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## **Chapter 3** Diagnosis of IPF

*Pahnwat T. Taweesedt, Kejal Gandhi, Reena Shah and Salim Surani*

#### **Abstract**

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung fibrosis with an unknown cause commonly seen in the elderly. Obtaining histories such as past medical history, exposure history, occupational history, and family history can be crucial parts to help to find other pulmonary fibrosis causes. Not only that, but thorough physical examination can rule out pulmonary fibrosis related to other diseases. Several diagnostic modalities have helped to improve the IPF assessment, including computer tomographic scan, histopathology, bronchoscopy lavage, serological testing, and serum biomarkers. Diagnostic of exclusion is required. The consensus from multidisciplinary IPF experts' discussion from various societies recommends the clinical practice for IPF diagnosis to help define this condition. In this book chapter, we will discuss the evidence for each of the diagnostic techniques for IPF.

**Keywords:** pulmonary fibrosis, IPF, telomere-related mutation, Hermansky-Pudlak syndrome, HRCT, UIP, IPF diagnosis, familial IPF, cryobiopsy

#### **1. Introduction**

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, fibrotic lung disease with unidentifiable etiology. IPF is commonly seen in the elderly aged group [1]. IPF associates with high morbidity and mortality. It is crucial to diagnose IPF, as specific antifibrotic therapy may improve survival from 2 to 5 years to 6.9–7.9 years [2].

In 2000, the American Thoracic Society (ATS), the European Respiratory Society (ERS), and American College of Chest Physician (ACCP) first collaborated and published a consensus statement for IPF diagnosis and treatment based on an experts' opinions. This initial definition of IPF included criteria such as usual interstitial pneumonia (UIP) finding on thoracic or open lung biopsy, restrictive lung function in patients with chronic fibrosing interstitial pneumonia after excluding other causes [3].

Eleven years later, ATS, ERS, the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) updated the guidelines with clinical, imaging, and histopathological findings in IPF diagnostic criteria based on the international evidence-based data [4]. Among patients for whom IPF was suspected, three high-resolution computed tomography (HRCT) pattens were reported; "UIP," "possible UIP," and "inconsistent with UIP" [4]. Surgical lung biopsy (SLB) was recommended in patients with suspected IPF who have the last two HRCT patterns [4]. SLB pattern is primarily divided into "UIP," "probable UIP", "possible UIP", "unclassifiable fibrosis," and "not UIP" [4]. Recommendations from French, German and Swiss have been proposed in 2013 and 2017, respectively [5].

#### *Idiopathic Pulmonary Fibrosis*

In 2018, the consensus statement from Fleischner Society and clinical practice guideline ATS/ERS/JRS/ALAT for UIP/IPF diagnosis were published with numbers of similar main components (**Table 1**) [6, 7]. With more support data from observational studies and randomized controlled trials than 2011 guidelines, diagnosis and treatment recommendations were improved from 2011. Recently, the German respiratory society updated the German guidelines for the diagnosis of IPF in 2021 [8].

Not only HRCT and SLB, but clinical manifestations, history, and other diagnostic modalities have also been proposed to help with IPF diagnosis.

*ATS: American Thoracic Society; CPG: clinical practice gruidline, ERS: European Respiratory Society; IPF: idiopathic pulmonary fibrosis, JRS: Japanese Respiratory Society; ALAT: Latin American Thoracic Society; HRCT: highresolution computed tomography; UIP: usual interstitial pneumonia.*

#### **Table 1.**

*Comparison of the 2018 Fleischner society consensus statement and clinical practice guideline from ATS/ERS/ JRS/ALAT 2018 for UIP/IPF diagnosis [6, 7].*

Multidisciplinary discussion is of utmost importance. Due to the rapidly growing of new data in the IPF field, guidelines from worldwide pulmonary societies consensus are necessary. We will discuss the current evidence that has been used to improve the diagnosis of IPF.

### **2. Clinical presentation, risk factors, and history**

#### **2.1 Clinical presentation and past medical history**

IPF is typically present at age above 50 years and is predominant in men [1, 9]. Lungs are the only organ involvement in IPF. Gradual onset of shortness of breath on exertion is the most common symptom that accounts for up to 86% of the patients with IPF, which can progress to shortness of breath at rest. Chronic nonproductive cough can be found in up to 75% of the cases [10]. Other symptoms include fatigue and decreased appetite. As IPF requires the diagnosis of exclusion, autoimmune diseases, connective tissue disease-related symptoms (e.g., arthralgia, dry eyes, Raynaud phenomenon), medications, radiation history, environment exposure (e.g., home, workplace, frequent visit places, hobbies), occupation, family history should be inquired in detailed to rule out any identifiable conditions. The physical exam is usually remarkable for bibasilar crackles and rales [6]. Digital clubbing was described in 20–30% of IPF cases [8].

Smoking is an undeniable risk factor of IPF in several studies [11]. Up to 70% of patients with IPF have a smoking history. Ever tobacco smoking or even secondhand smoking cases had a higher risk of developing IPF, although the latter had lower odds [9]. The pathogenesis of smoking as the risk factor of IPF is suggested to be due to oxidative stress [12].

Chronic obstructive pulmonary disease, co-morbidity that smoking is a potent risk factor, was found in one-third of the IPF cases. Gastroesophageal reflux disease (GERD) was noted in 60–90% of the patients with IPF and was thought to cause micro-aspiration that may precipitate IPF and acute exacerbation. The majority of GERD in IPF patients are asymptomatic. Nonetheless, the relationship between GERD and IPF remains controversial as there was no significant relationship after controlling for smoking in meta-regression [13]. Diabetes was positively correlated with IPF, but causal relationships still cannot determinate [14]. The presence of obstructive sleep apnea in patients with IPF was noted to be more than 50%, but true prevalence still cannot be concluded due to the small number of participants in those studies [15]. Chronic human herpes virus-7, human herpes virus-8, Ebstein-Barr virus, and cytomegalovirus infection could increase the risk of IPF [2]. However, acute infection of these viruses did not associate with IPF [2].

