Cough in Idiopathic Pulmonary Fibrosis

Table of Contents

Introduction

Review of Evidence

Article 1

Article 2

Article 3

Conclusion and Recommendations

References

Appendix

Introduction

The “Interstitial Lung Diseases (ILDs)” is a diverse collection of parenchymal diseases of the lung that are categorised with respect to numerous degree of fibrosis and inflammation (Van Manen, et al., 2016). Some of these diseases could take place secondary to recognised precipitants, for instance, drugs, “Autoimmune Connective Tissue Disease”, extreme sensitivity to the organic antigens that were inhaled, or the sarcoidosis, whereas the others “Idiopathic Interstitial Pneumonias (IIPs)”, attain no recognisable reason. “Idiopathic Pulmonary Fibrosis (IPF)” is a form of aggressive IIP, that are categorised by chronic and the progressive fibrosis that is linked with an inexorable decrease in the function of the lung, failure of the progressive respiratory and high rate of mortality (Bonvini and Belvisi, 2017). Precise diagnosis is fundamental in order to assist with prognostication, in addition to this optimise selection of treatment. IPF is a fatal and progressive fibrotic disorder of lung having no identifiable reason and no established pharmacologic therapy (Vigeland, Hughes and Horton, 2017).

It is one of the most general “Idiopathic Interstitial Pneumonia”, accounting for more than sixty percent of the scenarios; however, it is also from those diseases that are less treatable and attains the worst prognosis. Most of the patients that are suffering from this disease die within three to five years (Vigeland, Hughes and Horton, 2017). The major signs and the symptoms include cough, finger clubbing, inspiratory crackles and dyspnea. The history greatly differs between the patients, however, the decline in the functioning of the respiratory system worsen the life quality and ultimately results in death. It is one of the most severe lung diseases globally, as this disease affects three million individuals around the world annually (Saunders and Maher, 2017). According to research that was conducted in the UK, around 33,000 individuals that are residing in the UK are affected by IPF (Bargagli, et al., 2019).

In the research, it was also revealed that one in every hundred deaths occurring is because of IPF, which is approximately fifteen individuals every day. Despite the huge mortality rate of this disease, the reasons behind this disease and the reason behind the cough in this disease are still not much evident (Vigeland and Horton, 2016). More research and study is the only method by which this scenario could be changed. For the wellbeing of the individuals, proper diagnosis of IPF is required. However, this disease is hard to diagnose, in addition to this, an onset is observed frequently in the symptoms and precise diagnosis. The irreversible damage of lung that is caused by the progression of disease underscores the significance of early treatment. For the wellbeing of an individual, early treatment is critical to enhancing the prognosis of IPF (Upton, et al., 2015).

In the last few years, the importance and utilisation of “Evidence-Based Practice (EBP)” have surged up and has attained popularity as an approach that is transformative to the healthcare system. The utilisation of EBP by the nurses has resulted in the better outcomes of patients and a decrease in the costs, disregard of setting or facility (Rushforth, et al., 2015). There are four different phases to EBP that are, formulation of evident question from the problem of the patient, search for the literature for related clinical articles, examine the evidence for usefulness and validity and implement the findings that are useful in the medical practices. In this assignment, three articles are going to be evaluated regarding the cough treatment in IPF. Different methodologies, search strategies and data analysis method that was used in the articles will be discussed. In addition to this, the findings of all articles will be discussed and the recommendations will be given (Upton, et al., 2015).

Review of Evidence

For searching the articles related to the topic, a secondary qualitative search method was used. PICO method was used in order to formulate the keywords that could be used in order to search the relevant articles. PICO stands for the four processes that are, “Population or Problem or Patient”, “Intervention or Indicator”, “Comparison” and “Outcome of Interest” (McKeon and McKeon, 2015). In the first part, the problem was stated as a cough in IPF. In the second part, different interventions were taken into consideration. In the third part, different interventions were compared and in the last part, what would be the outcome of this research was discussed. After going through the elements of PICO, a search strategy was planned in which the major question elements were converted into subject descriptors. The keywords that were formulated in this method were, “Idiopathic Pulmonary Fibrosis”, “Cough”, “Interventions” and “Treatments” (McKeon and McKeon, 2015).

