Browsing by Subject "Idiopathic pulmonary fibrosis"

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  • Mäkelä, Kati; Mäyränpää, Mikko I.; Sihvo, Hanna-Kaisa; Bergman, Paula; Sutinen, Eva; Ollila, Hely; Kaarteenaho, Riitta; Myllärniemi, Marjukka (2021)
    A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p = 0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p = 0.01 and p = 0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p = 0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p = 0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.
  • Pesonen, Ida; Carlson, Lisa; Murgia, Nicola; Kaarteenaho, Riitta; Skold, Carl Magnus; Myllärniemi, Marjukka; Ferrara, Giovanni (2018)
    Background: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011-2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. Methods: Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. Results: One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p = 0.01) and diffusion capacity for carbon monoxide (DLCO), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) (p <0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95% CI 0.93-1.00, p <0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95% CI 2.65-11.33, p <0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. Conclusions: This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.
  • Pesonen, Ida; Carlson, Lisa; Murgia, Nicola; Kaarteenaho, Riitta; Sköld, Carl M; Myllärniemi, Marjukka; Ferrara, Giovanni (BioMed Central, 2018)
    Abstract Background Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011–2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. Methods Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. Results One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p = 0.01) and diffusion capacity for carbon monoxide (DLCO), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) (p <  0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95%CI 0.93–1.00, p <  0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95%CI 2.65–11.33, p < 0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. Conclusions This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.
  • Rajala, Kaisa; Lehto, Juho T.; Saarinen, M.; Sutinen, E.; Saarto, T.; Myllarniemi, M. (2016)
    Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with median survival from 2 to 7 years. Palliative care is an important part of patients' care as lung transplantation is not an option for the majority of patients. The aim of this study was to describe treatment practices, decision-making and symptoms during end-of-life care of IPF patients. Methods: We identified 59 deceased patients from a national prospective IPF cohort study (FinnishIPF) and analyzed retrospectively their health care documentation during the 6 months that preceded death. Results: Hospital was the place of death for 47 patients (80 %). A majority of the patients (93 %) were hospitalized for a mean of 30 days (range 1-96 days) during the last 6 months of their life. Altogether, patients spent 15 % of their last 6 months of life in a hospital. End-of-life decisions and do not resuscitate (DNR) orders were made for 19 (32 %) and 34 (57 %) of the patients, respectively, and 22 (42 %) of these decisions were made Conclusions: The majority of IPF patients died in a hospital with ongoing life-prolonging procedures until death. The frequent use of opioids is an indicator of an intention to relieve symptoms, but end-of-life decisions were still made very late. Early integrated palliative care with advance care plan could improve the end-of-life care of dying IPF patients.
  • Rajala, Kaisa; Lehto, Juho T; Saarinen, M.; Sutinen, E.; Saarto, T.; Myllärniemi, M. (BioMed Central, 2016)
    Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with median survival from 2 to 7 years. Palliative care is an important part of patients´ care as lung transplantation is not an option for the majority of patients. The aim of this study was to describe treatment practices, decision-making and symptoms during end-of-life care of IPF patients. Methods We identified 59 deceased patients from a national prospective IPF cohort study (FinnishIPF) and analyzed retrospectively their health care documentation during the 6 months that preceded death. Results Hospital was the place of death for 47 patients (80 %). A majority of the patients (93 %) were hospitalized for a mean of 30 days (range 1–96 days) during the last 6 months of their life. Altogether, patients spent 15 % of their last 6 months of life in a hospital. End-of-life decisions and do not resuscitate (DNR) orders were made for 19 (32 %) and 34 (57 %) of the patients, respectively, and 22 (42 %) of these decisions were made ≤ 3 days prior to death. During the final hospital stay, antibiotics were given to 79 % and non-invasive ventilation to 36 % of patients. During the last 24 h of life, radiologic imaging or laboratory tests were taken in 19 % and 53 % of the hospitalized patients, respectively. These tests and life prolonging therapies were more common in tertiary hospitals compared to other places of death. Dyspnea (66 %) and pain (31 %) were the most common symptoms recorded. Opioids were prescribed to 71 % of the patients during the last week before death. Conclusions The majority of IPF patients died in a hospital with ongoing life-prolonging procedures until death. The frequent use of opioids is an indicator of an intention to relieve symptoms, but end-of-life decisions were still made very late. Early integrated palliative care with advance care plan could improve the end-of-life care of dying IPF patients.
