Thoracic gas compression during forced expiration in patients with emphysema, interstitial lung disease and obesity.

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 <0.005), in emphysema subjects, at PEF and MEF75 (p < 0.05, p < 0.005) and in obese subjects at MEF75 (p <0.005) and MEF25 (p < 0.01). ILD patients showed the lowest difference between thoracic and mouth flows at MEF75 relative to controls and emphysema patients (p < 0.005, p < 0.001). Obese subjects did not differ from controls, however, the difference between thoracic and mouth flows was significantly higher than in patients with emphysema at MEF50 (p < 0.001) and MEF25 (p < 0.005). CONCLUSIONS: Alveolar gas compression distorts the forced expiratory flow volume curve in all studied groups at the middle fraction of forced expiratory flow. Consequently, mouth flows are underestimated and the reduction of flow measured at 75% and 50% of vital capacity is often considerable. However, gas compression profiles in stiff lungs, in patients with decreased elastic recoil in emphysema and in obesity differ; the difference between thoracic and mouth flows in forced expiration was minimal in ILD at the first part of forced expiration and was higher in obesity than in emphysema at the middle and last parts of forced expiration.

Idiopathic pulmonary fibrosis--a systematic review on methodology for the collection of epidemiological data.

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.

Virtual communication is commonly used in Finnish interstitial lung disease multidisciplinary meetings.

Multidisciplinary meeting (MDM) is a core element in the diagnosis of interstitial lung diseases (ILD). The aim of the study was to investigate the implementation and key elements related to ILD MDMs in Finnish specialized care, which is characterized by long travel distances and a large number of small centers treating patients suffering from ILDs. An electronic questionnaire was sent to ILD experts working at five academic centers of Finland regarding the implementation of ILD MDMs with the focus on utilization of virtual communication. Responses were received from all academic centers of Finland (n = 5) whose catchment areas cover all of Finland. ILD MDMs were organized in each center approximately every two weeks and the core participants included a radiologist, respiratory physicians, junior staff, pathologist and a rheumatologist. All non-academic centers could refer their patients to be evaluated in ILD MDM of an academic center. Virtual communication was utilized by all academic centers in the implementation of ILD MDMs, being most common among small centers located in Eastern and Northern Finland. Virtual access to ILD MDM of an academic center was available in most parts of Finland, enabling small centers to benefit from the ILD expertise of academic centers.

National data on prevalence of idiopathic pulmonary fibrosis and antifibrotic drug use in Finnish specialised care.

INTRODUCTION: The 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The 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.

ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.

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., Myllärniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.

[Idiopathic pulmonary fibrosis -- progress in sight]. / Idiopaattinen keuhkofibroosi -- edistystä näköpiirissä.

The review presents the main aspects of a new international statement on idiopathic pulmonary fibrosis (IPF), therapeutic trials with a new drug, pirfenidone, and a new Finnish IPF register. It is desirable to have patients reported to the register with the best possible coverage in order to obtain a view about the prevalence of the disease in Finland. In the future, the register can be utilized to standardize the diagnostics and treatment of IPF, and to rapidly launch therapeutic trials and investigations with new drugs.

[Allergic bronchopulmonary aspergillosis]. / Allerginen bronkopulmonaalinen aspergilloosi--muistetaanko sita edes epäillä?

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.

The fate of aspergilloma patients after surgical treatment-experience from 22 cases.

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.

Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry.

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.

Analysis of the Histologic Features Associated With Interobserver Variation in Idiopathic Pulmonary Fibrosis.

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.

Are physicians in primary health care able to recognize pulmonary fibrosis?

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.

The polymorphism C5507G of complement receptor 1 does not explain idiopathic pulmonary fibrosis among the Finns.

Idiopathic 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.

A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung.

BACKGROUND: Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.

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.

Occupational respiratory hypersensitivity in dental personnel.

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 to 1998 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 per 100,000 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.