IPF Patients Research Articles

Autophagy in Idiopathic Pulmonary Fibrosis

BackgroundAutophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.MethodsHuman lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β1 on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model.ResultsLung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β1 inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β1. In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin.ConclusionAutophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β1 may represent a mechanism for the promotion of fibrogenesis in IPF.

Role of BAL cellularity in assessment of severity of idiopathic pulmonary fibrosis

Background/aimStudy the role of BAL cellularity in assessment of the degree of severity of IPF. MethodsForty IPF patients underwent, history taking, clinical examination, HRCT chest, ABGs, 6MWT, spirometry, echocardiography, FOB and BAL. ResultsNeutrophils were present in 28 patients, mean value 57.25 and SD±31.27. The second predominant cell was Alveolar Macrophages with mean value 24.25 and SD±27.828.HRCT pattern and BAL cellularity, showed the most predominant cell neutrophils in the ground glass and Honey combing on HRCT. There was no statistical significance between the sex and the BAL cellularity, the most predominant cell was neutrophils in both sexes. Corticosteroids did not have an effect on BAL cellularity and the predominant cell was neutrophils in IPF patients using steroids and those not. BAL cellularity in relation to treatment by azathioprine and/or acetlycysteine showed no statistical significance between patients using those drugs and those not, the most predominant cell was neutrophils in both groups.Correlation between BAL cellularity and age, showed no statistical significance but there was a negative correlation between age to neutrophils and lymphocytes. There was a negative correlation between neutrophils and PaCO2, PaO2, SO2, FVC%, FEV1 and 6MWT with no statistical significance but with significance to FEF25–75%.Macrophages showed a positive correlation with age, PaO2, 6MWT, FVC%, FEV1% with no statistical significance but with significance to SO2 and FEF25–75% and a negative correlation with PaCO2 and PASP. ConclusionThere was a positive correlation between neutrophils and severity of the disease and a negative correlation between Macrophages and severity of the disease. Most commonly used drugs did not show any effect on BAL cellularity.

ProSP-B as a potential biomarker in diffuse parenchymal lung disease (DPLD)

Introduction: The surfactant protein B (SP-B) is thought to be the most important protein for respiratory physiology as its lack or deficiency is associated with lethal respiratory failure. SP-B is normally detectable in the systemic circulation at very low levels. Increased levels of SP-B have been reported in several respiratory diseases due to leakage of surfactant into the circulation. This feasibility study was conducted to investigate whether proSP-B and C-fragment pro SP-B (C-proSP-B) might serve as serum biomarkers to differentiate between DPLD and obstructive lung diseases. Material & Methods: We collected serum samples from patients with obstructive lung diseases (n=45) and patients with DPLD (n=24) at days 1, 7 and 21. Measurement was based on electrochemiluminescence immunoassay with mouse monoclonal anti-proSP-B antibodies. Levels were correlated to lung function, clinical and laboratory parameters. Results: Levels of proSP-B and C-proSP-B were similar with higher values for C-proSP-B. Highest C-proSP-B levels (mean, ng/ml) were found in DPLD (1542, n=24) compared to values found in Asthma (210, n=19) and COPD (369, n=26). A correlation between treatment of the respective lung disease and values was not found during short term monitoring. Furthermore, no significant correlations were found between SP-B levels and lung function. However, in DPLD highest levels were found for IPF patients. Conclusion: Plasma pro and C-proSP-B might distinguish DPLD from obstructive lung disease and might have a potential role as a biomarker in pulmonary diseases with alveolar or interstitial damage like ILDs, especially in IPF.

Clinical characteristics of patients with lung cancer and idiopathic pulmonary fibrosis in China.

