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Idiopathic Pulmonary Fibrosis (IPF) Exacerbations: How to identify them and how to treat them - Presented by Dr. Onofre Moran-Mendoza

By Maria Korovina, MSc Candidate, TMED801 Student

 

On October 27th, the students of TMED 801 had the pleasure of attending the Medical Grand Round at which Dr. Onofre Moran-Mendoza, MSc, PhD, MD, spoke on the current gaps in research surrounding the treatment and early identification of idiopathic pulmonary fibrosis exacerbations.

Idiopathic pulmonary fibrosis (IPF) is a form of interstitial lung disease characterized by chronic and progressive fibrosing pneumonia of unknown cause.1 IPF is progressive, unpredictable, and fatal with a reported median survival of 2-3 years after diagnosis without any treatment.2 Acute exacerbation (AE) IPF is defined as clinically significant respiratory deteriorations characterized by the worsening or development of dyspnea over one month, the appearance of new bilateral ground-glass opacities, and deterioration that are not fully explained by cardiac failure or fluid overload.3Dr. Moran-Mendoza highlighted the frequency of AE being greater in IPF patients compared to other fibrotic interstitial lung diseases (ILD), with a 1-year incidence of 7.6% in IPF and 3% in ILD.4,5 Furthermore, the increase in mortality from IPF following an AE was emphasized since the median survival of IPF-AE drops to 2.6 months.6

Considering the severity of IPF-AE, a minimal number of treatment options are currently available that are supported by evidence-based research. Two antifibrotic drugs, Pirfenidone & Nintedanib, are currently used to reduce the risk of exacerbations but are only used as preventative treatment due to their delayed effects.7,8 Furthermore, Dr. Moran-Mendoza discussed the frequent use of corticosteroids that have yet to be researched for their efficiency in managing IPF-AE but have shown some improvement in patient’s oxygen requirements.

Moreover, a number of trials that have been conducted in the past need further validation using newer data. A study conducted in Japan from 2001-2004 looked at the effects in treating IPF patients using prednisolone alone or with anticoagulation.9 The patient were prescribed oral warfarin after their first exacerbation, and IV Dalteparin was started if the patients were re-admitted due to respiratory failure. In the end, the study found that mortality in the Dalteparin group decreased from 71% to 18%.9 Nevertheless, duplications of this study have not been done to validate these findings, but further investigation needs to be conducted as this drug therapy may save many lives.

Considering the progression rate of IPF-AE, Dr. Moran-Mendoza provided an example of how he uses the recognition of early symptoms within his ILD clinic. If patients observe a drop in their oxygen level or a worsening in their breathing, they are instructed to notify the clinic. These observations are key for identifying flares early on, which have shown to help with prognosis. Nonetheless, there is no research-based evidence supporting early detection of oxygen level drops and its relationship with disease prognosis.

Following the MGR, Dr. Moran-Mendoza met with TMED students to further discuss how his research benefits patients, its representation in the lay press, as well as to share his career path. He discussed a recent study where patients within his ILD clinic were evaluated for fine crackles as a potential early sign of IPF. The study found that 93% of IPF patients had fine crackles during their first visit, which presented more often than other symptoms, illustrating the potential advantages fine crackles may have on early IPF diagnosis.10 Dr. Moran-Mendoza also highlighted the importance of circulating accurate information regarding IPF-AE to the lay audience before ending off on his final note regarding his career. He spoke on his career path which has allowed him to not only practice medicine but to investigate his own research interest. Thanks to these ambitions, Dr. Moran-Mendoza has created an ILD database with longitudinal clinical, radiologic, physiologic, and bronchoscopic data on over 700 ILD patients.

All in all, IPF-AE is an aggressive disease with gaps in therapeutic research that need to be addressed. Throughout his presentation, Dr. Moran-Mendoza highlighted the current treatment options that are widely used in the hospital along with the lack of evidence-based research to support these drugs. As a fellow TMED student, I want to thank Dr. Moran-Mendoza for shedding light on some of these challenges and providing examples of his work in contributing to a better understanding of IPF-AE.