For connecting different keywords and the search term the Boolean operators were used AND and OR, between those terms. The databases that were used for searching the articles were, “Google Scholar”, “ProQuest”, “PubMed”, “PsycINFO”, “Cochrane Library”, “TOXNET” and “Sociological Abstracts”. The articles that were related to IPF and the interventions that could be made to overcome this health disease were included in this study. Moreover, the articles in which cough was discussed as a symptom in IPF were included in this study. In addition to this, another inclusion criterion was made: the articles need to be published in English and after the year 2000. As the research regarding IPF surged after the year 2000. All the articles that were published before that date were excluded from this review. After adapting to these search strategies, seven articles were selected relevant to the topic. At last, three articles were selected as they met the entire criterion mentioned above.

Article 1

The title of the first article that is used for critical evaluation is “Thalidomide for the Treatment of Cough in Idiopathic Pulmonary Fibrosis” (Horton, et al., 2012). The aim of this research article was to determine thalidomide efficacy for suppressing the cough that was present in the IPF patients. Thalidomide is a type of a drug having not a popular history. The utilisation of this drug during pregnancy first trimester as an antiemetic caused severe defects in birth. However, in recent years, it is found that this drug could be a source of effective cancer treatment. The drug is a potent anti-inflammatory, antiangiogenic and immunomodulatory drug. Its properties of immunomodulatory propose that it might be a potential treatment for IPF. The utilisation of thalidomide was highlighted when an open-label medical trial took into place; the patients that received this drug reported decrement in cough (Horton, et al., 2012).

The main funding source in this research was “Celgene Corporation”. In this research, a primary quantitative research method was utilised. This research was a double-blind, 2-period, 2-treatment crossover trial having a treatment period of about two 12-week divided with the help of 2-week washout period without any drug. This research took place at “Johns Hopkins University School of Medicine, Baltimore, Maryland” (Horton, et al., 2012). The patients that were eligible for this study were informed regarding this research, and the patients who were interested in participating in this research were included (Eisen, et al., 2000). The selection period was between the year of 2008 and 2011. At the initial stage, 98 individuals contacted, however, 25 patients who were interested were shifted to the centre for additional examination. The eligibility criterion was; the individuals ageing over 50 years having a medical history with consistent IPF (with a duration of symptoms of above three months and below five years) and facing from a chronic cough (Stein, et al., 2011).

The chronic cough could be described as, consistent cough for a duration of above eight weeks, which affects the life quality adversely and whose reason was not already identified. The patients were having high-resolution chest scans of computed tomography constant with the IPF, FVC in the range of 40% until 90%. The major criterion for exclusion was pregnancy, environmental or toxic disclosure to the respiratory irritants, airflow obstruction, disease of collagen vascular, intolerance or allergy to thalidomide and having less than six months of life expectancy in the view of investigators. The participants were assigned randomly to receive placebo or thalidomide. The patients received the treatment for the period of twelve weeks with a washout period in the transition of the two treatments (Horton, et al., 2012). Patients started getting 50mg of the drug orally at the time of bed. The increment in dose was made for the patients in whom no improvements were recorded. The flow diagram is described in A.1.

For the follow-up, a questionnaire from “Cough Quality of Life Questionnaire (CQLQ)” was presented, which was having around 28 different questions regarding the cough. The primary evaluation was done when the scores were compared with placebo and after thalidomide treatment. The secondary assessment was done based on “10-cm Visual Analogue Scale” and respiratory life quality as examined by “St. George’s Respiratory Questionnaire (SGRQ)” (Lechtzin and Horton, 2013). The results from the CQLQ perceived that the patients who were taking thalidomide reported fewer cases of severe cough that could have an adverse effect on the life quality in comparison with the patients that took a placebo. Similar results were observed in SGRQ, the individuals who took thalidomide reported that their condition has significantly improved.  However, the individuals who were given thalidomide reported more for the adverse events in comparison with the patients taking a placebo (Tonelli, et al., 2017).

