PATHOPHYSIOLOGY to the interstitium due to exposure of



Interstitial lung
(ILD) generally refers to a broad category of lung diseases with the known and
unknown causes. 1,2 Pulmonary interstitium is a space located between
the capillaries and the alveolar space primarily supporting efficient gas
exchange. In normal state, there is a minimal connective tissue matrix,
fibroblasts, and inflammatory cells such as macrophages between the layer of
gas and capillary surface because of this pulmonary interstitium. An injury to
the interstitium due to exposure of asbestos, nitrofurantoin, moldy hay etc.
causes an autoimmune-mediated inflammation and gives rise to systemic
connective tissue diseases such as rheumatoid arthritis, or causes unknown
injury like idiopathic pulmonary fibrosis. Normally lung responds to the damage
to repair itself; however, persistent exposure of stimuli or a problematic repair
process causes development of scars and thickening replacing the normal pulmonary
interstitium. 3 This results into an impairment in gas exchange
due to ventilation-perfusion mismatching, shunt, and decreased diffusion across
the abnormal interstitium. Decreased lung compliance causes increased workload
of breathing, persistent cough, fatigue, clubbing of the fingers, intolerance
to exercise, death etc.

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Most recent studies show that ILD patients
may remain stable, improve after appropriate treatment, or even lead to death. 4
Several 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 Pulmonary
Fibrosis (IPF), Lymphangioleiomyomatosis (LAM), obstructive sleep apnea etc.
Some comorbidities may pre-exist or develop during any stage of ILD affecting
the patients’ quality of life and presents with clinical symptoms. Therefore, early
identification and treatment of comorbidities are clinically important.


Recent treatments
of ILD lead to an expectation of better outcomes and management. Even though antifibrotic
therapies in IPF and immunosuppressive agents in most other ILD show the benefits
in pharmaceutical trials, they do not always applicable to the general ILD
population. A reason for this may be a selection bias in pharmaceutical studies
like an exclusion of ILD patient with significant comorbidities and this might
impact on his/her survival as well as the quality of life. 4/5
Most common comorbidities in ILD with regarding diagnosis, management,
prevalence, and treatments are as below:

1.     Acute
and chronic infections

Several viral and bacterial
infections have been associated with the progression of IPF. Immunosuppression
treatments of IPF have shown to cause harmful effects lead to increase in
hospitalizations and mortality and so it is not advised to be used for IPF, but
they have been used for other types of ILDs. Some antibiotics have shown
significant effect not only in acute and chronic infections, but also in
pulmonary sarcoidosis. Antibiotics have been used in combination with
antifibrotic drugs, and treatments to chronic respiratory infections have shown
to face many challenges than acute infections.

2.     Gastroesophageal
reflux (GERD)

The prevalence of GERD and IPF have
been shown to be 0% to 96%. 6 The symptoms of GERD may be
suppressed with the usage of antacid therapies. GERD and IPF seem to be
occurring in a parallel manner regardless of no direct connection between them.
Pulmonary fibrosis leads to increased negative intrathoracic pressure distorting
the mediastinal structures and causes the microaspiration of gastric content by
weakening of the lower esophageal sphincter. Gastric content acts as a stimulus
for the repetitive damage to the alveolar epithelium.

3.     Pulmonary
hypertension (PH)

to the differences in PH manifestations between ILD and COPD, PH provides the
link between PH association with ILD like IPF and Idiopathic Interstitial
Pneumonia (IIP). PH have shown the prevalence of 32% to 85% in IPF.

4.     Cardiac

In sarcoidosis and IIP, cardiac
disease can be a consequence of direct involvement of the heart; however, the
diagnostic uncertainties occur in patients with ILD due to the presence of
occult cardiac disease. In IPF, the prevalence of coronary artery disease (CAD)
is high (60%) as a consequence of smoking, which is also associated with worse
survival. Drug-induced lung disease results from statins and amiodarone
(antiarrhythmic drug). Amiodarone causes lung toxicity, cough, dyspnea and shoes
new infiltrates on high-resolution computed tomography (HRCT); Statins, on the
other hand, widely used to reduce cardiovascular morbidity in patients with
known risk factors. 7

5.     Pulmonary
embolism (PE)

IIP Patients are at increased risk
of PE due to the presence of a pro-coagulant effect in IPF. 8 PE
is treated with vitamin K antagonists such as warfarin, which is in turns
associated with increased mortality of IPF patients. Recurrent episodes of PE are
associated with SLE and even though immunosuppression does not help in SLE, antibiotic
therapy lowers likelihood of persistent lupus anticoagulant positivity in SLE. 9

6.     Lung

The prevalence of lung cancer in
IPF varies from 4.4% to 9.8% suggesting that the fibrotic process may play a role
in the development of cancer along with the smoking. 10 Treatments
of lung cancer with chemotherapy and the usage of Epithelial growth factor
receptor (EGFR) tyrosine kinase inhibitors (TKIs) may lead to drug-induced ILD.

7.     Obstructive
Sleep Apnea (OSA)

The reported prevalence of OSA in
IPF was to be 60% to 90%, but OSA therapy reduces the clinical symptoms
associated with OSA in IPF patients. IPF patients who do not comply with CPAP
show the worse outcomes. 12 Oxygen supplementation alone may
alleviate the severity of desaturation in the patients with worsened PH, which is
occurred due to failure to treat OSA.

8.     Depression

and anxiety show high prevalence of >20% in patients with ILD. Depression
can be alone independently predicted based on the severity of dyspnea, sleep
quality, reduced FVC, and pain. Recent studies suggest that ILD patients should
be referred early in the stages to pulmonary rehabilitation based on fatigue,
functional capacity, and improvements in symptoms of depression and anxiety. 13 

Rheumatoid Arthritis (RA)

with some drug therapies or infectious precipitants, chronic immune activation
and inflammation occurs in RA that promotes aberrant fibro-proliferation, which
gives rise to RA-associated ILD (RA-ILD). 14 It has been shown
that RA-ILD significantly decreased the quality of life with high utilization
of healthcare resources and poorer mortality. 15 Treatments of RA include
methotrexate, leflunomide (LEF), and anti-tumor necrosis factor ? (anti-TNF?). 16
Immunomodulators such as mycophenolate and rituximab and newly studied
antifibrotic agents have shown promising effects. Prevalence of RA-ILD has been
reported from 3.6% to 60%.



Comorbidities in ILD have shown to
significantly impair the quality of life and to reduce life expectancy. Due to
different nature of each comorbidity or the adverse effects on each other, the
treatments for each of them can be further complicated. For example,
antifibrotic therapy is less likely to prolong life in IPF patients with
advanced lung cancer or severe PH. In some cases, immunosuppression may help to
alleviate the symptoms itself, however, it may further cause the worsening of
pre-existing or triggers the development of ILD. It is essential to study the comorbidities
in ILD because an early detection and its accurate management may have the potential
benefits in reducing morbidity and mortality in the future.


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