PATHOPHYSIOLOGY this pulmonary interstitium. An injury to the

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 PATHOPHYSIOLOGYInterstitial lungdisease(ILD) generally refers to a broad category of lung diseases with the known andunknown causes.

1,2 Pulmonary interstitium is a space located betweenthe capillaries and the alveolar space primarily supporting efficient gasexchange. In normal state, there is a minimal connective tissue matrix,fibroblasts, and inflammatory cells such as macrophages between the layer ofgas and capillary surface because of this pulmonary interstitium. An injury tothe interstitium due to exposure of asbestos, nitrofurantoin, moldy hay etc.

causes an autoimmune-mediated inflammation and gives rise to systemicconnective tissue diseases such as rheumatoid arthritis, or causes unknowninjury like idiopathic pulmonary fibrosis. Normally lung responds to the damageto repair itself; however, persistent exposure of stimuli or a problematic repairprocess causes development of scars and thickening replacing the normal pulmonaryinterstitium. 3 This results into an impairment in gas exchangedue to ventilation-perfusion mismatching, shunt, and decreased diffusion acrossthe abnormal interstitium. Decreased lung compliance causes increased workloadof breathing, persistent cough, fatigue, clubbing of the fingers, intoleranceto exercise, death etc. ABSTRACTMost recent studies show that ILD patientsmay remain stable, improve after appropriate treatment, or even lead to death. 4Several comorbidities in ILD include an acute and chronic infection,gastroesophageal reflux, pulmonary hypertension (PH), lung cancer,cardiovascular diseases, rheumatoid arthritis, Systemic Lupus Erythematosus(SLE), Sarcoidosis, Idiopathic Interstitial Pneumonia, Idiopathic PulmonaryFibrosis (IPF), Lymphangioleiomyomatosis (LAM), obstructive sleep apnea etc.

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Some comorbidities may pre-exist or develop during any stage of ILD affectingthe patients’ quality of life and presents with clinical symptoms. Therefore, earlyidentification and treatment of comorbidities are clinically important. INTRODUCTIONRecent treatmentsof ILD lead to an expectation of better outcomes and management. Even though antifibrotictherapies in IPF and immunosuppressive agents in most other ILD show the benefitsin pharmaceutical trials, they do not always applicable to the general ILDpopulation. A reason for this may be a selection bias in pharmaceutical studieslike an exclusion of ILD patient with significant comorbidities and this mightimpact on his/her survival as well as the quality of life. 4/5Most common comorbidities in ILD with regarding diagnosis, management,prevalence, and treatments are as below:1.

     Acuteand chronic infectionsSeveral viral and bacterialinfections have been associated with the progression of IPF. Immunosuppressiontreatments of IPF have shown to cause harmful effects lead to increase inhospitalizations and mortality and so it is not advised to be used for IPF, butthey have been used for other types of ILDs. Some antibiotics have shownsignificant effect not only in acute and chronic infections, but also inpulmonary sarcoidosis.

Antibiotics have been used in combination withantifibrotic drugs, and treatments to chronic respiratory infections have shownto face many challenges than acute infections. 2.     Gastroesophagealreflux (GERD)The prevalence of GERD and IPF havebeen shown to be 0% to 96%. 6 The symptoms of GERD may besuppressed with the usage of antacid therapies. GERD and IPF seem to beoccurring in a parallel manner regardless of no direct connection between them.Pulmonary fibrosis leads to increased negative intrathoracic pressure distortingthe mediastinal structures and causes the microaspiration of gastric content byweakening of the lower esophageal sphincter. Gastric content acts as a stimulusfor the repetitive damage to the alveolar epithelium.3.

     Pulmonaryhypertension (PH)Dueto the differences in PH manifestations between ILD and COPD, PH provides thelink between PH association with ILD like IPF and Idiopathic InterstitialPneumonia (IIP). PH have shown the prevalence of 32% to 85% in IPF.4.

     CardiacdiseaseIn sarcoidosis and IIP, cardiacdisease can be a consequence of direct involvement of the heart; however, thediagnostic uncertainties occur in patients with ILD due to the presence ofoccult cardiac disease. In IPF, the prevalence of coronary artery disease (CAD)is high (60%) as a consequence of smoking, which is also associated with worsesurvival. Drug-induced lung disease results from statins and amiodarone(antiarrhythmic drug). Amiodarone causes lung toxicity, cough, dyspnea and shoesnew infiltrates on high-resolution computed tomography (HRCT); Statins, on theother hand, widely used to reduce cardiovascular morbidity in patients withknown risk factors. 7 5.     Pulmonaryembolism (PE)IIP Patients are at increased riskof PE due to the presence of a pro-coagulant effect in IPF. 8 PEis treated with vitamin K antagonists such as warfarin, which is in turnsassociated with increased mortality of IPF patients.

Recurrent episodes of PE areassociated with SLE and even though immunosuppression does not help in SLE, antibiotictherapy lowers likelihood of persistent lupus anticoagulant positivity in SLE. 96.     LungcancerThe prevalence of lung cancer inIPF varies from 4.4% to 9.8% suggesting that the fibrotic process may play a rolein the development of cancer along with the smoking. 10 Treatmentsof lung cancer with chemotherapy and the usage of Epithelial growth factorreceptor (EGFR) tyrosine kinase inhibitors (TKIs) may lead to drug-induced ILD.117.     ObstructiveSleep Apnea (OSA) The reported prevalence of OSA inIPF was to be 60% to 90%, but OSA therapy reduces the clinical symptomsassociated with OSA in IPF patients.

IPF patients who do not comply with CPAPshow the worse outcomes. 12 Oxygen supplementation alone mayalleviate the severity of desaturation in the patients with worsened PH, which isoccurred due to failure to treat OSA. 8.     DepressionDepressionand anxiety show high prevalence of >20% in patients with ILD. Depressioncan be alone independently predicted based on the severity of dyspnea, sleepquality, reduced FVC, and pain. Recent studies suggest that ILD patients shouldbe referred early in the stages to pulmonary rehabilitation based on fatigue,functional capacity, and improvements in symptoms of depression and anxiety. 13  9.

    Rheumatoid Arthritis (RA)Alongwith some drug therapies or infectious precipitants, chronic immune activationand inflammation occurs in RA that promotes aberrant fibro-proliferation, whichgives rise to RA-associated ILD (RA-ILD). 14 It has been shownthat RA-ILD significantly decreased the quality of life with high utilizationof healthcare resources and poorer mortality. 15 Treatments of RA includemethotrexate, leflunomide (LEF), and anti-tumor necrosis factor ? (anti-TNF?). 16Immunomodulators such as mycophenolate and rituximab and newly studiedantifibrotic agents have shown promising effects. Prevalence of RA-ILD has beenreported from 3.6% to 60%.

 CONCLUSION        Comorbidities in ILD have shown tosignificantly impair the quality of life and to reduce life expectancy. Due todifferent nature of each comorbidity or the adverse effects on each other, thetreatments for each of them can be further complicated. For example,antifibrotic therapy is less likely to prolong life in IPF patients withadvanced lung cancer or severe PH. In some cases, immunosuppression may help toalleviate the symptoms itself, however, it may further cause the worsening ofpre-existing or triggers the development of ILD. It is essential to study the comorbiditiesin ILD because an early detection and its accurate management may have the potentialbenefits in reducing morbidity and mortality in the future.

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