#### **2.2 Environmental and occupational risk factors**

The environmental exposure was reported in up to 27% [10]. Various occupational exposure has been revealed to be associated with IPF (**Table 2**). Silica, wood dust, metal dust/fumes, and vapors/gases/dust/fume had population attributable fractions of 3,4, 8, and 26%, respectively [16]. Deposition of dust and fumes from metal in the lung may give rise to the disturbance in the immune system. IPF risk has been reported to be increased with the longer duration of work exposure. In a meta-analysis of case–control studies by Park et al., metal dust, wood dust, pesticide had a high odds ratio (OR) in the IPF group [11]. However, textile dust, stone, and sand dust did not significantly increase the risk of IPF in this meta-analysis study [11]. The agriculture sector and farming workers showed an increased risk of IPF

**Table 2.** *Potential risk factors for IPF.*

**Table 3.**

*Family history related to IPF.*

with an OR of 1.88 (95% CI 1.17–3.04). In contrast, demolition and building construction, and woodworker carpentry did not significantly increase the risk of IPF [11].

#### **2.3 Family history**

Although IPF cases occur sporadically, familial cases have been reported, such as familial pulmonary fibrosis (FPF), Hermansky-Pudlak syndrome (HPS), and telomere-related mutation (**Table 3**). Genetic testing is recommended in patients with early-onset (less than 50 years old) pulmonary fibrosis and positive family history.

FPF is defined by two or more people in the family with a confirmed history of pulmonary fibrosis [17]. It accounts for less than five to up to 25 percent of IPF cases [18]. Pulmonary fibrosis in the family had a significant association with IPF cases with an OR of 12.6 (95% confidence interval 6.5–24.2) [9]. In addition to aiding diagnosis, family history helps predict survival. Transplant-free survival in patientreported FPF is less in patients with IPF than patients with interstitial lung disease (ILD) other than IPF [18].

HPS, an autosomal recessive disorder, was first described in 1959 by Frantisek Hermansky and Paulus Pudlak [19]. This syndrome is characterized by oculocutaneous albinism, inflammatory bowel disease, platelet dysfunction, and pulmonary fibrosis. Pulmonary fibrosis is commonly found in HPS-1, HPS-2, and HPS-4 genetic types and affected middle-aged (HPS-1 and HPS-4) or children (HPS-2) [19].

Telomere-related mutation in IPF includes TERT, TERC, TINF2, NAF1, PARN, DKC1, and RTEL1 [20]. Premature shortening of the telomere, a region at the ends of the chromosome with repetitive DNA sections, may lead to the accelerated aging process in IPF. Screening for short telomeres should be done in patients with extrapulmonary organ involvements associated with short telomere syndrome, especially patients considered for a lung transplant. Patients with shortened telomeres have decreased lung transplant-free survival and faster disease progression [20].

### **3. Imaging**

High-resolution CT scan (HRCT) plays a central role in the diagnosis of IPF. As described earlier, diagnosis of IPF requires exclusion of other known causes of ILD in addition to the presence of UIP pattern on HRCT. If HRCT shows a definitive UIP pattern, further surgical lung biopsy is not required for diagnosis. HRCT patterns in suspected IPF patients can be divided into four patterns: UIP, intermediate UIP, probable UIP, and alternative diagnosis (**Table 4**). All the patterns are characterized by their distribution and lung parenchymal appearance [6].

UIP is the hallmark pattern of IPF. It has characteristic bilateral, peripheral, lower lobe predominance with parenchymal findings of honeycombing and traction bronchiectasis along with fine reticular opacities in the absence of extensive ground-glass opacities. Honeycombing is defined as a group of cystic airspaces 3 to 10 mm in diameter, with well-defined, thick walls. It is absent in intermediate and probable UIP patterns. Traction bronchiectasis or bronchiolectasis ranges from nontapering of the bronchial wall to marked airway dilatation and varicosity in the presence of parenchymal distortion [6]. A typical UIP pattern is only observed in 50% of IPF patients. Thus, the IPF spectrum varies from typical UIP patterns to atypical findings such as ground-glass opacities, nodules, consolidation, or atypical distribution [21]. Mild ground glass opacities and the reticular pattern can be seen in UIP. However, presence of GGO out of proportion to the reticular pattern is inconsistent with UIP.

Acute exacerbation of IPF is characterized by acute onset dyspnea and hypoxemia and development of bilateral ground-glass opacities and/or consolidation on a

*UIP = usual interstitial pneumonia; GGO = ground glass opacities; CT = computed tomography; CTD = connective tissue disease; RA = rheumatoid arthritis.*

#### **Table 4.** *HRCT pattern categories.*

UIP background. The clinical course of IPF can be correlated with progressive lung parenchymal changes seen on serial HRCT scans. However, there is no consensus on the role of serial HRCT scans in established patients to determine prognosis [22].

#### **4. Lab assay**

Serological testing is recommended in all patients with newly identified ILD to exclude identifiable connective tissue disease (CTD) [6]. CTD-associated ILD investigations include erythrocytes sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factors, anti-cyclic citrullinated peptide, myositis panel, muscle enzymes, and anti-neutrophil cytoplasmic antibodies. Other serologic testing may be obtained based on clinical signs and symptoms such as anti-U1 ribonucleoprotein, anti-PM/Scl75 (polymyositis/scleroderma 75), anti-PM/Scl100, anti-Ku, anti-nuclear matrix protein 2, anti-transcriptional intermediary factor 1-gamma, anti-signal recognition particle, anti-small ubiquitin-related modifieractivating enzyme, anti-3-hydroxy-3-methylglutaryl-CoA reductase, and anti-melanoma differentiation-associated protein 5 (**Table 5**) [8].

#### **5. Bronchoscopic approach**

Cellular analysis from bronchoalveolar lavage (BAL) fluid is suggested in suspected IPF cases with probable UIP, indeterminate UIP, or an alternative diagnosis pattern on HRCT. This work-up is not suggested for patients with HRCT patterns of UIP [6]. BAL is not used for the IPF diagnosis by itself but might support the detection of other conditions (**Tables 6** and **7**).