 Commonly, the individuals who took placebo reported that they were facing from dyspnea, sleepiness, infection in upper respiratory and constipation. Whereas, in the group of thalidomide the common negative events reported were dizziness, constipation, anorexia, asymptomatic bradycardia and malaise. From the above results that were attained from this research, it was stated that even low dose of thalidomide can have fundamental improvements as it reduced the cough severity in the individual that adversely affected their quality life (Horton, et al., 2012). The changes that were brought by thalidomide had a great impact on the betterment of the patients with IPF. The details of the adverse effects are given in A.2 in the appendix. Thus, the magnitude of the changes perceives to be important clinically.  A substitute action mechanism might associate to the anti-inflammatory thalidomide properties (Swigris, et al., 2014). Thalidomide might have advantageous immunomodulatory effects by affecting directly to the inflammation that leads towards IPF. However, the potential usage of this drug as a proper IPF treatment still requires large-scale medical trials (Horton, et al., 2012).

The cough with the patients facing from IPF is very general, however, it is often disabling. The patients that are facing from IPF often face from other comorbid illness as well, and the reason for the cough could be that disease as well or the usage of medicines. In this study, all of the patients that were involved in this research self-reported that the cough had negative effects of the life quality, 70% of the patients reported “Gastroesophageal Reflux Disease (GERD)”, 22% reported sinus disease and 30% were involved in the usage of “Angiotensin Converting Enzyme (ACE)” inhibitors (Tonelli, et al., 2017). However, the recent researches have found a lack of correlation between GERD or the sinus disease treatment or presence and cough presence in the patients suffering from IPF. However, still there is lack of clarity behind the cause of cough in patients suffering from IPF and still, no evident treatment is proposed for the IPF patients (Horton, et al., 2012). 

In this study, the researchers and the patients who were examined were blinded regarding the drug identity that they were given. However, few of the adverse effects of thalidomide, such as sedation and constipation might have alerted the individuals regarding the drug that was given to them, which might have influenced their view of thinking. According to the researchers that were involved in this research, the study signifies the first medical trial for demonstrating an operational cough treatment in IPF patients, with successive improvement in respiratory-specific and cough life quality. However, several strengths and weakness are present in this research study. One of the strengths of this study is that the “Celegne Corporation” funded it. In addition to this, another strength, which assisted the researchers in concluding the result, was the results of thalidomide could be compared with the patients that were being treated with placebo (Horton, et al., 2012).

However, this research had several weaknesses and limitations that obstructed the researcher in concluding to an evident conclusion. First, the research was not done on a large-scale, it was designed on a small-scale, the study took place at one place only, and therefore the results could not represent the patients from some other area (Horton, et al., 2012). Moreover, this study was not conducted for a long duration; it was only for a duration period of about three months. Which might not permit for the whole obligation of the negative effects associated with the drugs or the evaluation of cough suppression durability beyond three months. The evaluation of thalidomide safety and durability for a period of long-term is required, in order to conclude to a certain point. After conducting this research, the reason behind the patient’s cough was not evident. All the treatment processes and drugs need to be tested thoroughly before they are available for the individuals.

Article 2

The title of the second article that is selected for the critical assessment is “A Study of the Cough Reflex in Idiopathic Pulmonary Fibrosis”. This research had multiple aims, the first one was to evaluate the reflex of cough reaction to “Capsaicin” in a well-defined patient group facing from the disease of IPF, in which all other cough causes are excluded. The research was also designed to determine the response of cough to “Substance P (SP)” and “Bradykinin”, in addition to this, examine whether such peptides moderate the response of cough to capsaicin. The third aim of the research is to measure the neurotrophic aspects levels, such as “Growth Factor (NGF)”, “Brain-Derived Neurotrophic Factor (BDNF)”, and “Glial Cell Line–Derived Neurotrophic Factor (GCLDNF)” in epithelial fluid lining of the airways that are larger by examining the sputum that is induced (Hope-Gill, et al., 2003).