To identify distinguishing characteristics between patients with lung cancer and idiopathic pulmonary fibrosis (IPF-CA) and patients with IPF alone in China. The medical records of 24 IPF-CA patients and 80 IPF patients admitted to Peking Union Medical College Hospital (PUMCH) from 1999 to 2009 were reviewed. The incidence of lung cancer in IPF patients in our study was 23.1% (24/104), and the percentage of patients who smoked in the IPF-CA group was higher than the IPF group (87.5% and 55.0%, respectively, P = 0.004). Three symptoms, including productive cough, hemoptysis, and chest pain, were more common in IPF-CA patients than IPF alone patients. There was no significant difference in the percentage of patients with other abnormal serum tumor markers, except that the percentage of patients with abnormal neuron specific enolase was significantly higher in the IPF-CA group than in the IPF group (28.6% vs. 7.4%, P = 0.041). The most common histology type was adenocarcinoma (33.3%). The median overall survival for IPF-CA patients and IPF patients was 7.0 months (95% confidential interval (CI), 2.51-11.49) and 14.0 months (95% CI, 1.26-26.74), respectively, with no significant difference (P = 0.327). Due to a high proportion of IPF cases complicated with lung cancer, physicians should closely observe lung cancer incidence during the IPF follow-up period. Individualized treatment for lung cancer patients with IPF is emphasized. Hence, it is important to ensure the safety of cancer treatments.

477 Clinical Implications of Impedance Monitoring in Suspected Extraesophageal Reflux: Can the Traditional Physiologic Parameters Predict Impedance Results?

LES resting pressure compared to non-IPF patients (14.1 [4-32.5] vs. 16.7 [4-37.2]; p= 0.0999). Mean contraction amplitude in the distal and proximal esophagus were slightly higher in IPF compared to non-IPF patients (92.4 [40-190] vs. 84 [35-170] and 90.6 [10210] vs. 79.9 [10-210], respectively; p=ns), but the difference was not significant. In contrast, IPF patients had significantly higher (p<0.01) esophageal acid exposure (9.25[4.7-15.4] vs. 3.3[1.4-7.4] vs. 0.7[0-2.4.2]), number of acid (45[23-55] vs. 32[19-44] vs. 18[10-31]), weakly-acidic (34[19-43] vs. 21[11-33]) vs. 18[15-28]) and proximal reflux events (51[26.565.5] vs. 20[9.5-34.5] vs. 9[5-20]) compared to non-IPF patients and HVs. Pulmonary fibrosis HRCT-scores correlated well with reflux episodes in both distal (r2=0.567) and proximal (r2=0.6323) esophagus. Patients with IPF had more bile acids and pepsin (p<0.001) in BAL (62% and 67%) and saliva (61% and 68%) than non-IPF patients (40% and 40% in BAL, 33% and 36% in saliva) and controls (0% and 0% in both BAL and saliva). Conclusion: Increased acid and weakly acidic GER as well as more reflux reaching the proximal esophagus are prevalent in IPF. Patients with IPF have a relevant risk of gastric aspiration (increased bile acids and pepsin in saliva) or definite gastric aspiration (bile acids or pepsin in BAL). Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in IPF progression.

Interactions Between β-Catenin and Transforming Growth Factor-β Signaling Pathways Mediate Epithelial-Mesenchymal Transition and Are Dependent on the Transcriptional Co-activator cAMP-response Element-binding Protein (CREB)-binding Protein (CBP)

Interactions between transforming growth factor-β (TGF-β) and Wnt are crucial to many biological processes, although specific targets, rationale for divergent outcomes (differentiation versus block of epithelial proliferation versus epithelial-mesenchymal transition (EMT)) and precise mechanisms in many cases remain unknown. We investigated β-catenin-dependent and transforming growth factor-β1 (TGF-β1) interactions in pulmonary alveolar epithelial cells (AEC) in the context of EMT and pulmonary fibrosis. We previously demonstrated that ICG-001, a small molecule specific inhibitor of the β-catenin/CBP (but not β-catenin/p300) interaction, ameliorates and reverses pulmonary fibrosis and inhibits TGF-β1-mediated α-smooth muscle actin (α-SMA) and collagen induction in AEC. We now demonstrate that TGF-β1 induces LEF/TCF TOPFLASH reporter activation and nuclear β-catenin accumulation, while LiCl augments TGF-β-induced α-SMA expression, further confirming co-operation between β-catenin- and TGF-β-dependent signaling pathways. Inhibition and knockdown of Smad3, knockdown of β-catenin and overexpression of ICAT abrogated effects of TGF-β1 on α-SMA transcription/expression, indicating a requirement for β-catenin in these Smad3-dependent effects. Following TGF-β treatment, co-immunoprecipitation demonstrated direct interaction between endogenous Smad3 and β-catenin, while chromatin immunoprecipitation (ChIP)-re-ChIP identified spatial and temporal regulation of α-SMA via complex formation among Smad3, β-catenin, and CBP. ICG-001 inhibited α-SMA expression/transcription in response to TGF-β as well as α-SMA promoter occupancy by β-catenin and CBP, demonstrating a previously unknown requisite TGF-β1/β-catenin/CBP-mediated pro-EMT signaling pathway. Clinical relevance was shown by β-catenin/Smad3 co-localization and CBP expression in AEC of IPF patients. These findings suggest a new therapeutic approach to pulmonary fibrosis by specifically uncoupling CBP/catenin-dependent signaling downstream of TGF-β.

