COVID-19 & Pulmonology: 16 practice updates for 2021 & when 'not to use' certain medications: Dr. Viny Kantroo
M3 India Newsdesk Jan 19, 2021
The year of COVID-19- last year may as well have been called that. Major effort may have gone towards coronavirus research, but there were significant headways made in other fields of medicine too. In this review, Dr. Viny Kantroo lists 7 COVID and 9 pulmonology updates that will impact practice this year.
For our comprehensive coverage and latest updates on COVID-19 click here.
Pulmonology and critical care which have formed an integral part of healthcare for decades attained centre stage in 2020 when the horror of COVID-19 was unleashed on humans worldwide. A new disease caused a cluster of cases with “pneumonia of unknown cause” in December 2019 which was linked to the wholesale seafood wet market in Wuhan, China.
The novel coronavirus was isolated on 7th January 2020, and the first case of death due to 2019-nCoV later called SARS-COV2 occurred in China on the 9th of January 2020. Human-to-human transmission was documented by epidemiological evidence on 24th January.
Meanwhile, the first case of coronavirus was reported in Thrissur, in Kerala in India on 30th January, the same date when WHO declared COVID-19 disease outbreak of global health emergency. Subsequently, COVID-19 was declared a ‘pandemic’ on 11th March 2020 by the WHO.
At present, globally, there have been 80.85 million cases with 1.76 million confirmed deaths. There are 10.2 million confirmed cases and 147,901 deaths in India (as on 28th December 2020) making us the second worst hit nation. [1] We have all lived through and experienced the horror a pandemic can cause, with a mortality of around 1%. Fourteenth century plague is said have wiped out about 30-60% of the population which is alarming.
This pandemic has managed to stay in the news even after a year of its start due to its impact on social, economic, mental, travel, transport, trade, developmental and numerous other aspects of life, in addition to health and healthcare aspects and failure to die down.
Since the year 2020 has been the year of COVID-19 viral pandemic, this communication will be dominated by this unique viral infection in every way, with some highlights of non-COVID-19 breakthrough studies published this year. Major trials and their outcomes would be discussed here. More importantly, the take home points would give an insight about when ‘not to use’ certain medications which is a more important therapeutic decision always. This should not be considered a comprehensive and complete document for all major pulmonology and critical care studies published in 2020.
COVID trials & studies
Primarily, COVID-19 has taught us that not even developed nations are fully prepared to deal with the repercussions a pandemic can cause, neither on the health infrastructure front nor on the social and psychological front. It requires a lot of well-equipped hospital beds to deal with people getting sick at a single point in time. It also means that the elderly are the most vulnerable and lifestyle measures need to be inculcated well in advance to keep non-communicable diseases at bay which of course increases the vulnerability and damage caused by communicable diseases.
The major and large-scale clinical trials were designed in early 2020 by RECOVERY trial group in UK and by World Health Organisation (WHO) (SOLIDARITY CLINICAL Trials in COVID-19)
Dexamethasone in COVID-19 - RECOVERY collaborative group
One of the major outcomes in learning graph of COVID-19 has been the mortality benefit of steroids in severe COVID-19 infection. [2] This study, published in July 2020 in NEJM was a major breakthrough in therapeutic decisions. Six milligram of dexamethasone for 10 days reduced the 28 day mortality in patients on some form of oxygen therapy and those on mechanical ventilation by approximately 1/5th and 1/3rd respectively. This benefit was not replicated for those not requiring oxygen or any other respiratory support. Interestingly everyone by now knows that steroids have benefit in COVID-19 but unfortunately not many know that the benefit was also clear in patients who were being treated more than 7 days after symptom onset. Infact if we start using dexamethasone early it leads to more harm than good.
One of the major outcomes in the learning graph of COVID-19 has been the mortality benefit of steroids in severe COVID-19 infection. [2] This study, published in July 2020 in NEJM was a major breakthrough in therapeutic decisions. Six milligram of dexamethasone for 10 days reduced the 28-day mortality in patients on some form of oxygen therapy and those on mechanical ventilation by approximately 1/5th and 1/3rd respectively. This benefit was not replicated for those not requiring oxygen or any other respiratory support. Interestingly everyone by now knows that steroids have benefit in COVID-19 but unfortunately not many know that the benefit was also clear in patients who were being treated more than 7 days after symptom onset. In fact, if we start using dexamethasone early, it leads to more harm than good.
Key learning
The beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on selection of the right dose, at the right time, in the right patient. It is strongly recommended to discourage its indiscriminate use in early mild COVID-19 disease.
