One of the most important aspects of the scientific process is that assumptions are tested, and discarded when discredited, and new hypotheses take their place, with the same stringent measures firmly in place to ensure that they are rigorously tested as well. In other words, medicine is an evolving discipline; going a step further, it is a discipline that is brazenly unafraid of both challenge and change. In medicine, facts always win over hunches. 

It is worth briefly mentioning some of the paradigm shifts adopted in medicine—shifts in thinking that were beyond the pale at that time. One example is the shift from miasma theory (the idea that bad air causes diseases) to bacterial theory (the idea that invisible bacteria are responsible for infections). Another seismic shift is the acceptance of vaccines as a safe way to protect against certain diseases, a view that has saved countless lives during the COVID-19 pandemic. 

A Complex Pathogenesis

In addition, subtle changes occur all the time in medicinal thinking. In Clinics in Chest Medicine, Oldham and Vancheri chronicled how the thinking surrounding idiopathic pulmonary fibrosis (IPF) has evolved over the years. 


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One of the major evolutions in IPF is the name itself—IPF was once called fibrosing alveolitis, but that name has been dropped because IPF actually results in minimal alveolar inflammation. There have also been vast changes in the way we think about IPF’s pathogenesis, diagnosis, and treatment options. 

Read more about IPF etiology

In Pharmacology & Therapeutics, Spagnolo and colleagues wrote about how our thinking about the pathogenesis of IPF has changed over the years.

They wrote: “Significant progress over the past two decades has led to the current paradigm of IPF pathogenesis, which proposes that, in a genetically susceptible individual, recurrent environmental and/or endogenous injury to alveolar epithelium occurs, with increased cell death, aberrant epithelial repair, and dysregulated epithelial-fibroblast cross-talk promoting persistent mesenchymal activation and extracellular matrix (ECM) deposition.” 

As scientists study the pathogenesis of IPF, the more they realize the complexity involved, including the various cell types and signaling pathways that are implicated. The various factors that we now know influence the pathogenesis of IPF include: 

  • Dysregulation of alveolar epithelial cells 
  • Mutation in the surfactant protein C gene 
  • Dysfunctional epithelial repair 
  • Dysregulated immune response 
  • Cell senescence.

Physicians are also changing the diagnostic criteria for IPF. In the past, the standard way to diagnose the disease was through histological confirmation of usual interstitial pneumonia (UIP). Recent guidelines advocate for a diagnosis of IPF to be made in patients who are found to have UIP on high-resolution computed tomography (HRCT). Physicians are still encouraged to conduct a surgical lung biopsy in patients who have abnormal HRCT results that demonstrate pathology other than UIP. Later guidelines emphasize the role of multidisciplinary discussions when attempting to diagnose IPF.

A Changing Landscape of Therapies

One of the most notable changes in the way we think about IPF is in how we treat the disease. Because IPF was once characterized as a pathology primarily driven by inflammation, physicians for decades have sought to treat the disease by using immunosuppressive therapies, such as azathioprine and cyclophosphamide. This was supported by official guidelines up until 2000.

However, a clinical trial in 2011 revealed that IPF patients treated with immunosuppressive therapies had a higher hospitalization and mortality rate. This ended the era of treating IPF using immunosuppressive agents. 

Read more about IPF treatment

In La Presse Médicale, Torrisi and colleagues wrote, “The history of first clinical trials in IPF is characterized by several disappointing results [as a result of immunosuppressive therapies] . . . After several disappointments, the recent introduction of antifibrotic therapies has significantly changed the landscape of therapies, as, for the first time, they demonstrated to reduce lung function decline in IPF.” 

The current treatment regimen for IPF patients can include pirfenidone, nintedanib, or a combination of both. Each of these approaches is well supported by medical literature. Pirfenidone has been shown in clinical studies to significantly reduce lung function decline; nintedanib has been shown to slow the deposition of the extracellular matrix; and the combination of the two has demonstrated a manageable safety and tolerability profile in patients with IPF, combined with a notable reduction in lung function decline.

Lessons Left to Learn

In terms of understanding the pathophysiology of IPF, diagnosing it accurately, and treating it in a targeted manner, more work remains to be done. Simply put, the problem we are currently facing is that we are not diagnosing IPF quickly enough, which provides time for the disease to take root before any meaningful action is initiated. 

Oldham and Vancheri wrote, “A survey conducted in 2007 showed that more than 50% of respondents with IPF reported waiting more than a year from the time of symptom onset to diagnosis. A similar survey conducted a decade later showed little change in this experience.”

This is a problem because early diagnosis has been proven time and again to improve the prognosis of patients with IPF. In addition, IPF is a chronic, progressive disease, and current therapies do not change this unfortunate reality. If we are to defeat IPF in earnest, we must be willing to undergo further changes in the ways we think about its diagnosis, progression, and treatment. 

References

Spagnolo P, Kropski JA, Jones MG, et al. Idiopathic pulmonary fibrosis: disease mechanisms and drug developmentPharmacol Ther. 2021;222:107798. doi:10.1016/j.pharmthera.2020.107798

Oldham JM, Vancheri C. Rethinking idiopathic pulmonary fibrosisClin Chest Med. 2021;42(2):263-273. doi:10.1016/j.ccm.2021.03.005

Torrisi SE, Kahn N, Vancheri C, Kreuter M. Evolution and treatment of idiopathic pulmonary fibrosisPresse Med. 2020;49(2):104025. doi:10.1016/j.lpm.2020.104025