Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to the lungs. In the past, treatment was aimed at minimizing inflammation and slowing the progression of inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to anti-inflammatory therapies and the prognosis remains poor. In this review of literature, we will be focusing on main lines of treatment including current medications, supportive care, lung transplantation evaluation, and potential future strategies of treatment.


Medical therapies
Until now, there is no curative treatment for IPF; however, nintedanib and pirfenidone are two medications working on slowing disease progression [2,4,13] and do have a mortality benefit [14]. According to the current data, neither medication is superior in terms of efficacy; and thus, choosing between either of them will depend on the patient's tolerance to side effects. Table 2 demonstrates a detailed comparison between both medications.

Pirfenidone
Mechanism of action Tyrosine kinase receptor blocker preventing the release of fibrogenic growth factors and thus slows down fibrosis [15,16]. It interacts with CYP3A4 inducers and inhibitors.
Blocks transforming growth factor-beta (TGF-β)-stimulated collagen synthesis and decreases the extracellular matrix [17,18] Nintedanib is contraindicated in patients with moderate to severe liver disease [19]. A pregnancy test should be performed before starting the treatment, and pregnancy should be avoided throughout the treatment duration and at least for 3 months after the last dose [19].
Should be taken after meals to reduce GIT upset symptoms [21].

Supportive care
Supportive care is crucial for IPF patients and considered one of the main lines of treatment in IPF. It can be categorized in the following main points:

Supplemental Oxygen
Long-term oxygen therapy (LTOT) is considered an inevitable treatment in patients with IPF with disease progression, either intermittently during exertion or sleep or continuously with severe disease. Indications for continuous LTOT depend on arterial oxygen tension (PaO 2 ) and pulse oxygen saturation (SpO 2 ) [34]. In general, PaO 2 < 56 mmHg or SpO 2 < 89 mmHg is an indication for continuous LTOT. However, in cases where there is presence of cor pulmonale, polycythemia, or right-sided heart failure, PaO 2 < 60 mmHg or SpO 2 < 90 mmHg is an indication for continuous LTOT. The LTOT may be indicated during sleep if the patient meets the above criteria or if PaO 2 drops > 10 mmHg and/or SpO 2 drops >5% with clinical evidence of nocturnal hypoxemia including insomnia, morning headaches, and impaired cognitive function. LTOT may be indicated during exercise if the patient meets the general indication of LTOT. Some studies showed that hyperoxia improves exercise tolerance in a dose-dependent manner, up to an inspired oxygen fraction of 50% [35], and thus, oxygen therapy may be indicated if the patient is having significant dyspnea during exercise even if the patient is not desaturating [36]. It is important to note, however, that oxygen is neither beneficial nor does it provide symptomatic relief as a palliative treatment in dyspnea without hypoxemia in patients with advanced lung diseases.
LTOT may improve quality of life, mental function, and exercise capacity. It can also reduce the frequency of hospitalization, cardiovascular complications, and mortality [37][38][39]. Most of the trials done to assess LTOT benefits were on COPD patients. More studies are needed to be applied to IPF patients.
While oxygen therapy is needed to correct hypoxemia, the oxygen flow rate should be accurately adjusted depending on PaO 2 , SpO 2 , and PaCO 2 to maintain adequate acid-base status, which can be perfectly assessed through arterial blood gas measurements. Studies do not show an optimum level for PaO 2 or SpO 2 , which can improve survival or quality of life. However, a PaO 2 of 60-65 mmHg or SpO 2 of 90%-92% is generally considered an adequate range as hypoxemia is corrected without increasing the risk of CO 2 retention [40]. Moreover, this range has the least risk for oxidative stress caused by the oxygen therapy, which in turn causes cell remodeling, cell death, and tissue damage [41].

Pulmonary Rehabilitation
Dyspnea on exertion and poor exercise tolerance are the main symptoms of IPF. Several studies have shown that pulmonary rehabilitation can ameliorate these symptoms leading to improvement in quality of life [42][43][44][45].

Vaccination
Patients should be educated about the importance of vaccination against influenza and pneumonia as they decrease the risk and frequency of IPF exacerbations secondary to these infections. Influenza and pneumococcal polysaccharide vaccine should be offered to all IPF patients unless contraindicated.

Education and Palliative Care
Better outcomes were seen with patients who were educated about their diagnosis and management [46]. Palliative care discussion should be a part of the patient's education as it aims to relieve suffering at all stages of the disease and is not limited to the end of life care [47]. Understanding patient's beliefs and desires is crucial for goals of care [48].

Lung transplantation
IPF is the most common interstitial lung disease among referrals for lung transplantation [49]. Understanding the type of lung transplantation, timing and indication of referral, factors putting the patient at high risk for the procedure, and physiological changes occurring posttransplantation are all crucial for determining candidates for transplantation and a proper plan of management.
After transplantation, pulmonary function tests and oxygenation improve significantly as observed in the short-and long-term follow-up of the recipients [50].