#### **Table 5.**

*Laboratory workup for common connective tissue disease-related interstitial lung diseases.*

#### **Table 6.**

*Comparison of cellular analysis from bronchoalveolar lavage between a healthy individual and IPF [6].*

#### **Table 7.**

*Cellular analysis of bronchoalveolar lavage in different conditions.*

#### **6. Histopathology**

Multiple lung biopsies from few lobes are suggested in suspected IPF cases with probable UIP, indeterminate UIP, or alternative diagnosis patterns on HRCT. SLB is preferred over transbronchial lung biopsy and cryobiopsy. SLB be done by videoassisted thoracoscopic surgical (VATS) technique over open thoracotomy. When patients have a UIP pattern on HRCT, lung biopsy is not recommended in clinically suspected IPF patients after excluded other potential ILD etiologies. In these cases, diagnosis of IPF can be made without histopathology proof.

Similar to the HRCT pattern, histopathology patterns in suspected IPF individuals can be categorized into four groups; UIP, probable UIP, indeterminate UIP, and alternative diagnosis (**Table 8**) [6]. Classic "UIP" is the principal histopathologic feature of IPF. It frequently demonstrates dense fibrosis in paraseptal and subpleural areas of the lung with distortion of architecture, often resulting in microscopic honeycombing pattern accompanied by unaffected lung parenchyma in the low-magnification photomicrograph. For higher-magnification photomicrographs, fibroblast foci and patchy fibrosis are characteristics of UIP. The honeycombing pattern on biopsy is defined as fibrosed cystic airspace.

Accurate diagnosis of IPF requires the synopsis consideration of clinical manifestation, HRCT, and biopsy results (**Table 9**). When the HRCT pattern of clinically suspected IPF patients is not classic UIP or discordant with biopsy result, the multidiscipline decision from different subspecialties discussion such as pulmonologist, radiologist, and pathologist is suggested [6].

*HP = hypersensitivity pneumonitis; IIPs = Idiopathic interstitial pneumonias; LAM = Lymphangioleiomyomatosis; OP = organizing pneumonia; UIP = usual interstitial pneumonia.*

#### **Table 8.**

*Histopathologic feature of idiopathic pulmonary fibrosis [6].*

*HRCT = high-resolution computed tomography; IPF=Idiopathic pulmonary fibrosis; UIP = usual interstitial pneumonia.*

#### **Table 9.**

*Diagnosis of IPF using surgical lung biopsy result and high-resolution computed tomography finding [6].*

#### **7. Genetic biomarker**

Genetic factors affecting the susceptibility to IPF mainly depend on whether a patient has sporadic IPF or familial IPF. With the increase in the use of genome sequencing, multiple gene variants have been associated with IPF. Common variants with modest effects have been associated with sporadic IPF, whereas rare gene variants with more significant impact have been associated with a familial form of IPF.

#### **7.1 Genetic variants associated with sporadic IPF**

Mucin 5B (MUC5B) variant is a common variant associated with sporadic IPF. It is a glycoprotein involved in mucociliary clearance. A MUC5B promoter single nucleotide polymorphism (rs35705950) increases the susceptibility to developing IPF four-fold [23]. Despite this, MUC5B promoter SNP is associated with decreased mortality in IPF patients. However, it is not associated with systemic sclerodermarelated ILD can increase the risk of ILD in rheumatoid arthritis patients, especially in those having CT findings of UIP.

Toll interacting protein (TOLLIP) is a regulator of toll-like receptor (TLR), and variation in this gene leads to a decrease in TLR mRNA expression and increased risk of pulmonary infection [24]. TT TOLLIP genotype ((rs3750920) is associated with improved survival with N-acetyl cysteine treatment [25]. However, the other minor allele of TOLLIP (rs5743890) decreases the susceptibility to IPF development but is associated with increased mortality from IPF [26].

Desmoplakin (DSP) encodes for desmoplakin, an adhesion molecule between 2 cells and tethers the cytoskeleton to the cell membrane. Two variants in DSP have been identified in which one variant (rs2744371) is protective, whereas the other variant (rs2076295) increases the susceptibility to IPF [27].

A-kinase Anchoring protein 13 (AKAP13) is a regulator of rhoA, which is involved in the profibrotic signaling pathway. Single nucleotide polymorphism in AKAP13 has also been associated with an increased risk of IPF. AKAP 13 mRNA expression was higher in the lung biopsy section of IPF patients compared to controls [28].

#### **7.2 Genetic factors associated with familial IFP**

Various surfactant-producing gene mutations have been identified, such as SFPT-C and SFPT-A2 associated with IPF in families. Transcription and translation of the SFPT-C gene leads to pro-SPC formation, which is further processed in the endoplasmic reticulum before being secreted in the alveolar space. SFPT-C mutation leads to the formation of pro-SPC. However, it cannot be further processed and folded, leading to protein accumulation within the endoplasmic reticulum and thus, activating unfolded protein response (UPR) within the cell. Unfolded protein response helps to protect the cell and also enhances protein folding chaperones. However, prolonged standing activation of UPR system leads to alveolar epithelial cell death through apoptosis [29]. Studies have shown markers for endothelium reticulum stress and UPR pathway activation even in the absence of SFPT-C mutation. These studies demonstrate that this pathway may contribute to the pathogenesis of IPF [30]. Similarly, SFTP-A2 gene mutations have been identified in a family with 15 members who had familial IPF, bronchoalveolar carcinoma, or underlying lung disease. SFTP-A2 also accumulates mutant surfactant protein A within the endoplasmic reticulum, leading to stress and ultimate activation of the apoptotic pathway [31].

Telomerase complex mutations have been identified in families with UIP. Telomeres are the tandem repeats of TTAGGG found at both ends of chromosomes, protecting the end of chromosomes during cell division. Telomerase helps maintain these telomeres length. Telomerase mutation leads to the shortening of telomere in the alveolar epithelial cells, which was found to be involved in the disease process. Telomere shortening has also been observed in peripheral leukocytes in these patients. New studies have shown shortened telomere length in patients with sporadic IPF and non-telomerase complex mutation IPF, indicating it might play a role in the pathogenesis of IPF [32].