Decreased apoptotic rate of alveolar macrophages of patients with idiopathic pulmonary fibrosis.

Introduction. Increased apoptosis of epithelial cells and decreased apoptosis of myofibroblasts are involved in the pathogenesis of IPF. The apoptotic profile of alveolar macrophages (AMs) in IPF is unclear. Aim. To investigate whether AMs of patients with IPF exhibit a different apoptotic profile compared to normal subjects. Methods. We analyzed, by immunohistochemistry, the expression of the apoptotic markers fas, fas ligand , bcl-2, and bax in AM obtained from bronchoalveolar lavage fluid (BALF) of 20 newly diagnosed, treatment-naive IPF patients and of 16 controls. Apoptosis of AM was evaluated by Apoptag immunohistochemistry. IPF patients received either interferon-g and corticosteroids or azathioprine and corticosteroids for six months. Results. BALF AMs undergoing apoptosis were significantly less in IPF patients. No difference was found in the expression of fas or fas ligand, bcl-2 and bax between IPF and control group. No difference was found between the respiratory function parameters of the two treatment groups after six months. A positive correlation was found between the number of bcl-2 positive stained macrophages and DLCO after treatment. Conclusions. The decreased apoptotic rate of AM of patients with IPF is not associated with decreased expression of apoptosis mediators involved in the external or internal apoptotic pathway.

Lung cancer in idiopathic pulmonary fibrosis patients diagnosed during or after lung transplantation

Lung transplantation is an accepted therapy for patients with end-stage lung disease and offers a major survival benefit in selected patients. The most important indications are chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis besides cystic fibrosis and pulmonary arterial hypertension. The incidence of lung cancer in patients after Ltx is 20–25 times higher than in the general population. Diagnosis is often difficult in IPF patients because of the diffuse lung abnormalities due to the underlying fibrosis. Moreover, the lung cancer may mimic a pulmonary infection. Symptoms are often aspecific, diagnosis is difficult, and prognosis is extremely poor. We describe three patients who were transplanted for idiopathic pulmonary fibrosis and who developed a primary lung cancer.

Investigation of Telomerase/Telomeres system in Bone Marrow Mesenchymal Stem Cells derived from IPF and RA-UIP.

ObjectiveIdiopathic Pulmonary Fibrosis and Rheumatoid Arthritis associated usual interstitial pneumonia seem to have the same poor outcome as there is not an effective treatment. The aim of the study is to explore the reparative ability of bone marrow mesenchymal stem cells by evaluating the system telomerase/telomeres and propose a novel therapeutic approach.MethodsBM-MSCs were studied in 6 IPF patients, 7 patients with RA-UIP and 6 healthy controls. We evaluated the telomere length as well as the mRNA expression of both components of telomerase (human telomerase reverse transcriptase, h-TERT and RNA template complementary to the telomeric loss DNA, h-TERC).ResultsWe found that BM-MSCs from IPF, RA-UIP cases do not present smaller telomere length than the controls (p = 0.170). There was no significant difference regarding the expression of both h-TERT and h-TERC genes between patients and healthy controls (p = 0.107 and p = 0.634 respectively).ConclusionsWe demonstrated same telomere length and telomerase expression in BM-MSCs of both IPF and RA-UIP which could explain similarities in pathogenesis and prognosis. Maintenance of telomere length in these cells could have future implication in cell replacement treatment with stem cells of these devastating lung disorders.