  • Mäkelä, Kati; Ollila, Hely; Sutinen, Eva; Vuorinen, Vesa; Peltola, Emilia; Kaarteenaho, Riitta; Myllärniemi, Marjukka (2019)
    Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a dismal prognosis and an unknown etiology. Inorganic dust is a known risk factor, and air pollution seems to affect disease progression. We aimed to investigate inorganic particulate matter in IPF lung tissue samples. Using polarizing light microscopy, we examined coal dust pigment and inorganic particulate matter in 73 lung tissue samples from the FinnishIPF registry. We scored the amount of coal dust pigment and particulate matter from 0 to 5. Using energy dispersive spectrometry with a scanning electron microscope, we conducted an elemental analysis of six IPF lung tissue samples. We compared the results to the registry data, and to the population density and air quality data. To compare categorical data, we used Fisher's exact test; we estimated the survival of the patients with Kaplan-Meier curves. We found inorganic particulate matter in all samples in varying amounts. Samples from the southern regions of Finland, where population density and fine particle levels are high, more often had particulate matter scores from 3 to 5 than samples from the northern regions (31/50, 62.0% vs. 7/23, 30.4%, p = 0.02). The highest particulate matter scores of 4 and 5 (n = 15) associated with a known exposure to inorganic dust (p = 0.004). An association between particulate matter in the lung tissue of IPF patients and exposure to air pollution may exist.
  • Rajala, K.; Lehto, J. T; Sutinen, E.; Kautiainen, H.; Myllärniemi, M.; Saarto, T. (BioMed Central, 2018)
    Abstract Background Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a high symptom burden and poor survival that influences patients’ health-related quality of life (HRQOL). We aimed to evaluate IPF patients’ symptoms and HRQOL in a well-documented clinical cohort during their last two years of life. Methods In April 2015, we sent the Modified Medical Research Council Dyspnea Scale (MMRC), the modified Edmonton Symptom Assessment Scale (ESAS) and a self-rating HRQOL questionnaire (RAND-36) to 300 IPF patients, of which 247 (82%) responded. Thereafter, follow-up questionnaires were sent every six months for two years. Results Ninety-two patients died by August 2017. Among these patients, HRQOL was found to be considerably low already two years before death. The most prominent declines in HRQOL occurred in physical function, vitality, emotional role and social functioning (p < 0.001). The proportion of patients with MMRC scores ≥3 increased near death. Breathlessness and fatigue were the most severe symptoms. Symptom severity for the following symptoms increased significantly and reached the highest mean scores during the last six months of life (numeric rating scale/standard deviation): breathlessness (7.1/2.8), tiredness (7.0/2.3), dry mouth (6.0/3.0), cough (5.8/2.9), and pain with movement (5.0/3.5). Conclusions To our knowledge this is the first study demonstrating, that IPF patients experience remarkably low HRQOL already two years before death, especially regarding physical role. In addition, they suffer from severe breathlessness and fatigue. Furthermore, physical, social and emotional wellbeing deteriorate, and symptom burden increases near death. Regular symptom and HRQOL measurements are essential to assess palliative care needs in patients with IPF.
  • Rajala, K.; Lehto, J. T.; Sutinen, E.; Kautiainen, H.; Myllärniemi, M.; Saarto, T. (2018)
    BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic disease with a high symptom burden and poor survival that influences patients' health-related quality of life (HRQOL). We aimed to evaluate IPF patients' symptoms and HRQOL in a well-documented clinical cohort during their last two years of life.MethodsIn April 2015, we sent the Modified Medical Research Council Dyspnea Scale (MMRC), the modified Edmonton Symptom Assessment Scale (ESAS) and a self-rating HRQOL questionnaire (RAND-36) to 300 IPF patients, of which 247 (82%) responded. Thereafter, follow-up questionnaires were sent every six months for two years.ResultsNinety-two patients died by August 2017. Among these patients, HRQOL was found to be considerably low already two years before death. The most prominent declines in HRQOL occurred in physical function, vitality, emotional role and social functioning (p
  • Kauma, Iiro (Helsingfors universitet, 2016)
    Bronchopulmonary dysplasia (BPD) is a chronic lung condition of extremely premature neonates. In most cases BPD is a treatable condition, however it is still a major complication in neonatal intensive care. Inflammatory processes have been strongly linked to BPD pathophysiology. NF-κB is a transcription factor family, which is associated with immunity and cell stress responses. We assessed the association of NF-κB and bronchopulmonary dysplasia, elucidated the NF-κB activity during development of BPD and compared NF-κB activity in BPD and adult idiopathic pulmonary fibrosis. Methods: We assessed NF-κB activity with immunohistochemical methods. Respiratory distress syndrome (RDS) (n=7) and BPD (n=7) samples were gathered in autopsies. IPF (n=6) samples were taken from explanted lungs in transplant surgeries. Results: NF-κB activity in the RDS group was 0 %, whereas in the BPD group it was 57 %. 66 % of the samples in the IPF group were NF-κB active. NF-κB activity was significantly higher at a bronchiolar level in the BPD group compared to the RDS group (p= 0.024), no significant difference was observed at an alveolar level. BDP and IPF samples were similar when comparing bronchiolar level activity, but at an alveolar level, IPF samples were more active, although this failed to reach statistical significance (p=0.113). Conclusion: Our study does not implicate a central role for NF-κB in BPD pathophysiology. NF-κB activity, however, increased from RDS to BPD, which might underlie the disease development. IPF samples contained same pattern of NF-κB activity than BPD samples indicating that a similar mechanism could be driving fibrosis in both BPD and IPF. This is a new insight, since typically, inflammatory processes and NF-κB have not been associated with IPF.