Type of Transplantation Procedure
Single lung transplantation (SLT) is considered the standard procedure for IPF [49]. After SLT, the remaining native lung tissue with low lung compliance and high vascular resistance will divert the ventilation and perfusion to the normal transplanted lung tissue. Bilateral lung transplant (BLT) is preferred if lungs with IPF have developed cysts, bullae, and bronchiectasis, which can act as a nidus for infections in the transplanted lung in SLT. BLT has shown better long-term survival and higher forced expiratory volume in one second (FEV1) in some studies when compared to SLT [51,52]. Living donor lobar lung transplantation (LDLLT) can be considered as a lifesaving option for highly critical IPF patients who may die waiting for SLT.
A study was done on nine patients having LDLLT, and only one patient passed away after two lobes transplants, whereas the other eight patients' survival was between 10 and 48 months after transplant [53].

Timing of Referral for Transplantation
IPF patients are usually the most critical patients on the transplant list with the highest death rate, that is why early referral for transplant evaluation should be done even before assessing response to initial medical treatment [54]. IPF patients should be referred for transplantation if they meet the following criteria [55] including dyspnea or functional disability related to lung disease and desaturating below 89% at rest or exertion. Moreover, diffusing capacity (DLCO) < 40% of predicted, forced vital capacity (FVC) < 80% of predicted, and decline in FVC ≥ 5%-10% and DLCO ≥ 15% during six months of follow-up are the recommended spirometry criteria. Radiologically and histologically, a picture of usual interstitial pneumonia (UIP) is needed for referral.

Placing on Transplant List and Priority on the List
Patients are usually listed on the transplant list if they meet the following: [55] hospitalization due to respiratory decline or acute exacerbation, desaturating to <88% or distance walked <250 meters or >50-meter decline in distance walked over six months. The decline in FVC ≥ 5%-10% and DLCO ≥ 15% during six months of follow-up are the required spirometry criteria. Furthermore, right heart catheterization or echocardiogram showing evidence of pulmonary hypertension is needed for the patient to be listed.
Priority on the list is determined using a lung allocation score that can assess the medical urgency and expected outcome on a scale from 1 to 100, where a higher score indicates higher urgency and better outcome with transplantation.

Factors Increasing the Risk of Transplantation
There are some factors that can put IPF patients at a higher risk of complications if they undergo lung transplants, which include pulmonary hypertension, telomerase complex mutations, and glucocorticoid therapy. Mild-to-moderate secondary pulmonary hypertension preoperatively has shown an increased risk of reperfusion injury. However, it did not show any worsening survival in two retrospective studies [52,56]. Telomerase complex mutations in IPF patients are usually associated with hematological complications including thrombocytopenia, anemia, neutropenia or severe bone marrow failure, and/or myelodysplasia with a high death rate [57,58]. Glucocorticoid therapy effect on lung transplantation differs according to the dose. Lower doses have not shown adverse outcomes, whereas higher doses may have lower survival after transplantation [59,60].

Future treatment
Currently, there is no available curative treatment for IPF. All available treatments work for a subset of patients and have significant side effects, and survival is generally poor. There are some medications under trial, which seem to be less toxic and have promising outcomes.

Combination Nintedanib Plus Pirfenidone
As discussed above, each of these medications works on slowing down IPF progression. However, the efficacy of combining both medications is still under trial. Multiple trials were done by combining both medications together with different doses, and they were found to be safe and well-tolerated by the majority of patients without major adverse effects other than expected from either medication alone [61][62][63].

Pentraxin 2
Pentraxin 2 is a serum amyloid believed to have an antifibrotic and anti-inflammatory effect by inhibiting differentiation of monocytes into macrophages and fibrocytes, thus halting their profibrotic and proinflammatory effects. It also inhibits transforming growth factor (TGF)-beta1 production responsible for connective tissue formation. Pentraxin 2 serum level is found to be lower in IPF patients than in normal individuals [64]. The preliminary results for a randomized trial of IPF patients receiving recombinant human pentraxin 2 intravenous (IV) in comparison with placebo showed a slower decline in pulmonary function on the pentraxin 2 side [65].

GLPG1690
GLPG1690 is a potent and selective autotaxin inhibitor, which has a good safety and tolerability profile as it has the same adverse effects when compared to placebo in a small randomized clinical trial. However, larger randomized clinical trials are needed to determine its efficacy. Autotaxin is an enzyme responsible for the conversion of lysophospholipids (lysophosphatidic acid [LPA] from the hydrolysis of lysophosphatidic choline [LPC], the latter of which is produced in the liver). LPA is believed to stimulate dendritic cell differentiation and smooth muscle contraction and prevents apoptosis. Autotaxin may in part be responsible for the "chronic wound response." Little is known about the expression and function of autotaxin, LPA, and LPC in human diseases such as pulmonary fibrosis [66].

