X-ray of lung

Creativity is often absent from academic writing since it has to follow strict standards to ensure that future readers can easily follow the train of thought presented and build on the work in future research. 

A clinical study with a measure of creativity is a gift, and in this article, we will be exploring just such a study, entitled “Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra.” 

What did Rajagopal and colleagues have in mind when invoking Greek mythology to describe modern illnesses? In Greek mythology, Heracles is a demigod who had to face a series of 12 labors planned by the king Eurystheus for the purpose of seeing him fail. Among those was to vanquish the multiheaded sea monster Hydra. As the story goes, each time Heracles cut off the head of Hydra, it regenerated. 

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Eventually, Heracles discovered that he had to cauterize the neck stump after each decapitation finally defeat Hydra. 

How does this relate to the topic of co-occurring “idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH)? Rajagopal et al wrote, “This [parable] offers some lessons with respect to the presentation of PH in the setting of lung fibrosis where multiple mechanisms that lead to the development of PH and lung fibrosis easily represent the multiheaded Hydra.” 

A Dangerous Combination Working Synergistically 

The very serious point that Rajagopal and colleagues were trying to make is that IPF and PH are a dangerous combination since they work synergistically to worsen the patient’s condition and blunt the effect of any therapies.

Let’s review the available evidence on common antifibrotic therapies and their impact on the pulmonary vasculature. Despite the widespread usage of antifibrotics such as nintedanib and pirfenidone, Rajagopal and colleagues wrote that “little is known about how antifibrotic agents for use in IPF affects the pulmonary vasculature.” 

Read more about IPF etiology 

In Pharmacology & Therapeutics, Spagnolo and colleagues conceded that “at present, there is no treatment that can cure IPF.” They explained, “Pirfenidone and nintedanib are able to slow disease progression, but neither drug improves or even stabilizes lung function, or improves quality of life, and both therapies have tolerability issues.”

This means that neither drug is curative. Rajagopal et al quoted studies that indicated that the prolonged use of nintedanib did not correlate with an improvement in the diffusing capacity of the lungs for carbon monoxide (DLCO).

At best, the drugs buy patients more time; at worst, as some evidence suggests, they produce very little clinical benefit. For example, in terms of pulmonary hypertension, they seem to either have a minimal impact on the disease, or worse, actively cause it.

A study by Shimomura and colleagues, published in Internal Medicine, demonstrated that PH developed in an IPF patient after nintedanib was introduced. “After nintedanib administration, his dyspnea on exertion worsened and he was diagnosed with PH,” they wrote. This isn’t merely a one-off occurrence: the pattern of IPF patients developing PH after taking nintedanib has been observed elsewhere. 

Reporting on a study of a small patient cohort with idiopathic pulmonary arterial hypertension being treated with nintedanib, Rajagopal et al wrote, “Consistently, there was a deterioration in right ventricular pressure, and subsequently cardiac output, in patients treated with nintedanib.” 

The dreaded Hydra rears its head once again, refusing to be defeated. But no one said that treating IPF and PH was going to be easy, and we are by no means under the illusion that all drugs function exactly as we expect them to. 

However, the deeper point I think Rajagopal and colleagues are trying to make is that because there is such an intimate and mysterious correlation between IPF and PH, viewing these diseases as 2 separate entities that are prone to behave in a linear, predictable fashion is folly. 

A Comprehensive Approach for the Future  

The point here is that our therapeutic strategy for treating both illnesses must include a comprehensive approach that seeks to solve the problem at its roots. Otherwise, the disease will keep recurring, leading to frustration for both the physician and the patient. 

The good news is that progress has been made. Spagnolo et al wrote, “Our understanding of IPF biology has also dramatically improved over the last two decades, further supporting abandonment of some therapeutic strategies that were previously assumed to be valid options.” 

In terms of clinical trials for potential therapeutic candidates, we need to be more selective and monitor drug effects over longer periods of time (years, not months). We must be agile enough to learn from our mistakes, and change course at a moment’s notice. 

Read more about IPF treatment 

“In addition to assessing more rational and biologically plausible drug targets, it is critical that these large, multinational, and rigorous trials are also used to learn more about the disease by ensuring that participants contribute clinical data and biological samples,” Spagnolo and colleagues wrote. “This should ideally be done on a large scale and within an open science concept in order to facilitate the next generation of drug development.”


Rajagopal K, Bryant AJ, Sahay S, et al. Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the HydraBr J Pharmacol. 2021;178(1):172-186. doi:10.1111/bph.15036

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

Shimomura I, Abe M, Li Y, et al. Pulmonary hypertension exacerbated by nintedanib administration for idiopathic pulmonary fibrosisIntern Med. 2019;58(7):965-968. doi:10.2169/internalmedicine.1384-18