Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study.

BACKGROUND: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients' characteristics in the Greek national IPF cohort with suspected heritability. PATIENTS AND METHODS: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. RESULTS: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. CONCLUSION: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease's genetic "richesse," complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating "personalized" medical care driven by genotypes in the near future.

Myelodysplastic syndromes and idiopathic pulmonary fibrosis: a dangerous liaison.

Previous 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.

High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations.

INTRODUCTION: Controversy exists about the pathogenesis of idiopathic pulmonary fibrosis acute exacerbations (IPF-AEs). According to one hypothesis IPF-AEs represent the development of any etiology diffuse alveolar damage (DAD) upon usual interstitial pneumonia (UIP), whilst other researchers argue that an accelerated phase of the intrinsic fibrotic process of unknown etiology prevails, leading to ARDS. Different cytokines might be involved in both processes. The aim of this study was to assess pro-inflammatory and pro-fibrotic cytokines in the peripheral blood from stable and exacerbated IPF patients. METHODS: Consecutive IPF patients referred to our department were included. Diagnoses of IPF and IPF-AE were based on international guidelines and consensus criteria. The interleukins (IL)-4, IL-6, IL-8, IL-10, and IL-13 as well asactive transforming growth factor-beta (TGF-ß) were measured in blood from both stable and exacerbated patients on the day of hospital admission for deterioration. Subjects were followed for 12months. Mann-Whitney test as well as Tobit and logistic regression analyses were applied. RESULTS: Among the 41 patients studied, 23 were stable, and 18 under exacerbation; of the latter, 12 patients survived. The IL-6 and IL-8 levels were significantly higher in exacerbated patients (p=0.002 and p=0.046, respectively). An increase in either IL-6 or IL-8 by 1pg/ml increases the odds of death by 5.6% (p=0.021) and 6.7% (p=0.013), respectively, in all patients. No differences were detected for the other cytokines. CONCLUSION: High levels of IL-6 and IL-8 characterize early-on IPF-AEs and an increase in the levels of IL-6 and IL-8 associates with worse outcome in all patients. However, as the most representative pro-fibrotic cytokines, TGF-ß, IL-10, IL-4 and IL-13 were not increased and given the dualistic nature, both pro-inflammatory and pro-fibrotic of IL-6 further studies are necessary to clarify the enigma of IPF-AEs etiopathogenesis.

Acute Respiratory Events in Connective Tissue Disorders.

Subacute-acute, hyperacute, or even catastrophic and fulminant respiratory events occur in almost all classic connective tissue disorders (CTDs); they may share systemic life-threatening manifestations, may precipitously lead to respiratory failure requiring ventilatory support as well as a combination of specific therapeutic measures, and in most affected patients constitute the devastating end-of-life event. In CTDs, acute respiratory events may be related to any respiratory compartment including the airways, lung parenchyma, alveolar capillaries, lung vessels, pleura, and ventilatory muscles. Acute respiratory events may also precipitate disease-specific extrapulmonary organ involvement such as aspiration pneumonia and lead to digestive tract involvement and heart-related respiratory events. Finally, antirheumatic drug-related acute respiratory toxicity as well as lung infections related to the rheumatic disease and/or to immunosuppression complete the spectrum of acute respiratory events. Overall, in CTDs the lungs significantly contribute to morbidity and mortality, since they constitute a common site of disease involvement; a major site of infections related to the 'mater' disease; a major site of drug-related toxicity, and a common site of treatment-related infectious complications. The extreme spectrum of the abovementioned events, as well as the 'vicious' coexistence of most of the aforementioned manifestations, requires skills, specific diagnostic and therapeutic means, and most of all a multidisciplinary approach of adequately prepared and expert scientists. Avoiding lung disease might represent a major concern for future advancements in the treatment of autoimmune disorders.

Investigation of Lung Involvement in Connective Tissue Disorders.