The last aim of this research was to assess the “Oral Corticosteroid Therapy” effect on the response of cough to SP and capsaicin in a patient group facing from IPF and severe cough. The methodology that is used for achieving the aims of this study is the primary quantitative method. In this research, 13 patients that were satisfying the criteria given by “American Thoracic Society (ATS)” for IPF diagnosis were recruited (European and American Thoracic Society, 2002). All the individuals that were recruited in this study, were above aged and were possessing physiological and clinical characteristics consistent with IPF diagnosis. Moreover, they even had changes that were characteristic on the high-resolution chest scans of computed tomography, and because of that clinical “Lung Biopsies” were not executed.

The individuals who were excluded from the study included, individuals, having “Gastroesophageal Reflux Disease (GERD)” symptoms, smoking history within one year, asthma or any other disease related to the respiratory system. Detailed exclusion criteria are described in figure A.3 in appendix. All of these thirteen participants were having a methacholine problem to omit the airway hyperreactivity. The patients were given an inhibitor of proton pump named “Omeprazole” with a dose of 20 mg per day for a time period of one month before the study was initiated, this took into place in order to remove the subclinical GER. None of the patients was subjected to smoking for almost one year and was requested to grade their severity of cough between the scale of 0-10, 0 meant no cough and 10 was related to disabling (Quanjer, et al., 1997).

It was done by utilising a 10-cm “Visual Analog Scale (VAS)”.  The threshold of cough was termed as the concentration that is causing two or more coughs as “C2” and “C5” was also recorder for five or more than five coughs (Quanjer, et al., 1997). Ten of the patients went through an opening cough challenge by capsaicin with the help of compressed dosimeter that was air driven (Donaldson, et al., 2006). Two additional challenges took into place, the first one occurred one minute after the inhalation of SP and the second one occurred after an hour (Sterk, et al., 1993). Coughs that were produced within sixty seconds of the each SP inhalation were measured. Moreover, with the help of standard nebulizer, “Sputum” was induced in all of the thirteen patients. BDNF, NGF and GCLDNF, were examined in the samples of sputum by utilising a quantitative enzyme assay method termed as “Sandwich” (Pavord, et al., 1997).

In order to develop the response curves of the dose, the function of negative logarithmic was utilised. The nonparametric data were compared to utilising “Mann–Whitney U test” and “Wilcoxon’s Signed Rank Test” (Turner-Warwick and Haslam, 1987). In order to compare the SP and Bradykinin response “Fisher’s Exact Test” was used and the “Unpaired t-Test” was utilised for comparing the baseline variables. The pulmonary and demographic function information for the control subjects and the patients are described in appendix A.4 and the cough severity in table A.5. None of the subject coughed whilst inhalation of sodium chloride (Lynch, et al., 1992). After capsaicin inhalation, the response curve of cough took into place instantly and was completed consistently within the fifteen seconds. None of the subjects was having prolonged coughing bouts. No fundamental change in delayed or immediate “C2” or “C5” was recorded, when the participants were subjected to capsaicin after the inhalation of SP and Bradykinin (Hope-Gill, et al., 2003). 

The healthy individual perceived no response of cough to the inhalation of Bradykinin and SP. However, direct response of cough was recorded after the SP inhalation with the IPF patients. It was also perceived in this study that six patients belonging from an additional group that was treated with the therapy of corticosteroid, showed a major decrement in the sensitivity of cough reflex to the capsaicin. The induction of sputum was tolerated well in all of the subjects without any important drop in FEV. The sputum that got induced in all of the thirteen control subjects; though, tolerable supernatant for accessing level of NGF was attained in ten from thirteen patients and for analysis of BDNF in twelve from thirteen patients (Hope-Gill, et al., 2003).

