergillus disease, other deaths were unrelated to Aspergillus . Recurrent disease occurred in four cases. Three of these patients were asthma patients with allergic bronchopulmonary aspergillosis (ABPA). Conclusions: Overall results of surgery in this cohort were good and number of complications was low. Therapy with antifungals was diverse. Surgical treatment of aspergilloma can be life-saving for patients suffering of haemoptysis, and patients with restricted disease and well-preserved pulmonary capacity may benefit from surgery. Careful patient selection is crucial.

The histologic manifestation of idiopathic pulmonary fibrosis (IPF) is usual interstitial pneumonia (UIP), which is a good prognostic determinant of survival compared with other histologic interstitial lung disease patterns. According to the current international guidelines, the histologic features of suspected IPF/UIP are divided into 4 categories: UIP, probable UIP, possible UIP, and not UIP pattern. Four pulmonary pathologists who were blinded to clinicoradiologic information reevaluated 50 surgical lung biopsies (83.3%), 6 lung explant (10.0%), and 4 autopsy samples (6.7%) from the FinnishIPF registry (N=60) using the current diagnostic guidelines. Additional histologic features atypical for UIP were also evaluated and compared with clinicora-diologic information. The interobserver agreement of pathologists was examined by Cohen kappa (κ) coefficient; the survival of the patients was estimated with Kaplan-Meier curves. The histologic reevaluation indicated that 38 of 60 patients (63.3%) had definite UIP. Inflammation was the most common additional histologic finding (15/60, 25.0%). The interobserver agreement on histologic diagnosis ranged from slight (κ=0.044) to substantial (κ=0.779). The interobserver agreement varied extensively with regard to the presence of giant cells. The observed histologic features displayed no association with radiologic patterns or survival. Definite UIP and honeycombing findings in high-resolution computed tomography correlated with poor prognosis. A high level of interobserver variability was observed between pathologists, even in this well-defined cohort of IPF patients, which highlights the importance of multidisciplinary decision making in IPF diagnostics and stresses the need for a reassessment of the histologic criteria.

Idiopathic pulmonary fibrosis (IPF) is characterised by unpredictable disease course and poor survival. After the introduction of novel antifibrotic drugs, the prognosis of patients with IPF is probably changing. FinnishIPF, a nationwide registry of carefully characterised patients, was initiated in Finland in 2011. For the data analysis, we included 453 incident IPF patients diagnosed during 2011–2015. In this study, we describe the demographics and prognosis of these real-life patients. The median overall survival time of registered IPF patients was 4.5 years. The transplant-free survival at 1, 2, 3, 4 and 5 years was 95%, 83%, 70%, 58% and 45%, respectively. Smoking did not have any effect on survival. 117 (26%) patients received pirfenidone or nintedanib. Patients who received ≥6 months of treatment had better survival compared with those who did not receive treatment but this difference disappeared after age adjustment. The transplantation rate was 3%. Although IPF is diagnosed in Finland at a older age, the prognosis is better than expected due to a relatively well preserved lung function at diagnosis. Age and pulmonary function were identified as independent predictors of survival in the entire IPF patient population as well as in patients who had received antifibrotic treatment., Survival in idiopathic pulmonary fibrosis is better than previously reported. Independent predictors of survival are age and pulmonary function. Patients treated with antifibrotics have better prognosis but this is explained by younger age. http://bit.ly/2HWwCrH

Background: The early diagnosis of idiopathic pulmonary fibrosis (IPF) has become increasingly important due to evolving treatment options. IPF patients experience a significant delay in receiving an accurate diagnosis, thus delayed access to tertiary care is associated with higher mortality independently from disease severity. Objective: The aims were to evaluate whether there had been a delay in the referral process, and to determine whether the referring doctors had suspected IPF or other interstitial lung disease (ILD) already during the time of referral. Methods: Ninety-five referral letters of patients with IPF identified from the FinnishIPF registry were evaluated with respect to time of referral, referring unit, grounds for referral, symptoms, smoking status, occupational history, clinical examinations, co-morbidities, medication, radiological findings and lung function. Results: Fifty-nine percent of referral letters originated from primary public health care. The time from symptom onset to referral was reported in 60% of cases, mean time being 1.5 (0.8-2.3) (95% CI) years. The main reason for referral was a suspicion of interstitial lung disease (ILD) (63%); changes in chest X-ray were one reason for referring in 53% of cases. Lung auscultation was reported in 70% and inspiratory crackles in 52% of referral letters. Conclusions: Primary care doctors suspected lung fibrosis early in the course of disease. Lung auscultation and chest X-rays were the most common investigational abnormalities in the referrals. Providing general practitioners with more information of ILDs might shorten the delay from symptom onset to referral.

Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF).We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies. Patients that underwent lung transplantation were monitored for signs of herpesviral infection.A total of 11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation.Inflammatory cells are the main source of herpesviral DNA in the human IPF lung. Diagnostic tools should be actively used to elucidate whether herpesviral infection affects the pathogenesis, progression, and/or exacerbation of IPF.

Objectives: Body plethysmography is a lung function testing method usually applied for determination of thoracic gas volume and airways resistance, but option to measure work of breathing is available in most models. Although the method has been known over fifty years, assessment of work of breathing with it has not yet systematically studied in obesity. The aim of the study was to evaluate the relevance of work of breathing measured by body plethysmography in obese subjects and to compare the results with those of healthy controls and patients with pulmonary diseases of different pulmonary mechanics. Methods: Altogether sixty-two adults were studied prospectively: healthy non-smoking obese subjects (BMI > 30, N = 15), patients with interstitial lung disease (ILD) (N =15), emphysematic COPD (emphysema) (N = 16) and healthy non-smoking controls (controls) (N = 16). Inspiratory, expiratory and total work of breathing (WOBin, WOBex and WOB) and specific work of breathing (sWOBin, sWOBex and sWOB) were measured. Results: In obese subjects, WOB, WOBin (p < 0.001) and WOBex (p = 0.002) were elevated in comparison to controls. Also in ILD, WOB was significantly higher than in controls (p < 0.006). sWOBin, sWOBex and SWOB were significantly higher in emphysema than in the controls (p < 0.001). Conclusions: In obesity and ILD WOB whereas in emphysematic COPD sWOB differed significantly from controls, which is caused by differences in lung mechanics and lung volumes. The results concerning COPD correspond earlier study, but the present results suggest that body plethysmography is suitable for the assessment of work of breathing also in obesity.

The early diagnosis of idiopathic pulmonary fibrosis (IPF) is important due to improved treatment options. We have evaluated the quality of referral letters sent to tertiary care by primary health care physicians in relation to the recognition of IPF. Ninety-five referral letters of patients with IPF identified from a subcohort of patients in the FinnishIPF study were evaluated with respect to time of referral, referring unit, grounds for referral, symptoms, smoking status, occupational history, clinical examinations, co-morbidities, medication, radiological findings and lung function. The overall quality of the referral letter was also estimated. Fifty-nine percent of referral letters had originated from public health care. The quality of 53 % of the referral letters was estimated as either good or excellent. The time from symptom onset to referral was reported in 60% of cases, being 1.5 years on average. The main reason for referral was the suspicion of parenchymal lung disease (63%). Alterations in chest X-ray were listed as one reason for referring in 53% of cases. Cough (43%) and dyspnea (46%) were the most common symptoms. Inspiratory crackles in lung auscultation were reported in 52% of cases. Shortcomings in referral letters were estimated to have led to significant delays for eight (9%) subjects. IPF can be detected in primary health care based on symptoms as well as clinical and radiological examinations. Education, however, would improve recognition of IPF among primary health care physicians. Informing the general public of parenchymal lung diseases might also shorten the delay from symptom onset to seeking help from health care professionals.