Crackle Pitch Rises Progressively during Inspiration in Pneumonia, CHF, and IPF Patients

Objective. It is generally accepted that crackles are due to sudden opening of airways and that larger airways produce crackles of lower pitch than smaller airways do. As larger airways are likely to open earlier in inspiration than smaller airways and the reverse is likely to be true in expiration, we studied crackle pitch as a function of crackle timing in inspiration and expiration. Our goal was to see if the measurement of crackle pitch was consistent with this theory. Methods. Patients with a significant number of crackles were examined using a multichannel lung sound analyzer. These patients included 34 with pneumonia, 38 with heart failure, and 28 with interstitial fibrosis. Results. Crackle pitch progressively increased during inspirations in 79% of all patients. In these patients crackle pitch increased by approximately 40 Hz from the early to midinspiration and by another 40 Hz from mid to late-inspiration. In 10% of patients, crackle pitch did not change and in 11% of patients crackle pitch decreased. During expiration crackle pitch progressively decreased in 72% of patients and did not change in 28% of patients. Conclusion. In the majority of patients, we observed progressive crackle pitch increase during inspiration and decrease during expiration. Increased crackle pitch at larger lung volumes is likely a result of recruitment of smaller diameter airways. An alternate explanation is that crackle pitch may be influenced by airway tension that increases at greater lung volume. In any case improved understanding of the mechanism of production of these common lung sounds may help improve our understanding of pathophysiology of these disorders.

Genetic variability in the IL1RN gene and the balance between interleukin (IL)-1 receptor agonist and IL-1β in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease of unknown aetiology. Interleukin (IL)-1β plays an important role in inflammation and has been associated with fibrotic remodelling. We investigated the balance between IL-1β and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) and serum as well as the influence of genetic variability in the IL1B and IL1RN gene on disease susceptibility and cytokine levels. In 77 IPF patients and 349 healthy controls, single nucleotide polymorphisms (SNPs) in the IL1RN and IL1B genes were determined. Serum and BALF IL-1Ra and IL-1β levels were measured using a multiplex suspension bead array system and were correlated with genotypes. Both in serum and BALF a significantly decreased IL-1Ra/IL-1β ratio was found in IPF patients compared to healthy controls. In the IL1RN gene, one SNP was associated with both the susceptibility to IPF and reduced IL-1Ra/IL-1β ratios in BALF. Our results show that genetic variability in the IL1RN gene may play a role in the pathogenesis of IPF and that this role may be more important than thought until recently. The imbalance between IL-1Ra and IL-1β might contribute to a proinflammatory and pro-fibrotic environment in their lungs.

Short of breath, short of benefit: Important considerations for the rehabilitation of IPF patients

Short of breath, short of benefit: Important considerations for the rehabilitation of IPF patients

Significance of connective tissue disease features in idiopathic interstitial pneumonia

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-α and IFN-γ reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-α- and IFN-γ-stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-κB- and p38(mapk)-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF.

A Micro RNA Processing Defect in Rapidly Progressing Idiopathic Pulmonary Fibrosis

BackgroundIdiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.Methodology and Principal FindingsmiRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.ConclusionThese findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.

354 Viral Infection in IPF Native Lung Is an Independent Risk Factor for Primary Graft Dysfunction

Idiopathic pulmonary fibrosis-IPF- is a chronic progressive form of interstitial lung disease, unresponsive to medical treatment, and lung transplantation-LT- has been demonstrated as a viable therapeutic option.The etiology of the disease is unknown although herpesviruses have often been identified in IPF lungs and thought to be a potential cofactor for the development and/or progression of IPF. Preliminary studies report a poor prognosis of viral IPF patients. No data are available on the post-transplant follow-up in cases associated with viral infections.

