Sleep breathing disorders in patients with idiopathic pulmonary fibrosis (IPF)

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic irreversible diffuse interstitial lung disease of unknown etiology, characterized by progressive destruction of normal lung architecture and scarring of the lung parenchyma with the histologic / radiologic pattern of usual interstitial pneumonia (UIP). It is a fatal disease, with a median survival of three years after diagnosis, without effective treatment apart from medications that delay disease progression, treatment of respiratory failure and comorbidities when they occur. According to recent scientific data, sleep breathing disorders represent one of the most common comorbidities in IPF but have not been adequately studied.Aim: The description and study of sleep breathing disorders (SBDs) in patients with idiopathic pulmonary fibrosis (IPF), their relationship to clinical, functional and physiological parameters of disease and the study of their effect on survival and quality of sleep and life of patients with IPF.Μethods: In a group of 31 treatment naïve newly diagnosed patients with IPF who fulfilled the international diagnostic criteria of IPF / UIP, we prospectively studied sleep parameters with polysomnography. We prospectively investigated the relationship of SBD parameters such as apnea hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO2), and lowest sleep oxygen saturation (lowest SpO2) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal [6-min walk test (6MWT)] and maximal exercise variables [cardiopulmonary exercise test (CPET)], and right ventricular systolic pressure (RVSP) as well as with parameters of quality of life and sleep.Results: We found that obstructive sleep apnea syndrome (OSAS), defined by AHI>5, occurs at a rate of 90.3% in patients with IPF. Among the characteristics of sleep, oxygen desaturation during sleep significantly exceeded that of maximum exercise, and both parameters examined (the maxdiff-SaO2 and minimum SaO2 during sleep) were associated with survival. Maxdiff-SaO2 correlated inversely with DLCO% and SaO2 after 6MWT, and directly to the MRC, the AHI and RVSP, whereas the minimum SaO2 during sleep was related directly with functional parameters (TLC%, DLCO% ) as well as physiological parameters of exercise tests (6MWT distance, SaO2 after 6MWT, VO2 peak / kg, SaO2 peak), and inversely with the MRC, AHI and RVSP.After exclusion of the subgroup of patients with IPF who had been treated with CPAP for OSAS, AHI was associated with significantly decreased survival.Also, a significant correlation emerged between both desaturation parameters examined [ minimum SaO2 during sleep, the difference in oxygen saturation between wakefulness and sleep (maxdiff-SaO2)] and the RVSP with the questionnaire related to sleep-related quality of life (FOSQ, Functional Outcome of Sleep Questionnaire), the Athens insomnia scale (AIS, Athens Insomnia Scale) and Beck depression questionnaire (BDI, Beck Depression Inventory).Conclusions The main finding of this study is that in patients with IPF, intermittent sleep oxygen desaturation exceeds significantly that of maximal exercise and is associated with survival. Both sleep oxygen desaturation variables studied (maxdiff-SaO2, minimum SaO2), significantly correlated not only with survival but also with lung injury, as reflected by functional parameters (TLC%, DLCO%), sleep apneas-hypopneas, exercise oxygen desaturation, breathlessness, and systolic right ventricular pressure (RVSP). These results suggest that in patients with IPF a potential relationship and interaction exists between the degree of lung injury and sleep-apnea events in the generation, induction, and the size of the intermittent oxygen desaturation during sleep, and hence the role that desaturation may have in the burden of pulmonary hypertension and to the negative impact on survival of patients with IPF. Further studies are needed to clarify this issue and underlying pathophysiological mechanisms.