Lung involvement in connective tissue disorders (CTDs) may present as pleomorphic since any lung compartment may be involved such as airways, exocrine secretory and alveolar epithelia, interstitial lung structure, pulmonary vasculature and pleura as well as, in specific disorders, several tissues of the thoracoabdominal ventilator pump. Any combination of the above anatomic structures may be involved concomitantly although some specific combinations may include a determinant of rheumatic disorders. The diagnosis of a specific CTD requires the fulfilment of clearly defined clinical and laboratory criteria including in most cases positivity for autoantibodies, mostly specific serologic combinations. In this setting, serologic investigation targets mainly, although not exclusively, the detection of antinuclear antibodies. A specific serologic positivity or a combination of autoantibodies constitutes not only a diagnostic criterion for a specific CTD, but may also characterize the pattern of respiratory manifestation in a determinant rheumatic disorder. Therefore, the investigation of lung involvement in CTDs requires adequate skills in the ambit of a multidisciplinary approach and an extended spectrum of diagnostic tools and modalities able to detect both early clinical clues and serologic conversion as well as any pathophysiologic alteration that regards the complexity of respiratory functional status. Although many patients with CTDs suffer from a 'vicious' combination of lung involvement, lung drug toxicity and infections related to the above two as well as to the 'mater' disease, for space reasons this review will focus on the established lung manifestations that regard the 7 major CTDs.

Survival in Idiopathic pulmonary fibrosis acute exacerbations: the non-steroid approach.

BACKGROUND: Idiopathic pulmonary fibrosis acute exacerbation (IPF-AE) constitutes IPF's most devastating event, representing the unexpected superimposition of diffuse alveolar damage of unknown etiology. Guidelines recommend high-dose steroids treatment despite unproven benefit. We hypothesized that previous immunosuppression and the administration of high-dose steroids adversely affect IPF-AE outcome. METHODS: We studied all consecutive patients hospitalized in our department for IPF deterioration from 2007 to June 2013. Our protocol consisted of immediate cessation of immunosuppression (if any), best supportive care, broad-spectrum antimicrobials and thorough evaluation to detect reversible causes of deterioration. Patients were followed-up for survival; post-discharge none received immunosuppression. RESULTS: Twenty-four out of 85 admissions (28%) fulfilled IPF-AE criteria. IPF-AE were analyzed both as unique events and as unique patients. As unique events 50% survived; 3 out of 12 (25%) in the group previously treated with immunosuppression whereas nine out of 12 (75%) in the group not receiving immunosuppression (p = 0.041). As unique patients 35.3% survived; 3 out of 6 (50%) in the never treated group whereas three out of 11 (27.3%) in the group receiving immunosuppression (p = 0.685). The history of immunosuppression significantly and adversely influenced survival (p = 0.035). Survival was greater in the never treated group compared to the immunosuppressed patients (p = 0.022). Post-discharge, our IPF-AE survivors had an 83% 1-year survival. CONCLUSIONS: By applying the above mentioned protocol half of our patients survived. The history of immunosuppression before IPF-AE adversely influences survival. Avoiding steroids in IPF patients may favor the natural history of the disease even at the moment of its most devastating event.

Treating CTDs related fibrotic ILDs by immunosuppressants: "facts and faults".

Fibrotic interstitial lung diseases (ILDs) are commonly encountered in scleroderma where they significantly influence prognosis. The mainstay of treatment in idiopathic fibrotic ILDs for the past 30 years was based on the combined administration of prednisone and cyclophosphamide (CYC) or prednisone, azathioprine plus N-acetyl cysteine, recently proved ineffective and harmful. Rheumatologists also despite "facts" showing that CYC treatment has no beneficial impact on fibrotic ILDs in scleroderma continue to commit the same, in a manner of speaking, "faults" by "treating their fibrotic ILDs by immunosuppressants." In this issue of the journal, Panopoulos et al. (Lung, 191, 483-489, 2013) recognizing the minimal effect of CYC on fibrotic ILDs in scleroderma patients and the increased use in clinical practice of mycophenolate mofetil (MMF) as an alternative, report that MMF use to replace CYC in this setting is not supported, confirming that restoration of purely fibrotic damage in the lungs remains one of the most challenging fields in medicine.

Serologic evaluation in idiopathic interstitial pneumonias.