Exercise capacity in idiopathic pulmonary fibrosis: The effect of pulmonary hypertension

Increased pulmonary arterial pressure (PAP) usually coexists with impaired lung function in IPF. Data on the effect of pulmonary hypertension (PH) on cardiopulmonary responses during exercise in IPF patients is very limited. We sought to investigate the impact of PH on exercise capacity and the correlation between systolic PAP (sPAP) and pulmonary function testing, as well as cardiopulmonary exercise parameters, in patients with IPF and PH. Eighty-one consecutive patients with IPF, who were evaluated over a 6-year period, were retrospectively studied. Patients underwent pulmonary function testing, Doppler echocardiography and maximal cardiopulmonary exercise testing. PH was defined as sPAP > 35 mm Hg. PH was diagnosed in 57% of the patients. Categorization of patients according to severity of PH indicated a significant reduction in maximum work rate, peak O(2) uptake, anaerobic threshold and peak O(2) pulse in those with sPAP > 50 mm Hg. In IPF patients with PH, estimated sPAP correlated with peak O(2) uptake, anaerobic threshold, peak O(2) pulse and end-tidal CO(2) at anaerobic threshold, while the strongest correlation was between sPAP and ventilatory equivalent for CO(2) at anaerobic threshold (r = 0.611, P < 0.001). There were no differences in pulmonary function or exercise parameters indicative of lung volume reduction, across the patient categories, and none of these parameters correlated with sPAP. PH has a negative impact on exercise capacity in IPF patients. In IPF patients with PH, resting sPAP correlated with exercise parameters indicative of gas exchange and circulatory impairment, but not with defective lung mechanics.

Idiopathic pulmonary fibrosis‐related pulmonary hypertension; an exercising diagnosis?

Idiopathic pulmonary fibrosis‐related pulmonary hypertension; an exercising diagnosis?

Heart rate recovery after six‐minute walk test predicts pulmonary hypertension in patients with idiopathic pulmonary fibrosis

In patients with IPF, we sought to validate that abnormal heart rate recovery at 1 min (HRR1) after six-minute walk test (6MWT) predicts mortality and to explore the relationship between abnormal HRR1 and pulmonary hypertension (PH). We identified IPF patients who performed a 6MWT as part of their clinical evaluation between 2006 and 2009 and were followed to lung transplantation or death. Right heart catheterization (RHC) data were collated and analysed for the subgroup who had this procedure. There were 160 subjects who qualified for the survival analysis, and those with an abnormal HRR1 had worse survival than subjects with normal HRR1 (log-rank P = 0.01). Eighty-two subjects had a right heart catheter (RHC); among them, abnormal HRR1 was associated with RHC-confirmed PH (χ(2) = 4.83, P = 0.03) and had a sensitivity, specificity, positive predictive value and negative predictive value of 52%, 74%, 41% and 82%, respectively, for PH. In bivariate and multivariable analyses, abnormal HRR1 appeared to be the strongest predictor of RHC-confirmed PH (odds ratio (OR) = 4.0, 95% CI: 1.17-13.69, P = 0.02 in the multivariable analysis). This study adds to data that support the validity of abnormal HRR1 as a predictor of mortality and of RHC-confirmed PH in IPF. Research is needed to further investigate the link between abnormal HRR1 and PH and to elucidate heart-lung interactions at work during exercise and recovery in patients with IPF.

Ganciclovir Antiviral Therapy in Advanced Idiopathic Pulmonary Fibrosis: An Open Pilot Study

Hypothesis. Repeated epithelial cell injury secondary to viruses such as Epstein Barr and subsequent dysfunctional repair may be central to the pathogenesis of IPF. In this observational study, we evaluated whether a combination of standard and anti-viral therapy might have an impact on disease progression. Methods. Advanced IPF patients who failed standard therapy and had serological evidence of previous EBV, received ganciclovir (iv) at 5 mg/kg twice daily. Forced vital capacity (FVC), shuttle walk test, DTPA scan and prednisolone dose were measured before and 8 weeks post-treatment. Results. Fourteen patients were included. After ganciclovir, eight patients showed improvement in FVC and six deteriorated. The median reduction of prednisolone dose was 7.5 mg (44%). Nine patients were classified “responders” of whom four showed an improvement in all four criteria, while three of the five “non-responders” showed no response in any of the criteria. Responders showed reduction in prednisolone dosage (P = .02) and improved DTPA clearance (P = .001). Conclusion. This audit outcome suggests that 2-week course of ganciclovir (iv) may attenuate disease progression in a subgroup of advanced IPF patients. These observations do not suggest that anti-viral treatment is a substitute for the standard care, however, suggests the need to explore the efficacy of ganciclovir as adjunctive therapy in IPF.