Other molecular biomarkers such as elevated levels of matrix metalloproteinase 7 (MMP 7), mucin 1 (KL-6), CC chemokine ligand 18 (CCL 18), cancer antigen have also been associated with disease progression but have limited clinical value at present and requires further studies [33].

Thus, the use of genetic and biologic biomarkers can further help understand the pathogenesis of IPF and develop future targeted therapies. However, currently, more studies are required to use these markers for diagnostic purposes.

#### **8. Conclusion**

When encountering patients with clinical context and tempo of disease compatible with IPF, excluding identifiable causes by acquiring history and serology is recommended. Other investigations such as biomarkers may aid the defining of IPF. After that, IPF diagnosis can be made with the UIP pattern shown by HRCT. In patients with HRCT patterns of non-UIP, a surgical lung biopsy will assist the diagnosis. When a definite diagnosis cannot be concluded by UIP pattern from HRCT or biopsy result, the mutual agreement from the multidisciplinary discussion is recommended to help diagnose IPF.

*Idiopathic Pulmonary Fibrosis*

#### **Author details**

Pahnwat T. Taweesedt<sup>1</sup> , Kejal Gandhi<sup>2</sup> , Reena Shah<sup>3</sup> and Salim Surani4,5\*

1 Corpus Christi Medical Center, Corpus Christi, TX, USA

2 Department of Medicine, Georgetown University/Medstar Washington Hospital Center, Washington, DC, USA

3 Aga Khan University Hospital, Nairobi, Kenya

4 Texas A&M University, TX, USA

5 Research Collaborator, Mayo Clinic, Rochester, MN, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[32] Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine. 2008;**178**(7):729-737

[33] Neighbors M, Cabanski CR, Ramalingam TR, Sheng XR, Tew GW, Gu C, et al. Prognostic and predictive

biomarkers for patients with idiopathic pulmonary fibrosis treated with pirfenidone: Post-hoc assessment of the CAPACITY and ASCEND trials. The Lancet Respiratory Medicine. Aug 2018; **6**(8):615-626

Section 3

Treatment

**Chapter 4**

## Pharmacological Management of Idiopathic Pulmonary Fibrosis

*Ladan Panahi, George Udeani, Andrew Scott Tenpas, Theresa Ofili, Elizabeth Marie Aguilar, Sarah Burchard, Alexandra Ruth Ritenour, April Jacob Chennat, Nehal Ahmed, Chairat Atphaisit, Crystal Chi, Jesus Cruz III, Monica D. Deleon, Samantha Lee, Zack Mayo, Mackenzie Mcbeth, Mariel Morales, Jennifer N. Nwosu, Kelly Palacios, Jaycob M. Pena and Nitza Vara*

#### **Abstract**

Idiopathic pulmonary fibrosis (IPF) is a common interstitial lung disease (ILD) caused by environmental exposures, infections, or traumatic injuries and subsequent epithelial damage. Since IPF is a progressively fatal disease without remission, treatment is both urgent and necessary. The two medications indicated solely for treatment include the tyrosine kinase inhibitor nintedanib (Ofev®) and the anti-fibrotic agent pirfenidone (Esbriet®). This chapter discusses in detail the current treatment options for clinical management of IPF, specifically the mentioned two pharmacotherapeutic agents that decrease physiological progression and likely improve progression-free survival. The chapter also discusses the evolution of drug therapy in IPF management and the drawbacks and limitations learned throughout historical trials and observational studies.

**Keywords:** drug therapy, pharmacological management, idiopathic pulmonary fibrosis, review

#### **1. Introduction**

Idiopathic pulmonary fibrosis (IPF) is a common interstitial lung disease (ILD) caused by environmental exposures, infections, or traumatic injuries and subsequent epithelial damage [1, 2]. It is characterized by fibroblast activation, followed by excessive secretion of extracellular matrix in the bronchial walls and alveolar interstitium [3]. This uncontrolled deposition leads to stiffening of lung tissue, which impairs diffusion of gases and reduces blood oxygenation [3, 4]. More prevalent among males and adults over 65 years old, it has a high incidence in North America and Europe [1]. Smoking, family history, and genetic mutations associated with telomere length maintenance have been linked to increased risk of developing IPF, as well as the history of gastroesophageal reflux disease and obstructive sleep apnea [1].

Patients typically present with chronic, progressive dyspnea, and dry cough [5]. Their history may include long-term smoke or workplace exposure such as inhalation of wood or metal particulates [6]. On physical examination, bibasilar inspiratory crackles ("velcro rales") and finger clubbing may be seen [4, 7]. Pulmonary function tests (PFTs) usually demonstrate reduced lung capacity and reduced diffusion capacity for carbon monoxide, indicating restrictive disease and abnormal gas exchange [4, 8]. Exclusion of other interstitial lung diseases—including autoimmune diseases—is required before a diagnosis can be made. Additionally, the presence of a honeycomb fibrosis pattern on high-resolution computed tomography is necessary [4, 8]. Patients commonly have at least one comorbidity, such as chronic obstructive pulmonary disease (COPD), pulmonary hypertension, lung cancer, and diabetes mellitus [4, 8].

IPF is characterized by irreversible and potentially fatal lung deterioration [8, 9]. Patients may experience different rates of disease progression, ranging from gradual deterioration to stable periods lasting months or years. Symptoms associated with progression include worsening dyspnea, hypoxemia, and pulmonary hypertension, as well as fatal exacerbations, where respiratory function declines acutely and unpredictably [8, 9]. Although the disease course varies among patients, prognosis remain poor, with an average life expectancy of 3–5 years after diagnosis [4, 9].

#### **2. Standards of care**

Since IPF is a progressively fatal disease without remission, treatment is both urgent and necessary [10, 11]. The two medications indicated solely for treatment include the tyrosine kinase inhibitor nintedanib (Ofev®) and the anti-fibrotic agent pirfenidone (Esbriet®) [4, 12]. Both were approved in 2014 after clinical trials suggested that they halted the decline in lung function, including a decline in forced vital capacity (FVC) by 50% over a 1-year period [4, 11]. Moreover, they have been shown to be safe and effective in reducing severe respiratory episodes often seen in IPF [4].