We performed a genomewide scan in six multiplex families with familial idiopathic pulmonary fibrosis (IPF) who originated from southeastern Finland. The majority of the Finnish multiplex families were clustered in the region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified five loci of interest. The hierarchical fine mapping in an extended data set with 24 families originating from the same geographic region revealed a shared 110 kb to 13 Mb haplotype on chromosome 4q31, which was significantly more frequent among the patients than in population-based controls (odds ratio 6.3; 95% CI 2.5-15.9; P = .0001). The shared haplotype harbored two functionally uncharacterized genes, ELMOD2 and LOC152586, of which only ELMOD2 was expressed in lung and showed significantly decreased messenger-RNA expression in IPF lung (n = 6) when compared with that of healthy lung (n = 7; P = .05). Our results suggest ELMOD2 as a novel candidate gene for susceptibility in familial IPF.

Aims Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy-proven idiopathic pulmonary fibrosis (IPF) related to usual interstitial pneumonia (UIP).

Objective: The aim was to study the causes of respiratory hypersensitivity in dental personnel based on the statistics of the Finnish Register of Occupational Diseases (FROD; 1975–1998) and the patient material of the Finnish Institute of Occupational Health (FIOH; 1990–1998). Methods: Details about the cases of respiratory hypersensitivity were compiled from the FROD. The occupational rhinitis diagnoses studied at the FIOH were based on work-related symptoms and a change in the status of the nasal mucosa during challenge testing; and the diagnosis of occupational asthma based on reactions in challenge testing, or on IgE positivity and peak flow monitoring at work and during days off. Results: A total of 64 cases of occupational respiratory diseases (ORDs) was diagnosed in dental personnel during 1975 to1998 according to the FROD; two cases in 1975 to 1989, and 62 in 1990 to 1998. Twenty-eight cases were of occupational asthma (18 caused by methacrylates), 28 occupational rhinitis (six caused by methacrylates), seven allergic alveolitis and one organic dust toxic syndrome (ODTS). The non-acrylate-material diagnosed in 1990–1998 at the FIOH comprised three cases of asthma and one of rhinitis caused by chloramine-T (sodium-N-chlorine-p-toluene sulphonamide); as well as one case of asthma, seven cases of rhinitis, and two cases of combined rhinitis and conjunctivitis caused by natural rubber latex (NRL). Furthermore, one case of occupational rhinitis caused by Nobetec containing colophony was diagnosed. The incidence rate (IR) of ORD increased from 0 in 1988 to a peak of 105.1 new cases per100,000 working years in 1995. During the last observation year, i.e. 1998, the IR was 55 new cases per 100,000 workers. The IR in dental personnel was lower than in the whole working population in Finland up until 1992, but since then has been greater than in the whole population, peaking in 1995 when the IR of dental personnel was 2.55 times greater than in the whole population. Conclusion: The present study shows the increasing frequency of respiratory hypersensitivity among dental personnel. Besides methacrylates, important causes of respiratory hypersensitivity are NRL and chloramine-T.

SummaryIdiopathic pulmonary fibrosis is the most common of the idiopathic interstitial lung diseases referring to the histo-pathological entity of usual interstitial pneumonia. It has been hypothesized that inflammation may trigger the multiformic fibrotic lesions found in the affected lung, and defects in the innate immune defense, including the complement, can predispose to pulmonary fibrosis. The polymorphism C5507G in the Complement Receptor 1 gene has been recently associated with idiopathic pulmonary fibrosis. C5507G causes an amino acid change from proline to arginine, and opens a potential cleavage site for trypsin-like enzymes and, therefore, a potential mechanism for increased shedding of the molecule from the cell surface. We studied the polymorphism in 96 Finnish patients with idiopathic pulmonary fibrosis and 164 population based controls. All the patients and controls were C5507 homozygous suggesting that either the Finns do not carry the G5507 polymorphism or it is extremely rare. We conclude that G5507 is not a susceptibility allele for idiopathic pulmonary fibrosis among Finnish patients.