PURPOSE OF REVIEW: Diagnosis of idiopathic interstitial pneumonias (IIPs) requires the exclusion of, among others, concomitant connective tissue diseases (CTDs), which may present as interstitial lung disease (ILD). This review focuses on the evaluation required to separate these entities through serology, although not exclusively. RECENT FINDINGS: Several recent data suggest that patients diagnosed with IIPs can show evidence of CTDs on follow-up. This is especially true for nonspecific interstitial pneumonia but may also be seen with other forms of ILD. SUMMARY: ILDs may occur alone, IIPs, or in association with, among others, CTDs. In the latter case, they may present before, during or even several months or years after the fulfillment of undisputed criteria for CTDs. If present before, their presentation presupposes their occurrence in early undiagnosed, undefined or undifferentiated CTD, which occasionally indefinitely maintains this status of diagnostic uncertainty, especially if ILD is empirically treated by immunosuppressants. Serologic evaluation for autoantibodies assisted by serum inflammatory biomarkers, detailed search for clinical clues of CTDs and suggestive histopathologic features on lung specimens may provide a framework to build the correct diagnosis. Obtaining a diagnosis of ILD associated with CTD exceeds semantics as this subset of patients may present different natural history, pathobiology, treatment and prognosis.

Clinical review: idiopathic pulmonary fibrosis acute exacerbations--unravelling Ariadne's thread.

Idiopathic pulmonary fibrosis (IPF) is a dreadful, chronic, and irreversibly progressive fibrosing disease leading to death in all patients affected, and IPF acute exacerbations constitute the most devastating complication during its clinical course. IPF exacerbations are subacute/acute, clinically significant deteriorations of unidentifiable cause that usually transform the slow and more or less steady disease decline to the unexpected appearance of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) ending in death. The histological picture is that of diffuse alveolar damage (DAD), which is the tissue counterpart of ARDS, upon usual interstitial pneumonia, which is the tissue equivalent of IPF. ALI/ARDS and acute interstitial pneumonia share with IPF exacerbations the tissue damage pattern of DAD. 'Treatment' with high-dose corticosteroids with or without an immunosuppressant proved ineffective and represents the coup de grace for these patients. Provision of excellent supportive care and the search for and treatment of the 'underlying cause' remain the only options. IPF exacerbations require rapid decisions about when and whether to initiate mechanical support. Admission to an intensive care unit (ICU) is a particular clinical and ethical challenge because of the extremely poor outcome. Transplantation in the ICU setting often presents insurmountable difficulties.

Cardiovascular risk in pulmonary alveolar proteinosis.

We hypothesized that cardiovascular events and/or indices of cardiac dysfunction may be increased in pulmonary alveolar proteinosis (PAP). Systemic and pulmonary arterial hypertension, arrhythmias, pulmonary embolism, stroke and ischemic heart attack were reported. Patients underwent serum anti-GM-CSF antibodies, disease severity score (DSS), Doppler transthoracic echocardiograph, glucose, thyroid hormones, lipids, troponin and pro-Brain natriuretic peptide (BNP) examination. Thirteen patients (8 female) were studied, median age of 47. Pro-BNP inversely related to DLCO% and TLC%; troponin directly related to DSS, age, P(A-a)O2, left atrium-, left ventricle-end-diastole diameter and BMI. On multiple regression analysis DSS was the only parameter significantly and strongly related with troponin (R(2) = 0.776, p = 0.007). No cardiovascular event was reported during follow-up. In PAP cardiovascular risk indices relate to lung disease severity. Therefore, PAP patients could be at increased risk for cardiovascular events. Quantitation of its magnitude and potential links to lungs' physiologic derangement will be addressed in future studies.

Pulmonary alveolar proteinosis: time to shift?

Pulmonary alveolar proteinosis (PAP) is categorized into hereditary, secondary and autoimmune PAP (aPAP) types. The common pathogenesis is the ability of the alveolar macrophages to catabolize phagocytized surfactant is affected. Hereditary PAP is caused by mutations involving the GM-CSF signaling, particularly in genes for the GM-CSF receptor and sometimes by GATA2 mutations. Secondary PAP occurs in hematologic malignancies, other hematologic disorders, miscellaneous malignancies, fume and dust inhalation, drugs, autoimmune disorders and immunodeficiencies. aPAP is related to the production of GM-CSF autoantibodies. PAP is characterized morphologically by the inappropriate and progressive 'occupation' of the alveolar spaces by an excessive amount of unprocessed surfactant, limiting gas exchange and gradually exhausting the respiratory reserve. Myeloid cells' immunity deteriorates, increasing the risk of infections. Treatment of PAP is based on its etiology. In aPAP, recent therapeutic advances might shift the treatment option from the whole lung lavage procedure under general anesthesia to the inhalation of GM-CSF 'as needed'.