Treatment regimens for COPD, heart disease, and smoking cessation are also recommended to reduce respiratory strain if experienced concurrently [4, 13]. Patients suffering from hypoxemia and IPF often receive supplemental oxygen [4, 14]. Pulmonary rehabilitation, physical therapy, and oxygen are all recommended to improve exercise tolerance and duration, reduce dyspnea, prevent the development of pulmonary hypertension, and improve overall lung capacity [4].

Lung transplantation remains a viable option for those who meet the criteria for the procedure [11]. It must be considered earlier in disease progression, with early evaluation to maximize eligibility [4, 11]. Past treatments like warfarin, N-acetylcysteine, prednisone, and azathioprine are no longer recommended due to an overall lack of treatment efficacy [4, 15]. Furthermore, these pharmacotherapeutic options should be avoided in IPF until high-quality randomized control trials prove efficacy since they have failed to show relevant reductive changes in FVC, adverse events, or death [16].

#### **3. Non-pharmacological management and supportive care**

Though current drug therapies demonstrate a reduction in acute exacerbations due to their cytotoxic and immunosuppressive side effect profiles, non-drug measures are often considered. Unfortunately, patients opting for mechanical

#### *Pharmacological Management of Idiopathic Pulmonary Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.101390*

ventilation—often as a bridge to lung transplantation—suffer from low survival rates [17]. Poor prognostic indicators include a decline in 6-minute walk (6 MW) distance greater than 150 meters within one year, a decrease in FVC greater than 10% within 6 months, and a decline in diffusing capacity for carbon monoxide (DLCO) greater than 15% within 6 months [4].

Improvements in both quality of life and 6 MW distance can be seen in those undergoing pulmonary rehabilitation [4]. Length of survival is highly variable; patients diagnosed with mild, moderate, and severe diseases survive an average of 55.6, 38.7, and 27.4 months, respectively [4]. Ultimately, transplantation remains the only option for those with advanced IPF; those who do not undergo this procedure often have poorer outcomes [4, 12]. Approximately 66% of transplant recipients live for more than 3 years postsurgery, while 53% survive greater than 5 years [4]. Transplantation does carry certain complications such as cancer, infections, primary graft dysfunction, cytomegalovirus, and allograft rejection are all commonly seen [12]. Moreover, supplemental oxygen has been shown to improve symptom control during exercise, while lung transplantation may increase survival rates and improve patients' overall quality of life [14].

Since drug therapy is merely supportive therapy, patients are encouraged to take alternative measures to decrease their risk, including smoking cessation, supplemental oxygen, and pulmonary rehabilitation [4]. Ongoing GERD has been thought to worsen IPF, but the use of antacids based on clinical trials remains inconclusive [4]. Although the relation of GERD to IPF is still unknown, the prevalence of GERD and erosive esophagitis are observed more commonly in patients with IPF than in the general population [18, 19].

Lastly, patients should receive pneumonia and influenza vaccinations as part of complementary therapy, though there is no proven benefit for the previously mentioned interventions [14]. Although there is no documented outcome benefit with vaccination in the IPF setting, preventing pulmonary infections is essential as extrapulmonary comorbidities through interactions with environmental factors by various mechanisms are thought to contribute to IPF [20]. Vaccinations are especially recommended for post-transplantation patients since they may be more susceptible immunologically. In outpatient settings, pulmonary hypertension should be controlled with supplemental oxygen [21]. Unless a patient participates in a clinical trial, alternative therapies should be avoided.

#### **4. Previous therapies**

Although commonly used for their anti-inflammatory effects, corticosteroids do not improve clinical outcomes in IPF [14, 22]. When used as monotherapy, they show no survival benefit and actually increased risk of morbidity with long-term use [7, 14]. A regimen consisting of prednisone, azathioprine, and N-acetylcysteine (NAC) was once accepted therapy [7, 14]. However, trial data revealed that, compared to placebo, the combination increased risk of death and hospitalization [7, 14].

Ambrisentan (Letairis®), a potent type-A selective endothelin receptor antagonist, was once thought to decrease time to disease progression [7]. However, the ARTEMIS-IPF trial examined its use in IPF patients, finding it to be ineffective and associated with increased risk of hospitalizations and disease progression [7]. The trial was eventually terminated when an interim analysis found minimal efficacy [7]. Recent guidelines no longer recommend the anticoagulant warfarin since it was associated with a higher risk of mortality compared to placebo [7, 14].

#### **5. Current therapy: nintedanib**

After numerous studies yielded conflicting results, new treatment options were developed, including two novel anti-fibrotic agents capable of slowing disease progression [4]. Pirfenidone and nintedanib both demonstrated a significant reduction in annual FVC decline and improved survival [7].

Nintedanib (Ofev®), an oral tyrosine kinase inhibitor, inhibits the fibroblast proliferation leading to progression of lung fibrosis [3, 4]. It may also inhibit other growth factor receptors, including tyrosine kinase vascular endothelial growth factor receptor and platelet-derived growth factor receptor [3, 4, 7]. This multi-faceted inhibition makes it a first-line agent for IPF [3, 7]. The standard dose is 150 mg twice daily taken with food to increase bioavailability [4, 7]. However, dosing can be withheld or lowered to 100 mg twice daily if side effects become intolerable [7]. Once controlled, standard dosing can be resumed [7]. If adverse reactions persist, however, discontinuation should be considered [7]. The most common side effects associated with its use include diarrhea, nausea, and vomiting [7]. Other important side effects include weight loss and drug-induced hepatotoxicity, designated by a 3–5 fold increase in AST/ALT, with or without severe liver damage. Discontinuation or dose reduction is based on the presence of severe liver damage; details relating to specific therapeutic steps can be found in **Table 1**. Adverse reactions should be monitored alongside signs of increased bleeding, especially in those taking anticoagulants.

#### **Table 1.**

*Nintedanib pharmacokinetic parameters and special considerations [4].*

Arterial thromboembolic events have been noted in patients taking nintedanib, and caution should be exercised in those at high risk for cardiovascular events [4]. Basic pharmacokinetics and special population dosing can be found in **Table 1** [4].