Εισαγωγή: Η ιδιοπαθής πνευμονική ίνωση (IPF) είναι μία χρόνια μη αναστρέψιμη διάχυτη διάμεση πνευμονοπάθεια άγνωστης αιτιολογίας, η οποία χαρακτηρίζεται από την προοδευτική καταστροφή της φυσιολογικής αρχιτεκτονικής των πνευμόνων και την ουλοποίηση του πνευμονικού παρεγχύματος με το ιστολογικό/ακτινολογικό πρότυπο της συνήθους διάμεσης πνευμονίας (UIP). Είναι θανατηφόρος νόσος, με διάμεση επιβίωση τρία έτη από την διάγνωση, χωρίς αποτελεσματική θεραπεία πέραν από την προσπάθεια φαρμακευτικής επιβράδυνσης της πορείας της νόσου, την αντιμετώπιση της αναπνευστικής ανεπάρκειας όταν αυτή προκύπτει καθώς και των συννοσηροτήτων. Σύμφωνα με σχετικά πρόσφατα επιστημονικά δεδομένα, οι διαταραχές της αναπνοής στον ύπνο αποτελούν μια από τις συχνότερες συννοσηρότητες στην IPF που όμως δεν έχουν μελετηθεί επαρκώς.Σκοπός: Η περιγραφή και μελέτη των διαταραχών της αναπνοής στον ύπνο (SBDs) σε ασθενείς με ιδιοπαθή πνευμονική ίνωση (IPF) και ο τρόπος που αυτές σχετίζονται με κλινικούς, λειτουργικούς και φυσιολογικούς δείκτες της νόσου καθώς και η μελέτη της επίδρασης τους στην επιβίωση και στην ποιότητα ύπνου και ζωής των ασθενών με IPF.Μέθοδος: Σε μία ομάδα 31 πρωτοδιαγνωσμένων ασθενών με IPF οι οποίοι δεν ελάμβαναν θεραπευτική αγωγή και πληρούσαν τα διεθνή διαγνωστικά κριτήρια της IPF/UIP, μελετήσαμε προοπτικά παραμέτρους του ύπνου με πολυκαταγραφική μελέτη ύπνου και στη συνέχεια εξετάσαμε τη σχέση των SBDs παραμέτρων με την επιβίωση καθώς και με κλινικούς δείκτες, δείκτες πνευμονικής λειτουργίας όπως αυτοί αντικατοπτρίζονται στον πλήρη λειτουργικό έλεγχο της αναπνοής και στις δοκιμασίες άσκησης, με την πνευμονική υπέρταση όπως αυτή αντικατοπτρίζεται στη συστολική πίεση της δεξιάς κοιλίας (RVSP) από το υπερηχογράφημα καρδιάς καθώς και με παραμέτρους της ποιότητας ζωής.Αποτελέσματα: Διαπιστώσαμε ότι το σύνδρομο αποφρακτικής άπνοιας στον ύπνο (OSAS), έτσι όπως ο δείκτης AHI>5 καθορίζει, απαντάται σε ποσοστό 90.3% των ασθενών με IPF που μελετήθηκαν. Μεταξύ των χαρακτηριστικών του ύπνου, οι αποκορεσμοί οξυγόνου κατά την διάρκεια του ύπνου υπερέβησαν στατιστικά σημαντικά εκείνους της μέγιστης άσκησης ενώ και οι δύο παράμετροι που εξετάστηκαν (η διαφορά του κορεσμού σε οξυγόνο μεταξύ εγρήγορσης και ύπνου- maxdiff-SaO2 και ο ελάχιστος SaO2 κατά τη διάρκεια του ύπνου) σχετίζονταν με την επιβίωση. Ακόμα η maxdiff-SaO2 συσχετιζόταν αντιστρόφως ανάλογα με την DLCO% και τον SaO2 μετά 6MWT, και ανάλογα με την MRC, τον ΑΗΙ και την RVSP, ενώ ο ελάχιστος SaO2 κατά τη διάρκεια του ύπνου σχετιζόταν ανάλογα με λειτουργικές παραμέτρους (TLC%, DLCO%) καθώς και με φυσιολογικές παραμέτρους δοκιμασιών άσκησης (6MWT απόσταση, SaO2 μετά 6MWT, VO2 peak/kg, SaO2 peak) και αντιστρόφως ανάλογα με τις MRC, AHI και RVSP.Μετά από αποκλεισμό της υποομάδας των ασθενών με IPF που είχαν τεθεί σε θεραπεία με CPAP για OSAS, και ο ΑΗΙ βρέθηκε να συσχετίζεται σημαντικά με μειωμένη επιβίωση.Επίσης, αναδείχθηκε σημαντική συσχέτιση μεταξύ των δύο παραμέτρων αποκορεσμού που εξετάστηκαν [του ελάχιστου SaO2 κατά τη διάρκεια του ύπνου, της διαφοράς του κορεσμού σε οξυγόνο μεταξύ εγρήγορσης και ύπνου (maxdiff-SaO2)] καθώς και της RVSP με το ερωτηματολόγιο για την ποιότητα ζωής σχετιζόμενης με τον ύπνο (FOSQ Functional Outcome of Sleep Questionnaire), την κλίμακα αϋπνίας Αθηνών (AIS Athens Insomnia Scale) και το ερωτηματολόγιο κατάθλιψης του Beck (BDI Beck Depression Inventory).Συμπεράσματα: Το κύριο εύρημα της παρούσας μελέτης είναι ότι στους ασθενείς με ΙPF, οι αποκορεσμοί οξυγόνου κατά την διάρκεια του ύπνου υπερβαίνουν εκείνον της μέγιστης άσκησης, και σχετίζονται με την επιβίωση. Και οι δύο παράμετροι αποκορεσμού οξυγόνου στον ύπνο (maxdiff-SaO2, ελάχιστος SaO2) τις οποίες εξετάσαμε συσχετίζονταν σημαντικά όχι μόνο με την επιβίωση αλλά και με την πνευμονική βλάβη, όπως αυτή αντικατοπτρίζεται από τις λειτουργικές παραμέτρους (TLC %, DLCO %), τα υπνο-απνοϊκά επεισόδια, τον αποκορεσμό οξυγόνου στην άσκηση, την δύσπνοια, και την συστολική πίεση της δεξιάς κοιλίας (RVSP). Τα αποτελέσματα αυτά υποδηλώνουν πιθανά ότι σε ασθενείς με IPF υπάρχει σχέση και αλληλεπίδραση μεταξύ του βαθμού της πνευμονικής βλάβης και των υπνο-απνοικών επεισοδίων στην γένεση, επαγωγή και το μέγεθος των διαλειπόντων αποκορεσμών οξυγόνου κατά την διάρκεια του ύπνου και κατά συνέπεια στον ρόλο που ο αποκορεσμός μπορεί να έχει στην επιβάρυνση της πνευμονικής υπέρτασης και στην αρνητική επίδραση στην επιβίωση των ασθενών με IPF

Introducing transbronchial cryobiopsies in diagnosing diffuse parenchymal lung diseases in Greece: Implementing training into clinical practice.