References

1.         Barratt SL, Creamer A, Hayton C, Chaudhuri N. Idiopathic Pulmonary Fibrosis (IPF): An Overview. J Clin Med. Aug 6 2018;7(8)doi:10.3390/jcm7080201

2.         Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. Mar 15 2011;183(6):788-824. doi:10.1164/rccm.2009-040GL

3.         Collard HR, Ryerson CJ, Corte TJ, et al. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. Aug 1 2016;194(3):265-75. doi:10.1164/rccm.201604-0801CI

4.         Yoo J-W, Kim J, Song JW. Impact of the revised definition on incidence and outcomes of acute exacerbation of idiopathic pulmonary fibrosis. Scientific Reports. 2022/05/25 2022;12(1):8817. doi:10.1038/s41598-022-12693-5

5.         Biondini D, Balestro E, Sverzellati N, et al. Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF): an overview of current and future therapeutic strategies. Expert Rev Respir Med. Apr 2020;14(4):405-414. doi:10.1080/17476348.2020.1724096

6.         Salonen J, Purokivi M, Bloigu R, Kaarteenaho R. Prognosis and causes of death of patients with acute exacerbation of fibrosing interstitial lung diseases. BMJ Open Respir Res. Apr 2020;7(1)doi:10.1136/bmjresp-2020-000563

7.         Richeldi L, Cottin V, du Bois RM, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med. Apr 2016;113:74-9. doi:10.1016/j.rmed.2016.02.001

8.         Ley B, Swigris J, Day BM, et al. Pirfenidone Reduces Respiratory-related Hospitalizations in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. Sep 15 2017;196(6):756-761. doi:10.1164/rccm.201701-0091OC

9.         Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest. Sep 2005;128(3):1475-82. doi:10.1378/chest.128.3.1475

10.       Moran-Mendoza O, Ritchie T, Aldhaheri S. Fine crackles on chest auscultation in the early diagnosis of idiopathic pulmonary fibrosis: a prospective cohort study. BMJ Open Respir Res. Jul 2021;8(1)doi:10.1136/bmjresp-2020-000815

Comments

Name
Jill Greenlaw

Thu, 11/03/2022 - 19:58

Hi Maria,

Thanks for a great summary of Dr. Moran-Mendoza’s presentation! Both Dr. Moran-Mendoza’s talk and your summary highlighted lack of evidence-based therapies and treatment regimens for IPF, as even commonly used therapies such as corticosteroids have not yet been supported by clinical trials. It is apparent that further research is needed to validate the findings of existing studies and evaluate the impact of currently used therapies and early treatment for IPF exacerbations, to inform and support clinical treatment decisions. Given the unmet need for more efficacious treatments for IPF, and the lack of research-based evidence for existing therapeutics, what barriers do you think exist that are preventing these much-needed trials from being conducted for IPF?

Name
Jill Greenlaw

Hi Jill,

Thank you for your question. There is a clear need for more randomized clinical trials to prove these treatments work. In the example you brought up, corticosteroids have been shown to work within the hospital setting, but there is no research-based evidence supporting this improvement in health. One barrier that Dr. Moran-Mendoza spoke on during the MGR was the ethical dilemmas surrounding randomized control trials. If physicians already see improvements in their patients using corticosteroids, how many patients will be harmed during a randomized clinical trial when trying to prove this beneficial effect? The experimental group may be receiving the corticosteroids, but having a control group not receive treatment may cause harm to the patients. These harmful outcomes may outweigh the potential benefits that may come out of the study. Hence, there should be more discussions surrounding these barriers and how these treatment options can be proven beneficial while resulting in minimal harm to patients involved in the trial.

Name
Maria Korovina

Name
Abhishek Shastry

Mon, 11/07/2022 - 22:10

Hi Maria,
I thought your summary was very informative and included important details regarding recognizing and responding to early signs of IPF. Dr. Moran-Mendoza had mentioned that he checks for drops in oxygen level or patient-describing worsening of breathing in order to inform his subsequent treatment recommendations. This was interesting as you also mention that there is no current "research-based evidence" that supports these checks. What do you think the effect of this disconnect between individual physician observations and recommended detection guidelines is on overall diagnosis and how do you think we can ameliorate this disconnect?

Best,
Abhishek

Name
Abhishek Shastry

Hi Abhishek,

Thank you for your questions. By nature, idiopathic pulmonary fibrosis (IPF) is a very progressive, and unpredictable disease. As a result of these two factors, IPF becomes very difficult to diagnose and even harder to study. In addition, Dr. Moran-Mendoza spoke on how IPF acute exacerbations (IPF-AE) are hard to characterize and deteriorations are not fully explained by cardiac failure or fluid overload. Furthermore, due to the similarity in clinical features between infections and IPF-AE, as well as the increased susceptibility to infections, it becomes even more difficult to exclude the possibility of an infection at the time of IPF-AE diagnosis (1). With all this in mind, it is clear how this disconnect leads to the overall poor diagnosis of the disease. To answer your question as to how we can ameliorate this disconnect, I believe it all comes down to collaboration. Although the availability of ILD clinics is limited, trying to implement other early diagnostic measures into primary care clinics may help this disconnect. Dr. Moran-Mendoza gave an example from one of his studies where he used fine crackles as an early diagnostic tool (2). Implementing these potential measures from the ILD clinic into primary care to help study whether this method is effective may help improve this disconnect.