Innate immunity alterations in idiopathic interstitial pneumonias and rheumatoid arthritis-associated interstitial lung diseases.

BACKGROUND: This is a prospective cohort study elucidating innate immunity in idiopathic pulmonary fibrosis (IPF), cryptogenic organizing pneumonia (COP), rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) and RA-associated non specific interstitial pneumonia (RA-NSIP). METHODS: 23 IPF subjects, 9 COP subjects, 5 RA-UIP subjects, 8 RA-NSIP subjects were enrolled. 10 subjects were excluded. 19 healthy subjects served as controls. Blood and bronchoalveolar lavage (BAL) were obtained. Natural killer (NK) and NKT cells, NK cells apoptosis and the expression of triggering receptor expressed on myeloid cells type 1 (TREM-1) were assessed. Tumor necrosis factor-α (TNF-α) production was measured in cell cultures after stimulation with lipopolysaccharide endotoxin (LPS) and Pam3CysSK3, and in BAL. Surface expression of Toll-like receptors (TLR) 2 and 4 on peripheral blood monocytes (PBMC's) and circulating NK cells was also assessed. RESULTS: RA-NSIP had low blood NKs, marginally insignificant (p=0.07). These NKs poorly produced TNF-α after LPS stimulation. TLR's expression on NK cells was similar throughout disease groups and controls. PBMC's mainly from IPF patients exhibited low TNF-α production after LPS stimulation but not after Pam3CysSK3 stimulation, while TLR4 expression on PBMC's was found normal in all study groups. TLR2 expression on PBMC's was increased in IPF, but mainly in COP, RA-UIP and RA-NSIP (p=0.015). TREM-1 expression was significant on COP monocytes and on COP neutrophils versus controls. RA-NSIP monocytes also exhibited TREM-1 expression (p=0.07). Decreased TNF-α concentration in BAL was finally observed in IPF and RA-UIP. CONCLUSIONS: Innate immunity in the lungs and the peripheral circulation in IPF and RA-UIP are similar and more fibrotic than in RA-NSIP which is characterized by NK cell depletion and dysfunction. TREM-1 and TLR's likely affect patterns of inflammation in various interstitial lung diseases.

Patterns of airway involvement in inflammatory bowel diseases.

Extraintestinal manifestations occur commonly in inflammatory bowel diseases (IBD). Pulmonary manifestations (PM) of IBD may be divided in airway disorders, interstitial lung disorders, serositis, pulmonary vasculitis, necrobiotic nodules, drug-induced lung disease, thromboembolic lung disease and enteropulmonary fistulas. Pulmonary involvement may often be asymptomatic and detected solely on the basis of abnormal screening tests. The common embryonic origin of the intestine and the lungs from the primitive foregut, the co-existence of mucosa associated lymphoid tissue in both organs, autoimmunity, smoking and bacterial translocation from the colon to the lungs may all be involved in the pathogenesis of PM in IBD. PM are mainly detected by pulmonary function tests and high-resolution computed tomography. This review will focus on the involvement of the airways in the context of IBD, especially stenoses of the large airways, tracheobronchitis, bronchiectasis, bronchitis, mucoid impaction, bronchial granulomas, bronchiolitis, bronchiolitis obliterans syndrome and the co-existence of IBD with asthma, chronic obstructive pulmonary disease, sarcoidosis and a1-antitrypsin deficiency.

Idiopathic pulmonary fibrosis acute exacerbations: where are we now?

Considerable controversy is haunting the treatment of IPF 'acute exacerbation', its most devastating complication. The consensus coined term 'acute exacerbation' implies that on an unknown etiology disease such as IPF, an unknown etiology superimposed acute lung injury/acute respiratory distress syndrome (ALI/ARDS) represents the end-life event in a consistent proportion of patients and are treated by high dose steroids despite unproven benefit. Inversely, ALI/ARDS treatment recommendations are based on the provision of excellent supportive care plus an extensive search and appropriate treatment of the etiologic precipitant and all intensive care clinicians in the absence of an obvious etiology, considering that occult infection is the most probable and also the most treatable underlying condition, universally administer extensive spectrum antimicrobials. Viewing the persistent high mortality in IPF 'acute exacerbations' treated with steroids we strongly believe that a study comparing the two arms of the steroid and non-steroid approach is greatly awaited by scientists and owed to the patients.