IntroductionDiffuse parenchymal lung diseases (DPLD) constitute a heterogeneous group of disorders, sometimes requiring surgical lung biopsies (SLB) to obtain a definite diagnosis. Transbronchial cryobiopsy (TBCB) is a new promising interventional bronchoscopic method of obtaining lung tissue that is gaining ground against SLB.MethodsFifty consecutive patients with indeterminate DPLD (definite/possible UIP excluded), after expert panel review referral, were retrospectively analyzed from January 2016 to August 2018. Patients underwent TBCB under deep sedation with endotracheal intubation and spontaneous breathing at a single, tertiary-care, reference hospital.ResultsA total of 110 TBCBs (2.7 per patient, range 1 to 4) were performed. Frequent complications included mild pneumothorax in 5 patients (10%), requiring only oxygen supplementation, and bleeding in 31 patients (62%) that was mild in 19 patients and moderate in 12 patients. No serious bleeding was observed. There was zero mortality and no serious adverse events. Adequate samples for diagnostic purposes were obtained in 46 patients (92%) and pathologic histologic diagnosis was reached in 40 patients (80%). The most frequent histopathological patterns were organizing pneumonia (OP) (25%) and non-specific interstitial pneumonia (NSIP) (15%). After an expert panel review of all cases a final diagnosis was achieved in 38 patients, corresponding to a diagnostic yield of 76% for TBCB.ConclusionOur single center cohort demonstrates that establishing TBCBs as a new technique is safe and feasible after proper training in specialized centers, resulting in low complication rates and adequate diagnostic yields

Control of asthma in real life: still a valuable goal?

Although studies show that control of asthma can be achieved in the majority of patients, surveys repeatedly show that this is not the case in real life. Important measures to implement in order to achieve asthma control are trained healthcare professionals, a good patient–doctor relationship, patient education, avoidance of exposure to triggers, personalised management and adherence to treatment. These measures help the majority of asthma patients but have not yet been widely implemented and there should be a concerted action for their implementation. Moreover, further and focused research is needed in severe/refractory asthma

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

International audienceBackground: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing

Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing

Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison

International audiencePrevious studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may occur without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered

Peripheral blood natural killer cells in sarcoidosis are associated with early cardiac involvement

Aim To evaluate the distribution of circulating immune cell subsets in peripheral blood of patients with sarcoidosis and investigate if there is an association with an underlying cardiac involvement. Methods and results Eighty-five newly diagnosed treatment-naive patients with sarcoidosis (50 women) were included in the study. All patients underwent a thorough cardiac investigation, including cardiac magnetic resonance imaging (CMR). Of all patients, 19 (23.53%) had myocardial involvement, and the NK subpopulation in these patients in peripheral blood was significantly decreased compared to patients without (n = 63, p = 0.001 and p = 0.003 respectively). The absolute number of NKT cells (CD3+CD16/56(+)) in patients with cardiac involvement was highly correlated with T2 map increased values in MRI (r = -686, p = 0.041) showing that low NKT cell count correlates with the inflammatory process of the heart. No difference in CD19, CD3, CD4, CD8 and CD3(-)NK cell counts was found between groups. Lung severity was not found to correlate with the number of NK cells. Conclusion We found that low NK cell count in peripheral blood of patients with sarcoidosis is associated with cardiac involvement, and the number of NK-T cells correlates with CMR findings indicative of myocardial inflammation. This finding might have a potential clinical application in detecting clinically silent cardiac involvement in sarcoidosis and may also suggest potential targets for therapeutic interventions

Autoimmune PAP (aPAP) in children

In childhood, a multitude of causes lead to pulmonary alveolar proteinosis (PAP), an excessive surfactant accumulation in the alveolar space, limiting gas exchange. Autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF) causing autoimmune PAP, the principal aetiology in adults, are rare. In this first case series on autoimmune PAP, we detail the presentation and management issues of four children. Whereas three children presented insidiously with progressive dyspnoea, one was acutely sick with suspected pneumonia. During management, one patient was hospitalised with coronavirus disease 2019, noninvasively ventilated, and recovered. All treatment modalities known from adults including whole-lung lavage, augmentation of GM-CSF by inhaled GM-CSF, removal of neutralising antibody by plasmapheresis and interruption of antibody production using rituximab were considered; however, not all options were available at all sites. Inhaled GM-CSF appeared to be a noninvasive and comfortable therapeutic approach. The management with best benefit-to-harm ratio in autoimmune PAP is unknown and specialised physicians must select the least invasive and most effective treatment. To collect this cohort in a rare condition became feasible as patients were submitted to an appropriate registry. To accelerate the authorisation of novel treatments for autoimmune PAP, competent authorities should grant an inclusion of adolescents into trials in adults