### **6. Current therapy: pirfenidone**

Pirfenidone (Esbriet®) is an oral synthetic pyridine derivative with anti-fibrotic and anti-inflammatory properties [7, 12, 23, 24]. Its anti-fibrotic effects arise from down-regulation of transforming growth factor (TGF) β and tumor necrosis factor (TNF) α [7, 23, 25]. It may inhibit fibroblast proliferation, expression of heat-shock protein 47, and collagen synthesis as well [7, 23–25]. Clinically, pirfenidone reduces worsening of FVC and may reduce risk of hospitalization [7, 23, 26]. Several studies like CAPACITY, ASCEND and RECAP have confirmed its long-term safety, efficacy, and favorable tolerability [7, 12].

Common side effects and clinical pharmacology can be found in **Table 2**. Most prevalent are gastrointestinal (GI) and skin-related adverse drug effects, which generally wane after the first 6 months and do not impact a patient's ability to continue and maintain a high-dose intensity [12]. Several side effects like fatigue, photosensitivity, and GI distress may require dose reductions [7, 12]. Fatigue, in particular, is observed

**Table 2.**

*Pharmacokinetic parameters and special considerations [7, 12, 27–29].*

within the first few weeks of treatment and may substantially affect the quality of life. It may be difficult to distinguish from the disease itself, though it can be managed by dose modifications or even discontinuation [7, 12]. Several studies have examined the importance of taking pirfenidone with food [27, 28, 30, 31]. Administration after meals slows absorption and may mitigate GI side effects [7, 12, 27, 28].

Updated practice guidelines recommend both nintedanib and pirfenidone [15]. Though both have been shown safe and effective, a lack of head-to-head trials makes it difficult to recommend one over the other [15]. The two agents have a different mechanism of action, making the prospect of combination therapy intriguing [12, 32]. However, when investigated, it was found that the combination led to greater photosensitivity and GI side effects [12, 32].

#### **7. Acute exacerbations**

Acute exacerbations (AE) are defined as an acute downturn in blood oxygenation, increased lung attenuation per computed tomography scan, and acute worsening of dyspnea [33]. Common causes include exposure to particulate matter (PM) ≥ 2.5 μm or crocin peptide released by *S. nepalensis*, bronchoscopy or lung biopsy, and inhalation of water repellant [33–36]. Sources of PM include tobacco smoke, candles, forest fires, and dust [33, 37]. The exact incidence of exacerbations is unknown but is estimated to vary between 5 and 20% [36, 38].

Since AE mortality rates range between 60 and 80% within a 90-day period, most care is strictly palliative in nature [39]. The two primary therapies include corticosteroids like prednisone and cytotoxic medications like cyclophosphamide. However, no proven benefit for these therapies has been demonstrated [40]. In addition, mechanical ventilation should not be employed due to poor outcomes [41]. Novel therapy involving administration of polymyxin B-immobilized fiber column (PMX-DHP), originally developed to manage sepsis by removing plasma endotoxins, has shown increased effectiveness [38, 42]. One limitation of its use is it can lower white blood cell counts via absorption of neutrophils [38, 39]. It remains most effective if administered within 3–7 days of AE onset [38, 39].

#### **8. Clinical evidence for efficacy**

The SENSCIS trial was a 52-week randomized, placebo-controlled, doubleblind study examining the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD) with nintedanib [43, 44]. It was shown to decrease FVC

*Pharmacological Management of Idiopathic Pulmonary Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.101390*

decline rate (mL/year) within the treatment group compared to placebo [3, 43]. An annual difference of −52.4 mL/year for nintedanib versus −93.3 mL/year for placebo was shown at 52 weeks [3, 43]. The INPULSIS trial, a 52-week, randomized, double-blind, phase 3 trial, showed a similar reduction in FVC decline rate with nintedanib versus placebo [3, 45]. TOMORROW, a 52-week, randomized, doubleblind, placebo-controlled, phase 2 trial—alongside INPULSIS—showed a decrease in acute exacerbations with nintedanib compared to placebo [4, 45]. The INBUILD trial, a 52-week, randomized, double-blind, placebo-controlled, parallel-group trial, examined patients with progressive fibrosing interstitial lung diseases other than IPF [3, 46]. Treatment groups received nintedanib 150 mg twice daily or placebo [3, 46]. Reduction in FVC decline rate was uniform across the five subgroups [46, 47].

Three major trials have recently examined pirfenidone, including CAPACITY 004, CAPACITY 006, and ASCEND [4, 12]. The two CAPACITY trials were run side-by-side for 72 weeks [48, 49]. CAPACITY 004 showed a significant reduction in FVC decline with pirfenidone, though only a significant difference up to week 48 was seen in CAPACITY 006 [48, 49]. The ASCEND trial, a 52-week, phase 3 trial, found that patients with a predicted FVC > 50% at baseline received benefit from pirfenidone over 1 year, reducing the rate of decline by approximately 50% [4, 49]. ASCEND also analyzed 6 MW distance [49, 50]. There was a significant difference between baseline and week 52 with the two treatments, including a 27.5% reduction in the pirfenidone group [49, 50]. Pooled population data from all three trials showed a 48% reduced risk of death at 1 year compared to placebo [48, 49].

#### **9. Comparison: nintedanib vs. pirfenidone**

As mentioned above, both agents have been shown safe and effective in placebocontrolled, randomized trials [51–53]. Both may slow the FVC decline rate by almost 50% over 1 year [51]. The two treatments have also demonstrated remarkable efficacy in minimizing severe respiratory hospitalizations and acute exacerbations [51, 54]. Though both agents may reduce mortality, each cost over \$100,000 annually [51, 55].

#### **9.1 Mechanisms of action**

Nintedanib has a unique mechanism of action compared to pirfenidone. It inhibits tyrosine kinase, an enzyme that targets growth factor (GF) pathway receptors like fibroblast GF, platelet-derived GF, and vascular endothelial GF [3, 4]. Elevated bleeding risk is seen in patients taking concomitant anticoagulation therapy [7, 15]. Patients should regularly monitor liver function and GI disturbances, including diarrhea [43, 46]. Conversely, pirfenidone inhibits collagen synthesis, downregulates TGF-β, tumor necrosis factor-α, and reduces fibroblast proliferation [7, 24, 26]. Side effects include abnormal liver function, anorexia, nausea, photosensitive rashes, and vomiting [56].