Pamrevlumab (FG-3019)
Pamrevlumab is a monoclonal antibody targeting connective tissue growth factor, which has a role in fibrosis pathogenesis. Studies have shown that it has a good safety profile, and it slows the decline in FVC compared with pirfenidone and nintedanib. It may become a potential IPF treatment [67]. Further larger trials are needed.

Treatment for Gastroesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) is a common cause of chronic cough in the general population, but it is also found to be more common in IPF patients [68,69]. Moreover, in the presence of possibility of microaspiration with GERD, some studies hypothesized GERD as an important risk factor for the development or worsening of IPF [70][71][72] and the associated cough [73]. According to this hypothesis, several studies were done to monitor the effect of anti-GERD medications and surgery on progression and outcomes of IPF.
Upon using anti-GERD medications, some studies have shown decreased radiographic fibrosis scores on chest CT scans and better survival rates [74], while others showed a smaller decline in pulmonary function tests [75]. Some observational studies have shown a reduction in IPF-related mortality but not overall mortality [76].
Studies done on IPF patients after anti-reflux surgery showed it to be a well-tolerable procedure. Larger randomized trials are needed for the efficacy of the procedure on IPF progression [77].

Medications that should not be used anymore
The following are medications that were used in the past, but studies have recommended against using them either because of no benefit or severe side effects including higher mortality.

Anticoagulation
Anticoagulation with warfarin was previously used in IPF patients due to the assumption of the existence of prothrombotic state [78] and was found to improve mortality after three years follow-up when used with prednisone in comparison to prednisone alone in a non-blinded trial [79]. However, the Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis trial (ACE-IPF) results showed increased mortality in patients on anticoagulation for IPF without other indications for anticoagulation, and thus, anticoagulation should not be used in IPF unless there is another indication for it [4].

N-Acetylcysteine in Combination With Either Azathioprine-Prednisone or With Pirfenidone
Azathioprine-prednisone in combination with N-acetylcysteine or even N-acetylcysteine as a monotherapy has been used for many years as it was supposed to have some benefit according to the preliminary results of IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring (N) acetylcysteine I Annual) trial [80]. However, PANTHER trial results showed more frequent hospitalizations and adverse effects including higher mortality with this combination therapy in comparison to placebo. We recommend against using this combination treatment [81]. Moreover, a recent study has shown that combination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF [82].

Endothelin Receptor Antagonists
Several trials were done on endothelin receptor antagonists to check their efficacy in IPF treatment, but they did not show any significant benefit, and sometimes they were even harmful to the patient. Bosentan was used in IPF for its anti-fibrotic properties, but it did not show any improvement in exercise tolerance or quality of life according to BUILD 1 trial (Efficacy and Safety of Oral Bosentan in Patients With Idiopathic Pulmonary Fibrosis) [83] or any improvement in mortality or frequency of exacerbations according to BUILD 3 trial (Bosentan Use in Interstitial Lung Disease 3) [84]. Macitentan was also used in IPF treatment in MUSIC trial (Macitentan Use in an IPF Clinical Study), which also did not show any significant benefits [85]. Ambrisentan was tested in ARTEMIS-IPF trial for the treatment of IPF, which did not show any benefit but instead showed more frequent hospitalizations and exacerbations in comparison to placebo [86].

Phosphodiesterase Inhibitors
Trials of sildenafil in patients with IPF for improving exercise tolerance and quality of life have shown minimal benefit [87,88], so sildenafil is not advised for routine use in IPF.

Methotrexate
Methotrexate use did not show any benefit in the treatment of IPF, but instead, sometimes it induced pneumonitis that cannot be differentiated from an IPF exacerbation. However, methotrexate may be of benefit if IPF resulted from an autoimmune disease that can be treated with methotrexate, for example, as in rheumatoid arthritis [89].

Conclusions
This is a review of literature on the treatment options of stable IPF. We discussed the different severities and prognosis of IPF according to the clinical picture, radiographic findings, PFTs, 6 MWT, and P(A-a)O2. Nintedanib and pirfenidone are two medications that work on slowing disease progression and having a mortality benefit. However, supportive care is crucial for IPF patients and considered one of the main lines of treatment in IPF including supplemental oxygen, pulmonary rehabilitation, vaccination, patients' education, and palliative care discussions. IPF is the most common interstitial lung disease among referrals for lung transplantation. These patients are usually the most critical patients on the transplant list with the highest death rate. However, they need to fulfill certain criteria for lung transplantation referral and listing on priority list. Currently, there is no available curative treatment for IPF. There are some medications under trial, which seem to be less toxic and have promising outcomes including combination nintedanib plus pirfenidone, treatment for GERD, Pentraxin 2, and others. Some other medications were used before, but studies have recommended against them either due to no benefit or severe side effects including higher mortality. These therapies include anticoagulation, azathioprine-prednisone-N-acetylcysteine, endothelin receptor antagonists, phosphodiesterase inhibitors, methotrexate, and others.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.