Four critical patients respond well to new drug; need to verify, say experts

Four severely critical Covid-19 patients who were on ventilator support due to extensive scarring of lung tissues that leads to low oxygen levels — a complication

Four severely critical Covid-19 patients who were on ventilator support due to extensive scarring of lung tissues that leads to low oxygen levels — a complication induced by Sars-CoV-2 virus — were sent home on minimal oxygen support after pulmonologists at the Pune-based Army Institute of Cardiothoracic Sciences (AICTS) administered a new line of treatment using anti-fibrotic drug nintedanib.

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“We had lost hope on these four patients. But when we administered Nintedanib with a combination of steroids, their condition turned around. Very safely and without any complications or side-effects, they could be sent home with minimal oxygen support,” said Brigadier (medical) HQ MG&G (Maharashtra, Gujarat and Goa) area, adding that this subset of patients had clear evidence of having suffered pulmonary fibrosis in CT-scans. Nintedanib costs approximately ₹65,000 or less for a month (60 tablets).

Lung fibrosis is usually seen in patients who are detected late and have extensive pneumonia. Many a times, it becomes difficult to wean these patients off oxygen despite anti-inflammatory therapies, such as steroids, and they remain in the intensive care unit for a long time.

A patient infected with the novel coronavirus associated pulmonary fibrosis is put on high-flow oxygen or other ventilatory supports because he/she cannot maintain normal oxygen saturation levels on his/her own. While oxygen saturation levels for most healthy individuals is around 95% or more, it can drop to as low as 75% among Covid-19 patients, causing death.

Dr Lancelot Pinto, pulmonologist at Hinduja Hospital, said that anti-fibrotics such as pirfenidone and nintedanib may have anti-fibrotic potential, but their efficacy needs to be validated in randomised control trials (RCTs).

“We have seen several patients with high oxygen requirements and bilateral lung disease improve gradually, and get weaned off oxygen with time. The recovery can be slow, and at times we have discharged patients on home oxygen support, and eventually weaned them off,” said Pinto.

He added, “In the absence of a control arm, it is impossible to know whether it was the drug or time that caused the resolution of clinical and radiological features. Already an RCT assessing the safety and efficacy of pirfenidone is underway, and we are looking forward to the results.”

“There are plenty of observational studies of drugs for Covid (such as HCQ) that have had promising results, but have failed to show efficacy over placebo in clinical trials. We should definitely not change practice based on a case series of 4 patients,” said Pinto.

The team said anti-fibrotic drugs are generally used to treat other types of lung fibrosis such as secondary to autoimmune diseases — rheumatoid arthritis and idiopathic pulmonary fibrosis (IPF).

“Nintedanib is a medicine which has often been used by some immunologists and rheumatologists in cases where the lungs have developed fibrosis as a result of an autoimmune disease in which the body’s own immunity goes haywire, begins recognising its own organs as foreign and starts attacking it,” said a spokesperson of the team. “In some of those conditions, lungs develop fibrosis and Nintedanib has been used effectively for clinical management of the condition because it’s an expensive drug,” the spokesperson added.

Taking this as a cue, the pulmonology department at AICTS decided to try a combination of steroids with nintedanib in four patients with Covid-19-associated lung fibrosis who were difficult to wean off of oxygen due to extensive lung fibrosis and their condition was steadily deteriorating. Doctors said the anti-fibrotic drug was used on four patients who were at a very advanced stage of Covid-19 that required intense treatment.

Having recovered, these patients will have to be on minimal oxygen support at home even after turning Covid-19 negative, and follow-ups will continue clinically and through laboratory investigations and CT-scan imaging. The team said nintedanib is reasonably safe but may cause diarrhoea followed by liver function derangement in some.

“A patient cannot be discharged unless oxygen saturation level is not above 93-94% which will help him/her carry on with daily activities. The reason these four patients require low-level oxygen and follow-ups is because while their saturation levels will stay at 93-94% when stationery (like sitting), it will drop to 90-91% with little activity,” said the spokesperson.

As an observational study, a report is in the pipelines for an internationally peer-reviewed scientific journal on the clinical management using ninetedanib on these four patients. Going forward, the team proposes to recognise similar subsets and utilise the same treatment protocol.

The team said that at present there is no published case report of this drug being used on patients who have developed severe pulmonary fibrosis due to Covid-19 and are unable to wean off ventilator.

HOW THE PATIENTS ARE CHOSEN

Covid-19 patients who are detected late or progressed to the critical phase of illness — meaning they are unable to maintain their oxygen saturations without high-flow oxygen or ventilator support — are evaluated extensively.

Computerised tomography pulmonary angiography is carried out to rule out the possibility of pulmonary embolism (clots in the lungs) and check the extent of fibrosis that may have developed in the lung.

The patients also undergo various blood tests to look for ongoing inflammation by evaluating the inflammatory markers among other parameters.

If the inflammation is controlled with steroids (which are the first line for Covid-19) and CT pictures reveal evidence of prominent fibrosis leading to the patient requiring continued supplemental oxygen and make it difficult to wean him/her off, the therapy with nintedabin begins.