1. Kim DS. Acute Exacerbations in Patients With Idiopathic Pulmonary Fibrosis. Interstitial Lung Disease. 2018;131-139. doi:10.1016/B978-0-323-48024-6.00011-2

2. Moran-Mendoza O, Ritchie T, Aldhaheri S. Fine crackles on chest auscultation in the early diagnosis of idiopathic pulmonary fibrosis: a prospective cohort study. BMJ Open Respir Res. Jul 2021;8(1)doi:10.1136/bmjresp-2020-000815

Name
Maria Korovina

Name
Abby Mocherniak

Thu, 11/10/2022 - 13:29

Hello Maria,
I really enjoyed reading your overview of Dr. Moran-Mendoza's presentation! You did a great job of summarizing the topic and emphasizing important information relevant to IPF. In his presentation, Dr. Moran-Mendoza discussed challenges in treating IPF due to a lack of research-based evidence informing treatment protocol. Considering IPF is of unknown cause, I am curious if you believe the lack of treatment guidelines for IPF is most likely attributable to challenges for researchers in approaching investigation due to the unknown etiology of disease, or whether you think knowledge gaps surroundings its pathogenesis play a more significant role in the lack of treatment information? Additionally, I am wondering if similarities for a lack of evidence surrounding treatment exist for other idiopathic conditions?
I look forward to hearing your thoughts!

Best,
Abby

Name
Abby Mocherniak

Hi Abby,

To start, I believe that the lack of treatment options is more likely due to the gaps surrounding the pathogenesis of idiopathic pulmonary fibrosis (IPF). This is not to say that the unknown etiology of IPF has no impact on treatment gaps, but I believe etiology plays a more significant role in the lack of early diagnostic tests. During the MGR, Dr. Moran-Mendoza discussed two current anti-fibrotic drugs, Pirfenidone & Nintedanib, that have been shown to help with survival by slowing down the accelerated decline of lung function. Nonetheless, there are no current cures for IPF. The lack of new drug development for IPF can be due to the absence of suitable biomarkers to provide an early indication of improvement (1). IPF has also been shown to have a different disease course over time depending on the various clinical phenotypes (2,3). Nonetheless, I believe the most significant reason for the lack of treatment options is the current availability of anti-fibrotic drugs, making it difficult to demonstrate any added efficacy of other proposed treatments during clinical trials involving such an aggressive disease. An example of another idiopathic condition with similar aggressive progression rates is idiopathic giant-cell myocarditis (GCM). Without immunosuppressive therapy to help reduce inflammation, the survival for GCM is only three months (4). As a result, controlled treatment trials, let alone the use of a placebo arm, is virtually impossible due to the aggressiveness of GCM, leading to a lack of treatment guidelines (5).

References:
1. White ES, Thomas M, Stowasser S, Tetzlaff K. Challenges for Clinical Drug Development in Pulmonary Fibrosis. Review. Frontiers in Pharmacology. 2022-January-31 2022;13doi:10.3389/fphar.2022.823085
2. Buendía-Roldán I., Mejía M., Navarro C., Selman M. Idiopathic pulmonary fibrosis: Clinical behavior and aging associated comorbidities. Respir. Med. 2017;129:46–52. doi: 10.1016/j.rmed.2017.06.001
3. Fell C.D. Idiopathic Pulmonary Fibrosis: Phenotypes and Comorbidities. Clin. Chest Med. 2012;33:51–57
4. Ghaly M, Schiliro D, Stepczynski J. Giant Cell Myocarditis: A Time Sensitive Distant Diagnosis. Cureus. 2020;12(1):e6712. Published 2020 Jan 20. doi:10.7759/cureus.6712
5. Kandolin R, Lehtonen J, Salmenkivi K, Räisänen-Sokolowski A, Lommi J, Kupari M. Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression. Circulation: Heart Failure. 2013;6(1):15-22. doi:doi:10.1161/CIRCHEARTFAILURE.112.969261

Name
Maria Korovina

Name
Nicole Morris

Thu, 11/10/2022 - 13:59

Hi Maria,

Your summary of Dr. Moran-Mendoza's presentation was excellent. Unfortunately I was unable to attend the facilitated discussion, so I hope my questions are not repeating a topic that has already been addressed. You write that based on work in his own clinic, Dr. Moran-Mendoza has found fine crackles to be an early indicator of IPF. You also mention that early detection can help to improve disease prognosis. I can't help but wonder about the disparities that may exist in timely diagnosis and treatment across the population, given that specialized ILD clinics are not common. Moreover, it is becoming increasingly difficult for Canadians to find a family doctor (according to Statistics Canada approximately 4.6 million Canadians did not have regular access to a primary care provider in 2019). Is there any research being done to investigate the impacts of these socioeconomic and demographic disparities on patient outcomes? Moreover, do you have any ideas on steps we can take to address them?