Apart from this, the other arms of RECOVERY trial in interim results revealed no benefit from azithromycin, hydroxychloroquine, and lopinavir-ritonavir. The results of use of steroids vs colchicine vs intravenous immunoglobulins in children and eligible patients allocated simultaneously to no additional treatment vs convalescent plasma vs synthetic neutralising antibodies (REGN-COV2), are awaited and recruitment is ongoing. Also, separately, all participants aged 18 years or older will be allocated to either aspirin or control. The study allows a subsequent randomisation for patients with progressive COVID-19 to no additional treatment vs tocilizumab.
SLOIDARITY clinical trial
The SOLIDARITY trial published interim results on 15 October 2020. [3] It found that all 4 treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalised patients.
Remdesivir in COVID-19
The only FDA-approved drug for COVID-19 is remdesivir. It inhibits viral replication by blocking RNA-dependent RNA polymerase. Remdesivir was found to be superior to placebo in shortening the time to recovery in adults who were hospitalised with COVID-19 and had evidence of lower respiratory tract infection in ACTT-1 trial. [4]
Key learning
In our clinical experience of more than 3000 patients at a tertiary care centre in Delhi, remdesivir did show clinical benefit in patients and especially among those, where we suspected a prolonged viral phase leading to non-resolving fever and/or lower respiratory tract involvement. We also do need well-designed randomised controlled trials to study its use in early disease in the first week as theoretically that is the time when it should have maximum benefit.
IL6 levels in COVID-19
IL-6 is a pleiotropic, proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. COVID-19 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. COVID-19 causes cytokine storm which causes hyperinflammatory response. It has, however been seen to be elevated in other inflammatory states including septic shock also. Cortegiani etal has recently concluded that benefit of Tocilizumab (anti-IL6 therapy) in COVID-19 is still doubtful despite about 28 studies on this drug. [5] The randomised, double-blinded, placebo-controlled COVACTA and EMPACTA trial did not show any difference in 28-day mortality between tocilizumab and placebo. [6,7]
Key learning
IL6 is elevated in COVID-19 but then it is not the only marker, which is elevated, and it is still unclear whether targeting this single inflammatory marker will actually save the damage COVID causes. Anti-IL6 therapy leads to immunosuppression and difficult to treat secondary infections. Hence, use of anti-IL6 therapy at present is strongly recommended as part of drug trials. Also, it may be easier and cost effective to follow up serial CRP levels instead of IL6 levels especially when anti-IL6 therapy is not being planned to be used.
PlasmaAr study group results
Plasma therapy too did not live up to its hype in COVID-19. PlasmaAr study group published their results in NEJM in late November. Besides this there are other studies which did not see any mortality benefit from plasma therapy. [8] The PLACID trail carried across multiple centres in India also did not find any mortality benefit or prevention of progression to severe disease. [9]
Key learning
The indiscriminate use of plasma therapies and early use of steroids especially in mild cases will yield more harm than benefit. Mild cases just need proper and close monitoring apart from symptomatic treatment.
Anticoagulation in COVID-19
It is now well-established that COVID-19 is a procoagulant state with tendency for venous and arterial thromboembolism. Hence, all hospitalised patients with COVID-19 should receive prophylactic LMWH which can be increased to therapeutic doses in case the patient is on oxygen and has evidence of d-dimer more than 1000 ng/ml. COVID-19 patients with increased D-dimer concentration at admission (>1000 ng·mL−1) were reported to have an 18-times higher risk of in-hospital mortality than those with normal D-dimer levels. [10] The American College of Chest Physicians and International Society on Thrombosis and Haemostasis also recommend use of LMWH in hospitalised patients.
Key learning
The immediate follow up of patients with COVID-19 up to 6-8 weeks should include good history taking for features of thromboembolic disease and measurement of D-dimer levels. Often rising D-dimer levels are an indication of ongoing inflammation and predisposition to pulmonary embolism. These patients do need post discharge anticoagulation which can be prescribed if there is low risk of bleeding and high risk of thromboembolic disease especially in those with sedentary lifestyles.
Role of post-discharge rehabilitation
This should involve not only physical rehabilitation in the form of assessment of deconditioning, respiratory muscle training, good nutritional support, but also mental and psychological rehabilitation especially in severe cases with post trauma stress disorder. [11]
Key learning
COVID-19 leads to quick deconditioning. This may be due to the myositis caused by intense inflammation. Simple spirometry exercises early in disease course whenever a patient can do them, goes a long way in regaining the pre-disease lung capacity. It helps to wean the patients off oxygen. Also, the fatigue, post COVID recovery seems to respond well to graded exercises and hence all patients should be encouraged to get back to their pre-COVID exercise regime as soon as they can.