  • Vartiainen, Ville; Raula, Janne; Bimbo, Luis M.; Viinamäki, Jenni; Backman, Janne T.; Ugur, Nurcin; Kauppinen, Esko; Sutinen, Eva; Joensuu, Emmi; Koli, Katri; Myllärniemi, Marjukka (2018)
    The aim of this work was to study the antifibrotic effect of pulmonary administration of tilorone to lung fibrosis. L-leucine coated tilorone particles were prepared and their aerosolization properties were analyzed using two dry powder inhalers (Easyhaler and Twister). In addition, the biological activity and cell monolayer permeation was tested. The antifibrotic effect of tilorone delivered by oropharyngeal aspiration was studied in vivo using a silica-induced model of pulmonary fibrosis in mice in a preventive setting. When delivered from the Easyhaler in an inhalation simulator, the emitted dose and fine particle fraction were independent from the pressure applied and showed dose repeatability. However, with Twister the aerosolization was pressure-dependent indicating poor compatibility between the device and the formulation. The formulation showed more consistent permeation through a differentiated Calu-3 cell monolayer compared to pristine tilorone. Tilorone decreased the histological fibrosis score in vivo in systemic and local administration, but only systemic administration decreased the mRNA expression of type I collagen. The difference was hypothesized to result from 40-fold higher drug concentration in tissue samples in the systemic administration group. These results show that tilorone can be formulated as inhalable dry powder and has potential as an oral and inhalable antifibrotic drug.
  • Kaunisto, Jaana; Kelloniemi, K.; Sutinen, E.; Hodgson, U.; Piilonen, A.; Kaarteenaho, R.; Makitaro, R.; Purokivi, M.; Lappi-Blanco, E.; Saarelainen, S.; Kankaanranta, H.; Mursu, A.; Kanervisto, M.; Salomaa, E-R.; Myllärniemi, M. (2015)
    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 31st 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.
  • Fadista, Joao; Kraven, Luke M.; Karjalainen, Juha; Andrews, Shea J.; Geller, Frank; Baillie, J. Kenneth; Wain, Louise; Jenkins, R. Gisli; Feenstra, Bjarke (2021)
    Background: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease, characterized by progressive lung scarring. Severe COVID-19 is associated with substantial pneumonitis and has a number of shared major risk factors with IPF. This study aimed to determine the genetic correlation between IPF and severe COVID-19 and assess a potential causal role of genetically increased risk of IPF on COVID-19 severity. Methods: The genetic correlation between IPF and COVID-19 severity was estimated with linkage disequilib-rium (LD) score regression. We performed a Mendelian randomization (MR) study for IPF causality in COVID-19. Genetic variants associated with IPF susceptibility (P Findings: We detected a positive genetic correlation of IPF with COVID-19 severity (rg=0.31 [95% CI 0.04-0.57], P = 0.023). The MR estimates for severe COVID-19 did not reveal any genetic association (OR 1.05, [95% CI 0.92-1.20], P = 0.43). However, outlier analysis revealed that the IPF risk allele rs35705950 at MUC5B had a dif-ferent effect compared with the other variants. When rs35705950 was excluded, MR results provided evidence that genetically increased risk of IPF has a causal effect on COVID-19 severity (OR 1.21, [95% CI 1.06-1.38], P = 4.24 x 10(-3)). Furthermore, the IPF risk-allele at MUC5B showed an apparent protective effect against COVID-19 hospitalization only in older adults (OR 0.86, [95% CI 0.73-1.00], P = 2.99 x 10(-2)) . Interpretation: The strongest genetic determinant of IPF, rs35705950 at MUC5B, seems to confer protection against COVID-19, whereas the combined effect of all other IPF risk loci seem to confer risk of COVID-19 severity. The observed effect of rs35705950 could either be due to protective effects of mucin over-produc-tion on the airways or a consequence of selection bias due to (1) a patient group that is heavily enriched for the rs35705950 T undertaking strict self-isolation and/or (2) due to survival bias of the rs35705950 non-IPF risk allele carriers. Due to the diverse impact of IPF causal variants on SARS-CoV-2 infection, with a possible selection bias as an explanation, further investigation is needed to address this apparent paradox between variance at MUC5B and other IPF genetic risk factors. (C) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
  • Myllärniemi, Marjukka; Tikkanen, Jussi; Hulmi, Juha J.; Pasternack, Arja; Sutinen, Eva; Ronty, Mikko; Lepparanta, Outi; Ma, Hongqiang; Ritvos, Olli; Koli, Katri (2014)