#### **9.2 Dosing**

Pirfenidone comes in a 267 mg capsule, initially dosed as one capsule three times daily the first week [56, 57]. During the second week, the dose can be increased to 534 mg three times daily, and—after two weeks—it can be fully titrated to 801 mg three times (2,403 mg or nine pills per day). It is recommended that each dose be taken after a full meal to minimize GI side effects like nausea, dizziness, and vomiting [56, 57]. Patients may be treated with nintedanib first-line if intolerability to pirfenidone occurs [56–58]. The maximum recommended dose is 150 mg twice daily [58, 59].

#### **9.3 Research similarities and differences**

In a 1-year evaluation of both medications, there was a slight decrease in FVC, especially in those with comorbidities, which may account for increases in hospitalization and all-cause mortality [60, 61]. In combined studies, pirfenidone displayed a slower rate of FVC decline than nintedanib, helping to explain increased hospitalizations and mortality with its use [60, 61].

#### **9.4 Side effect profiles**

Though pirfenidone is frequently associated with GI complications, diarrhea, and involuntary weight loss is more common with nintedanib [57, 58, 61]. Pirfenidone's side effects include dyspepsia, nausea, loss of appetite, phototoxic reactions, and difficulty concentrating. Sunscreen use is recommended when taking it. Conversely, nintedanib displays less nausea but greater transaminase elevations [57, 58, 61]. Pirfenidone is older and better studied more nintedanib, which may explain why its gastrointestinal and cognitive side effects are better understood [57, 58, 61]. Phototoxicity is generally absent with nintedanib [57, 61].

#### **10. Therapeutic drawbacks**

Though pirfenidone and nintedanib may slow disease progression, neither will cure IPF or markedly improve current symptoms [4, 62]. Symptom management, especially cough and dyspnea, is crucial to maintaining the quality of life [4, 63]. This is somewhat challenging given the lack of clinical evidence showing improvement in such symptoms and guideline focus on lung function [4, 63].

Both agents have noteworthy side effects. Nintedanib is most frequently associated with diarrhea, nausea, vomiting, and elevated liver enzymes [62]. By comparison, pirfenidone may cause nausea, diarrhea, dyspepsia, anorexia, and gastroesophageal reflux, as well as rash, upper respiratory infections, and fatigue [62, 64].

Another significant burden of IPF is cost [4, 65]. A recent systematic review estimated its annual cost in the United States at \$20,000 per patient per year, about three times greater than the national health care resource use per capita [4, 65]. Hospitalizations and acute exacerbations are key drivers of this cost, with an average cost exceeding \$16,000 for each IPF-related hospitalization [4, 66]. Due to their specialty drug and brand-only status, pirfenidone and nintedanib remain extremely expensive, with costs exceeding \$10,000 per month per agent [4]. However, nintedanib is associated with fewer acute exacerbations and, consequently, decreased medical costs [4, 62, 67]. A recent comparison analysis from the United Kingdom found that the two drugs were comparable in estimated cost and health-related quality of life benefit [4, 68].

It is important to remember that the INBUILD trial was not powered to provide sufficient evidence for the use of nintedanib in rarer, specific fibrosing ILD [47]. However, it can be challenging to recruit patients with these rarer disease states. The fact that nintedanib reduced the rate of disease progression (i.e., FVC decline) in a wide range of progressive fibrosing ILD suggests utility in such populations [47].

#### **11. Novel research/pipeline drugs**

In recent decades, our understanding of IPF pathogenicity and management has improved significantly [15, 69]. However, many limitations, such as an inability

#### *Pharmacological Management of Idiopathic Pulmonary Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.101390*

to translate experimental findings in animal models to human subjects, remain a challenge [69, 70]. Current therapies like nintedanib and pirfenidone are limited to pathways involved in reducing disease progression and physiological decline in those with mild-to-moderate impairment [15, 69]. Second-line treatments capable of improving functional capacity for such patients or benefiting the severely impaired are still needed [15, 70].

Other viable agents have been recently investigated [9]. Increased concentrations of endothelin receptors have been observed in IPF lung tissue [15]. As a result, several clinically significant endothelin receptor antagonists have been previously tested, including ambrisentan, a selective type-A antagonist, and bosentan and macitentan, type-A and type-B antagonists [71, 72]. Nonetheless, recent guidelines strongly discourage the use of ambrisentan given its risk of harm and lack of benefit, along with a conditional recommendation against the use of bosentan and macitentan [15, 73].

The phosphodiesterase-5 inhibitor sildenafil has been investigated due to its role in pulmonary vasodilation and improved gas exchange [15]. Past studies and analyses reported a slight but significant improvement in the degree of dyspnea and quality of life compared to placebo [15]. However, it has failed to demonstrate improvements in mortality, acute exacerbations, and adverse events [15]. Recent guidelines discourage its use, though it continues to be investigated [15, 73].

N-acetylcysteine (NAC), a precursor of the antioxidant glutathione, has also been examined for use in IPF [74]. A pooled analysis compared NAC monotherapy to placebo in IPF patients [15]. Ultimately, there was no significant difference in the rate of death or acute exacerbation, as well as no significant benefit in mortality, quality of life, or adverse outcomes [15]. Current guidelines strongly discourage its use in practice [15, 74].

A recent randomized clinical trial investigated imatinib mesylate (Gleevec®), a tyrosine kinase inhibitor. It showed a statistically significant increased risk of adverse events and no improvement in preventing disease progression or mortality [15, 74]. This distinct lack of benefit has led to its use being discouraged in IPF [15, 74].

Several active interventional and observational trials are currently underway. Recent novel studies suggest that genetic factors may play a crucial role in overall risk, disease progression, and therapeutic response [70, 75]. Future trials and drug development will likely focus more on genetic variation in IPF patients [70, 75].