Best,

Nicole

References

Canadian Medical Association. (2022 May 9). Critical family physician shortage must be addressed: CMA. https://www.cma.ca/news-releases-and-statements/critical-family-physici…

Name
Nicole Morris

Hi Nicole,

You pose a great question! A recent study looked into the management of AE-IPF in specialized ILC clinics and non-specialized centers worldwide. The study collected data from 509 pulmonologists from 66 different countries. Of these, 334 worked in specialized ILD clinics and 142 in non-specialized ILD centers, including general pulmonology departments, and intensive care units. The study found similarities in diagnostic methods, including corticosteroid treatment, high-flow oxygen, radiology, screening for infection, and non-invasive ventilation for the critically ill (1). Most differences in care were related to preventative measures such as antacid medication and pathogen testing in urine, but also treatments like recombinant thrombomodulin, and cyclosporine (1). In the end, the study concluded that clinical trials and guidelines are needed to help improve patient care and prognosis in AE-IPF.

During the facilitated discussion, Dr. Moran-Mendoza mentioned the need to adapt early diagnostic methods, such as fine crackle detection in primary care settings. Nonetheless, the shortage of family doctors within the country makes it hard for individuals to access these diagnostic tests. This shortage is a multi-layered problem for which I do not have a solution. However, establishing universal early diagnostic methods within intensive care units may help rule in IPF as a diagnosis and start management earlier. Additionally, circulating accurate lay information surrounding IPF may aid those with limited access to primary care. A recent cross-sectional analysis looking at the content of IPF within Facebook groups found that most common sources were coming from nonmedical users and had a high likelihood of containing potentially harmful content (2). If we aim to circulate lay information regarding IPF and its triggers, this may raise awareness within the population.

References

1. Polke M, Kondoh Y, Wijsenbeek M, et al. Management of Acute Exacerbation of Idiopathic Pulmonary Fibrosis in Specialised and Non-specialised ILD Centres Around the World. Front Med (Lausanne). 2021;8:699644. Published 2021 Sep 27. doi:10.3389/fmed.2021.699644

2. Kochan A, Ong S, Guler S, Johannson KA, Ryerson CJ, Goobie GC. Social Media Content of Idiopathic Pulmonary Fibrosis Groups and Pages on Facebook: Cross-sectional Analysis. JMIR Public Health Surveill. 2021;7(5):e24199. Published 2021 May 31. doi:10.2196/24199

Name
Maria Korovina

Name
Hailey Schincariol

Sun, 11/13/2022 - 11:09

Hi Maria,

Thank you for the excellent summary of Dr. Moran-Mendoza’s grand rounds - You did great job facilitating the TMED discussion! I found it most interesting how fast IPF-AE can become fatal while also being unrecognizable for years. When reading the literature, I also noticed common concern regarding the lack of international guidelines for the management of IPF-AE (Kreter et al., 2020). Likewise, Dr. Moran-Mendoza mentioned several clinical trials that have investigated the efficacy of novel drug therapies, yet there remains many unanswered questions surrounding . Why do you think there is this significant gap in the research of IPF-AE?

Kreuter, M., Polke, M., Walsh, S. L., Krisam, J., Collard, H. R., Chaudhuri, N., ... & Bendstrup, E. (2020). Acute exacerbation of idiopathic pulmonary fibrosis: international survey and call for harmonisation. European respiratory journal, 55(4).

Name
Hailey Schincariol

Hi Hailey,

Thank you for your kind words and for your question! Similarly to what I have mentioned in past responses, it all comes down to the nature of IPF-AE. Having an aggressive and fetal disease, such as IPF-AE, limits the options for clinical research. As a result, it can be unethical to use a placebo arm in a novel treatment study. Furthermore, the complexity of diagnosing IPF-AE adds more uncertainty to the field and creates additional knowledge gaps. Dr. Moran-Mendoza spoke on the importance of implementing early diagnostic guidelines throughout primary care. For instance, utilizing fine crackles for early detection of IPF-AE may give an advantage in studying its pathogenesis (1). This information may reveal new aspects of the disease and help close some gaps. In the end, these factors highlight the need for further research on IPF-AE and collaboration with experts in the field.

References

1. Moran-Mendoza O, Ritchie T, Aldhaheri S. Fine crackles on chest auscultation in the early diagnosis of idiopathic pulmonary fibrosis: a prospective cohort study. BMJ Open Respir Res. Jul 2021;8(1)doi:10.1136/bmjresp-2020-000815

Name
Maria Korovina

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