Non-COVID pulmonary critical care
ILD treatment
SENSCIS trial was a phase 3 trial to evaluate ninetedanib in systemic sclerosis associated lung fibrosis. This was found to be effective in slowing FVC decline in patients with systemic sclerosis-associated ILD. [12]
Similarly, INBUILD was a well-designed clinical trial showing that nintedanib is effective in slowing FVC decline in patients with a broad range of progressive fibrosing ILDs. This was further substantiated in subgroup analysis published in Lancet in 2020. [13]
Key learning
Anti-fibrotic therapy now has a broader range of indications other than idiopathic pulmonary fibrosis. Do take care to follow up on patients for adverse effects which include diarrhoea and liver function derangement.
ILD guidelines
The Indian Chest Society and National College of Chest Physicians (NCCP) published a consensus statement on the management of interstitial lung diseases in Lung India in July 2020. This aimed to provide a comprehensive and better understanding of non-IPF ILD for physicians in diverse healthcare systems in India and beyond. [14]
Key learning
We do need better understanding of our population and region-specific statistics and guidelines.
Asthma
Previous observational studies have demonstrated that higher maternal vitamin D level is associated with lower risk of asthma-related outcomes among children. However, prenatal vitamin D supplementation in pregnant women did not prevent asthma or recurrent wheeze at the age of 6 years. [15]
Key learning
This study did show benefit of less episodes of wheezy bronchitis up to the age of 3 years.
COPD treatment
ETHOS trial established twice daily, triple therapy [(long-acting beta agonist (LABA) + long-acting muscarinic agonist (LAMA) + inhaled corticosteroid (ICS)] was found to be associated with lower rate of moderate to severe exacerbations in moderate to very severe COPD patients as compared to double therapy of LABA + LAMA or LABA + ICS. There was a mortality benefit with use of higher dose of inhaled corticosteroid. [16,17]
Key learning
Though many patients of very severe category feel better with triple therapy, do take care that these patients don’t land up with excessive drying of airway which leads to difficulty in bringing out the sputum which sometimes can be a problem in selected patient groups.
Lung cancer
The NELSON study identified a reduction in lung cancer mortality in the screening group in both men (24% reduction) and women (33% reduction). Screen-detected cancers were more commonly stage IA or IB (58.6%), with a much smaller percentage being stage IV (9.4%). [18]
Key learning
Further study is needed to determine if and why lung cancer screening has a greater relative benefit to women compared to men, and the optimal interval and duration of lung cancer screening.
Mechanical ventilation
The ICU-ROX group demonstrated, in a randomised controlled trial, that excessively high fractional inhalation of oxygen (FiO2) may not be deleterious as compared to conservative FiO2 use to reduce the oxidative damage to lung and systemic tissues. [19] This is in contrast to a preliminary study which showed survival benefit with use of conservative oxygen therapy.
Key learning
This may need further studies to demonstrate the effect is reproducible in all forms, lung affections and diseases. There may be patient subgroups which might suffer damage due to this blanket approach especially in the era of COVID-19 pandemic when hypoxemic respiratory failure is very common. These types of studies can hence be feasible and helpful to prevent fibrosis and oxidative damage to the lungs.
Oxygen therapy for chronic lung diseases
ATS/ERS in September 2020 published evidence-based guidelines regarding the use of home oxygen therapy in adults with COPD or ILD. They also highlighted the need for additional research to guide clinical practice. [20]
Key learning
Oxygen should be prescribed as a medicine keeping risk/benefit ratio in mind. This will prevent further damage in already compromised lungs.
Stress ulcer prophylaxis in ICU
The PEPTIC trial did not find any 90-day mortality difference in the patients prescribed proton pump inhibitor (PPI) or type 2 histamine receptor blockers (H2RB). [21]
Key learning
Even though, there was a statistically significant reduction in clinically important gastrointestinal bleeding in the PPI group, there was no difference between treatment group in rates of other secondary outcomes, including Clostridioides difficile infection and ICU and hospital length of stay.
Sleep medicine
Pitolisant, a new histamine-3 receptor antagonist/inverse agonist has received approval for excess daytime sleepiness in Narcolepsy and Obstructive Sleep apnoea. Zolpidem is now available in new dosage forms of sprays and sublingual tablets. [22]
Key learning
Pharmacological therapy should always be seen as an adjunct to multipronged approach in excessive daytime sleepiness in Obstructive sleep apnoea.
The year 2021 is going to be the year of COVID-19 vaccine. Of course all eyes will be on the most efficacious vaccine available and how the world leaders manage to protect their citizens. This would also further tell us if a respiratory RNA virus like SARS-CoV2 can be tamed due to its ever changing nature and appearance of new variants. Hopefully, the variants should be less virulent as they have been with other viruses till date.
What is also important, is how we deal with future pandemics in terms of jumping of pathogen species between humans and animals. This needs further investigation. It is also high time we try and restore the environment to prevent mayhem due to re-emergence of various viral or bacterial diseases.
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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The author, Dr. Viny Kantroo is a Respiratory, Critical Care, and Sleep Medicine Specialist from Delhi.
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