#### **12. Conclusions**

IPF is a common ILD that is progressive and potentially fatal [4, 9]. It is characterized by decreased lung function stemming from abnormal fibrotic processes, ultimately leading to scarring tissue formation, diminished gas exchange, and reduced blood oxygenation [4, 7]. Though there is no known cause, it is more common in males and elderly patients and is associated with risk factors like smoking, environmental exposure, and multiple comorbidities [4, 9]. Due to insufficient understanding of its pathophysiological mechanisms, there are currently no therapies capable of preventing or reversing IPF [7, 9, 76]. Current management includes antifibrotic drugs like nintedanib (Ofev®) and pirfenidone (Esbriet®), which have been shown to slow lung deterioration [4, 7, 13]. Recent investigations examining nintedanib use in other ILDs with progressive phenotypes have shown favorable results, suggesting that such ILDs share similar mechanisms and may thus benefit from similar treatment [3, 77]. Imatinib mesylate (Gleevec®) is not recommended due to the increased risk of adverse events and no improvement in disease progression or mortality [17, 73]. Similarly, the use of ambrisentan (Letairis®)

#### *Idiopathic Pulmonary Fibrosis*

is discouraged due to lack of effectiveness and increased risk of hospitalization [7]. Other IPF management strategies include smoking cessation, immunization, respiratory rehabilitation, oxygen supplementation, and management of comorbidities [4, 20]. More recent approaches have targeted biological processes linked to IPF, such as aging, oxidative stress, and epithelial-to-mesenchymal cell transition (EMT) [9, 76]. Ultimately, a better understanding of its underlying mechanisms is necessary to develop more effective treatments and reduce mortality [7, 9, 76].

#### **Author details**

Ladan Panahi1,2\*, George Udeani1,2, Andrew Scott Tenpas1,2, Theresa Ofili1,2, Elizabeth Marie Aguilar1,2, Sarah Burchard1,2, Alexandra Ruth Ritenour1,2, April Jacob Chennat1,2, Nehal Ahmed1,2, Chairat Atphaisit1,2, Crystal Chi1,2, Jesus Cruz III 1,2, Monica D. Deleon1,2, Samantha Lee1,2, Zack Mayo1,2, Mackenzie Mcbeth1,2, Mariel Morales1,2, Jennifer N. Nwosu1,2, Kelly Palacios1,2, Jaycob M. Pena1,2 and Nitza Vara1,2

1 Department of Pharmacy Practice, Texas A&M Rangel College of Pharmacy, Kingsville, Texas, USA

2 Department of Pharmacy Practice, Texas A&M Rangel College of Pharmacy, College Station, Texas, USA

\*Address all correspondence to<EMAIL_ADDRESS>
© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pharmacological Management of Idiopathic Pulmonary Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.101390*

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Section 4


**10. Light Fastness of Untreated and Treated Polyester Fabrics with ZnO or TiO2 NPs**

The light fastness property of all colored polyester fabric samples that were treated with ZnO or TiO2 NPs of disperse dyes **26a**, **26b**, **22h**, and **22i** were measured, and the results were more significant. Table 7 shows that, with the exception of dye **26a**, using ZnO or TiO2 NPs more effectively resulted in treated polyester fabrics having stronger light fastness than the untreated samples (Table 7).

### **11. Antimicrobial Activity of Untreated and Treated Polyester Fabrics with ZnO or TiO2 NPs**

The untreated and treated polyester fabrics are tested against the pathogenic fungi *Aspergillus flavus* and *Penicillium chrysogenum,* as well as the Gram-positive bacteria *Bacillus subtilis* and the Gram-negative bacteria *Klebsiella pneumoniae*. Table 8 revealed that untreated polyester fabrics with ZnO or TiO2 NPs did not exhibit antibacterial activity against all of the microorganisms [64,73].

**Table 8.** Inhibition zone diameters of the dyed polyester fabrics of disperse dyes 26a and 26b against Gram-positive, Gram-negative bacteria and yeast.

(NI): No inhibition.

While only *Bacillus subtilis* was the target of the antibacterial activity of nano ZnO treated polyester fabrics of dispersion dye **26a**, nano ZnO treated polyester fabrics of disperse dye **26b** were effective against both *Bacillus subtilis* and *Klebsiella pneumoniae*. ZnO NPs had antibacterial activity against bacteria, and its mechanism involved either ZnO nanoparticles or TiO2 nanoparticles influencing bacterial membranes to inhibit bacterial growth. Alternatively, nano ZnO may enable the generation of peroxide, which may offer antibacterial properties [65,73].

According to the antifungal screening results given in Table 8, the two harmful fungi *Aspergillus flavus* and *Penicillium chrysogenum* were not resistant to the treated polyester dyed fabrics with TiO2 NPs of dispersion dye **22i**. *Aspergillus flavus* and *Penicillium chrysogenum* were resistant to *Aspergillus flavus* and the treated polyester colored fabrics with TiO2 NPs of dispersion dye **22h**.

#### **12. Conclusions**

Our original work highlighted that the synthesis of new disperse dyes, with the help of microwaves, could be carried out in the presence of small quantities or sometimes in the absence of any amounts of organic solvents, which are harmful to the environment, in a short time that did not exceed minutes and gave great yields compared to the synthesis of those dyes using traditional methods. It is known that cytotoxicity is one of the most important markers of biological evaluation in laboratory tests, so we presented two examples of new disperse dyes as one of the examples of in vitro cytotoxicity examination.We showed that these dyes possess anticancer activities against some common cancers such as lung, breast, liver and colon cancer. The added value of these new disperse dyes was also discussed and presented by showing the biological activity and clarifying that these dyes have a great biological activity against Gram-positive and Gram-negative bacteria, as well as various

fungi and yeasts. It is worth noting here that polyester fabrics dyed with these dyes had biological activity, which makes these fabrics able to be used in many medical activities. We presented and discussed the use of ultrasound energy to dye polyester fabrics, as it gave a high color strength compared to traditional dyeing methods. In this review, we also discussed the methods of treating polyester fabrics with nano-zinc oxide or nano-titanium dioxide and presented the advantages of this strategy in endowing the dyed polyester fabrics with multiple functions, such as self-cleaning property, maximizing light fastness property and maximizing antimicrobial activities.

**Author Contributions:** Writing—review and editing, A.M.A.-E. and M.A.E.-A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.