Background: Dynamic gas compression during forced expiration has an influence on conventional flow-volume spirometry results. The extent of gas compression in different pulmonary disorders remains obscure. Utilizing a flow plethysmograph we determined the difference between thoracic and mouth flows during forced expiration as an indication of thoracic gas compression in subjects with different pulmonary diseases characterized by limitations in pulmonary mechanics. Methods: Patients with emphysema (N = 16), interstitial lung disease (ILD) (N = 15), obesity (N = 15) and healthy controls (N = 16) were included. Compressed expiratory flow-volume curves (at mouth) and corresponding compression-free curves (thoracic) were recorded. Peak flow (PEF) and maximal flows at 75%, 50% and 25% of remaining forced vital capacity (MEF75, MEF50 and MEF25) were derived from both recordings. Their respective difference was assessed as an indicator of gas compression. Results: In all groups, significant differences between thoracic and mouth flows were found at MEF50 (p < 0.01). In controls, a significant difference was also measured at MEF75 (p

The number of patients with allergic bronchopulmonary aspergillosis is estimated to be between 2500 and 5000 in Finland. Genetic factors and bronchial epithelial cells in those having asthma or cystic fibrosis may upon exposure to Aspergillus fungus lead to airway inflammation that can slowly damage the lung tissue. Treatment of the disease is primarily based on settling of the inflammation with an oral corticosteroid and currently often also with itraconazole medication directed to the inflammation and attempting to eradicate aspergillus. Long-term prognosis is quite good, provided that the disease is detected and treated at an early stage.

Viral infections and abnormal host response are thought to cause epithelial injury in idiopathic pulmonary fibrosis (IPF). To understand IPF pathogenesis, we have used overexpression cell models and expression microarrays to discover genes networked with ELMO domain containing 2 (ELMOD2) gene genetically implicated in IPF. The identified pathways were confirmed in vitro, and ELMOD2 protein expression was characterized in tissue samples. Here 303 genes were significantly altered after ELMOD2 transfection of human alveolar epithelial A549 cell line. The enriched pathways were interferon induction, viral response, antigen processing and presentation, and I-/nuclear factor-kappaB signaling. ELMOD2 showed immunoreactivity in macrophages and type II alveolar epithelial cells in normal human lung. In A549 cells, forced expression of ELMOD2 increased type I and type III interferon mRNA expression, and ELMOD2-specific siRNA molecules inhibited expression of these antiviral cytokines in response to Toll-like receptor three (TLR3) activation. In human macrophages silencing of ELMOD2 inhibited TLR3-dependent expression of type I and type III interferon genes. Influenza A virus infection decreased ELMOD2 mRNA expression in A549 cells and macrophages suggesting negative regulation in viral infections. In summary, our results show that TLR3 pathway is dependent on ELMOD2.-Pulkkinen, V., Bruce, S., Rintahaka, J., Hodgson, U., Laitinen, T., Alenius, H., Kinnula, V. L., Myllarniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.

Background The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. Methods We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31 st of December in 2012 was calculated using the reported population in each university hospital city as the denominator. Results Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group – on the basis of patient records assessed by pulmonologists only 20–30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients’ mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. Conclusions Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports. BioMed Central open access

Background Recent studies suggest that the incidence of idiopathic pulmonary fibrosis (IPF) is rising. Accurate epidemiological data on IPF, however, are sparse and the results of previous studies are contradictory. This study was undertaken to gain insight into the various methods used in the epidemiological research of IPF, and to get accurate and comparable data on these different methodologies. Methods A systematic database search was performed in order to identify all epidemiological studies on IPF after the previous guidelines for diagnosis and treatment were published in 2000. Medline (via Pubmed), Science Sitation Index (via Web of Science) and Embase databases were searched for original epidemiological articles published in English in international peer-reviewed journals starting from 2001. After pre-screening and a full-text review, 13 articles were accepted for data abstraction. Results Three different methodologies of epidemiological studies were most commonly used, namely: 1) national registry databases, 2) questionnaire-based studies, and 3) analysis of the health care system’s own registry databases. The overall prevalence and incidence of IPF varied in these studies between 0.5–27.9/100,000 and 0.22–8.8/100,000, respectively. According to four studies the mortality and incidence of IPF are rising. Conclusions We conclude that there are numerous ways to execute epidemiological research in the field of IPF. This review offers the possibility to compare the different methodologies that have been used, and this information could form a basis for future studies investigating the prevalence and incidence of IPF.