The primary observations of this research affirm that the earlier research findings that the individuals suffering from IPF have much greater reflex sensitivity of cough to the inducted capsaicin in comparison with the healthy individuals, in addition to this the response of cough is reproducible highly. Moreover, the exclusion was done to propose that these factors enhanced the sensitivity of the cough in IPF patients. Moreover, it was shown for the firm time that majority of the patients facing IPF cough when the SP was inhaled but not with the inhalation of bradykinin. It was also demonstrated that the therapy of oral corticosteroid decreased the sensitivity of cough reflex to subsequent challenge of cough, as examined by the VAS. It is confirmed in this study that the sensitivity of cough reflex is enhanced in the patients that are suffering from IPF (Hope-Gill, et al., 2003).

Furthermore, it explains that the majority of the patients attains direct response of cough to SP. The enhanced reaction to the capsaicin that is c-fibre-specific backs the assumption that there exist an operational upregulation of sensory nerves of the respiratory tract in IPF. The direct response of cough to the SP in few of patients, effects abrogation with the help of steroid therapy and the neurotrophins presences in the airway lining fluid of epithelia back the notion that the process of inflammatory might affect further proximal airways. The description that the presence of cough in the IPF patient is amenable to the intervention of therapeutic is motivating and it should further promote the investigation in this area. However, the research is limited as only a small group is examined in it; therefore, there is still a requirement of further investigation into this matter before coming to an evident conclusion regarding the cough treatment in the IPF patients (Hope-Gill, et al., 2003).

Article 3

The title of the third article that is used for the critical evaluation is “A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial”. The purpose of this research is to examine and evaluate the safety and efficacy of PA 101 that is inhaled by the patients suffering from chronic cough and IPF. Moreover, the research article also aims to discover PA 101 antitussive mechanism and the patients that are suffering from “Chronic Idiopathic Cough (CIC)” were examined in this research. In order to achieve different aims of the research, a primary quantitative research method was developed (Birring, et al., 2017).

The cough could be a debilitating “Idiopathic Pulmonary Fibrosis (IPF)” symptom and it is not easy to get rid of this problem (Johansson, et al., 2018). However, PA101 is stated to be an innovative sodium cromoglicate formulation that could be delivered through an e-Flow nebuliser of high frequency, which attains importantly higher deposition of drug in an individual’s drug when it is compared with the formulations that are already available and are used for the treatments (Knoch and Keller, 2005). Therefore, in this research, it is aimed to examine its safety and efficacy if it is utilised for treatment on patients.  Presence of chronic cough in IPF has a fundamentally negative effect of the life quality of the individuals and is normally refractory to medical therapy (Van Manen, et al., 2016).

Currently, no drug is approved for the treatment of cough that occurs quite often in IPF patients. “PubMed” was the database used in this research method, for finding the previous article that worked over similar aims and objectives, without any language or date restrictions. This proof-of-concept, pilot study is comprised of double-blind, placebo-control, randomised trail present in the patients suffering from chronic cough and IPF. Moreover, another parallel study was conducted with a related design in the patients that were going through CIC. The participants that were facing chronic cough and IPF were selected from seven different centres, present in the Netherlands and the UK. Moreover, the participants were randomly assigned by the staff of site to be given PA 101, with a dose of 40 mg or the related placebo 3 times in a day through mouth inhalation for a period of around two weeks (Birring, et al., 2017). 

This intake was followed by a washout period of about two further weeks and afterwards crossed-over to another arm. The participants, study staff, the sponsor of the research and the investigators were masked to the team tasks until all of the participants in the research study has finished the study. The initial endpoint of efficacy was varied from the baseline in the objective daytime frequency of cough. The initial analysis of efficacy contained all of the participants, who took at a minimum of one study dose and had a minimum of post-baseline measurement or assessment of the efficacy. The analysis of safety included all of the participants who took at a minimum of one study dose of the drug (Birring, et al., 2017).

 In the second unit, the participants that were facing from CIC were assigned randomly in an assessment across the four centres with identical endpoints and design. Both of the treatments were regulated with the help of E-Flow nebuliser of high efficiency (Leaker, et al., 2015). The E-Flow is multi-use, silent, portable, single patient, electronic battery-operated nebuliser, which utilises a mesh membrane that is vibrating, in order to produce a smaller aerosol particle that permits for more homogenous and targeted drug deposition in the patient’s lung when compared with a nebuliser that is used generally. Every participant first went through the screening, in order to examine whether the participants are eligible for the research or not (Leaker, et al., 2015).

Between the year of 2015 and 2016, twenty-four different participants suffering from IPF were assigned randomly to the groups of treatment. The twenty-eight participants that were facing from CIC were also enrolled in the identical period, from which twenty-seven received the treatment from this study. With the help of PA 101 the patients that were suffering from cough and IPF observed decrement in the daytime frequency of cough by approximately 31% on the day fourteenth when they were compared with placebo. The daytime frequency of cough reduced from a mean of approximately 55 per hour to 39 per hour at the 14^th day when the patients were treated with PA 101 (Birring, et al., 2017).

However, when the group was treated with placebo, the daytime frequency of cough was increased from a number of 51 per hour to 52 per hour. In contradiction to this, the PA 1010 was not proven beneficial for the patients that were suffering from CIC cohort. The mean decrement of the daytime frequency of cough at the 14^th day for PA 101 was adjusted for the placebo was around 6.21%. PA 101 was quite well endured in both of the cohorts. The adverse effects incidents were identical, either getting treated by placebo or getting treated by PA 101. Majority of the adverse effects that took place during the treatment were mild in the context of severity, in addition to this, no severe negative events were conveyed (Birring, et al., 2017).

From the above results of this article, it could be stated that the cough mechanism in the patients facing from IPF is disease explicit. PA 101 was quite well tolerated by the participants and no serious or severe adverse event were recorded (Birring, et al., 2017). This study has assisted the researchers and directed them for research in this area. However, this study has still several limitations and weaknesses that need to be covered in future studies. As the study was done on a small scale and for a very short period of time, therefore the usage of PA 101 for such patients could not be recommended for the patients that are from other areas. There is still a large requirement for future studies in order to cope with this disease and come up with a specific and precise result or conclusion.

Conclusion and Recommendations

“Idiopathic Pulmonary Fibrosis” is considered a fatal disease not only in the UK but also in the whole world, because of its high rate of mortality and lack of any evident treatment. Most of the patients that are facing from such type of disease also face from severe cough situation. This disease requires diagnosing at an early stage and treating by the team having expertise in the treatment of “Interstitial Lung Diseases”. Since more benefits could be achieved by the early actions over the patients having preserved function of the lung, it is quite necessary to enhance the IPF management and early detection by recognising the unique biomarkers, increasing awareness and enlightening the professionals of health care and the population or community. In addition to this placing the policies or strategies of management, which assists quick referral to the centres that are specialised in this treatment and accurate and early treatments of patients facing IPF.

From the above articles, it could be concluded that several studies have focused on penetrating for the treatment for the IPF patients that are also suffering from severe cough. Numerous results have been attained such as inhalation of SP, thalidomide, PA 101, etc. but none of these studies has come to an evident conclusion regarding the cause of cough in IPF patients. Therefore, there is still a requirement of a number of studies that should be conducted for a period of long-time, in order to come to a clear conclusion and formulate the treatments for IPF patients. It could take around ten to fifteen years or more of research in order to formulate a specific drug for the patient.

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Appendix

Figure A.1: Flow Diagram of the Study

Figure A.2: Adverse Effects in Article 1

Figure A.3: Exclusion Criteria in Article 2

Figure A.4: Baseline Data

Figure A.5: Cough Severity