In previous issues of our e-newsletters, we covered the importance of community health in combating diseases, including the spread of infectious disease ("Health and the Community" by Dr Ben Fong, March 2020 issue) and deliberated the merits of enhancing our innate defense to counter the onslaught of pandemic ("Beyond Vaccine" by Professor Leung Ping-chung. September 2020 issue). For this issue, we turn our attention to the work of Hong Kong’s frontline medical professionals and their experience in combating the pandemic. The article written by Dr Wu Tak Chiu, Head of the Division of Infectious Diseases in one of our busiest public hospitals in Hong Kong provides a glimpse of the management approach, the multi-prone treatment methods in dealing with the unprecedented situation.
Indeed, Hong Kong researchers at local universities (and the affiliated teaching hospitals) have been in the forefront of testing drugs to tackle COVID-19. Apart from the treatment of using the combination of three drugs (lopinavir-ritonavir, ribavirin and interferon beta-1b) mentioned in the article by Dr Wu, which was tested by researchers from Hong Kong University (article in The Lancet, 8 May 2020 issue), researchers from the same university have recently announced that a drug used to treat stomach ulcers, ranitidine bismuth citrate (RBC), is shown to reduce the viral loads in coronavirus-infected cells by over 1,000-fold. Whilst the world is still awaiting a new vaccine to combat COVID-19, it is important to look for effective treatment of the virus and our hospitals are continuing their efforts on this front relentlessly.
The emergence of COVID-19 pandemic has posed an unprecedented challenge to the world. This article focuses on the clinical management of COVID-19 patients admitted to the hospital isolation wards under the Hospital Authority.
For our patients, good teamwork is the only way to ensure a positive outcome. In the airborne infections isolation wards, an assembly of subspecialty experts, nursing, allied health colleagues and supporting staff have been working day and night to take care of COVID-19 patients. With years of development after SARS, the budding subspecialty of infectious diseases gears up with respirologists to form the backbone of the attending clinical team. The paediatricians have taken up the role in taking care of the infected infants, children and adolescents all together. Many frontline doctors volunteered to join shortly afterwards. Despite our best efforts, some patients unfortunately deteriorated into respiratory failure and required urgent, machine-aided breathing. Dedicated "crash team" led by experienced anesthetists and intensive care physicians scrambled to perform endotracheal intubation and ensure the safe transfer to the intensive care units.
SARS-CoV-2 is a novel pathogen. For treating COVID-19 patients, clinicians can only consider existing antiviral drugs, especially those that have shown effectiveness against other coronaviruses like SARS-CoV and the MERS-CoV. The initial candidates include lopinavir-ritonavir and ribavirin which have shown positive clinical response in SARS-infected patients. 1 Much hope has been put into remdesivir, a broad spectrum antiviral drug initially developed for treating a number of serious infections including Ebola. Results from clinical trials, however, suggested that it may not be the silver bullet as people might expect. 2–4 Researchers in Hong Kong have shown that early combination therapy consisted of lopinavir-ritonavir, ribavirin and interferon beta-1b was superior to lopinavir-ritonavir alone in alleviating symptoms and shortening hospital stay in patients with mild to moderate COVID-19. 5
Steroid and Other Immunomodulating Agents
With ongoing research and accumulating knowledge about the virus, it was soon realized that COVID-19 is more than a simple viral infection. Rather, it is an interplay between the pathogen and the human immune system. While the majority of the infected have an uneventful or even asymptomatic disease courses, some patients’ body defense overreact and run amok. A dysregulated immune system ultimately hurts its host and results in an overt inflammatory state, or the so-called "cytokine storm". Since it takes time for the body to mount an immune response, the observed full-blown inflammation usually happens at around 1-2 weeks after symptom onset. An extreme example is observed in some children who developed a multi-system inflammatory syndrome similar to those suffered from the Kawasaki disease. 6
Systemic corticosteroid has been widely used for controlling immune dysregulation caused by different causes, for instance, autoimmune diseases like systemic lupus erythematosus. In the same vein, physicians have tried corticosteroid in COVID-19. Preliminary data from the RECOVERY trial showed that corticosteroid therapy resulted in a lower mortality among hospitalized COVID-19 patients who were receiving invasive mechanical ventilation or oxygen alone at randomization.7 The World Health Organization (WHO) recently gives a strong recommendation for systemic corticosteroid therapy in patients with severe and critical COVID-19. 8
Other than steroids, medications that can modify the immune system via different mechanisms of action are considered for COVID-19 treatment. In particular, the interleukin (IL)-6 inhibitor, tocilizumab has come into attention due to favourable preliminary data. 9,10 However, the COVACTA trial 11, which is the first randomized controlled phase III trial at a global scale, did not meet both its primary and key secondary endpoints. 12 We need more data from well-designed clinical trials to determine the optimal immunomodulation strategies for different groups of COVID-19 patients.
People have used convalescent plasma to treat infectious disease since the 1900s of the last century. 13 Transfusion of COVID-19 convalescent plasma showed encouraging results in critically ill COVID-19 patients. 14,15 As more patients received the treatment, larger observational studies suggested that convalescent plasma therapy is generally safe in hospitalized patients with COVID-19. 16
COVID-19 is the test of our times. Clinical management of COVID-19 patients involves multidisciplinary collaboration. Other than antiviral drugs, immunomodulating agents, especially corticosteroid, may have a role in selected individuals. In the face of difficulties, our colleagues at Hospital Authority display their dedication, heartiness, and professionalism through teamwork for the good of the general public.
- Chu CM, Cheng VCC, Hung IFN, Wong MML, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59: 252–256.
- Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395: 1569–1578.
- Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020;382: 2327–2336.
- Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020. doi:10.1001/jama.2020.6019
- Hung IF-N, Lung K-C, Tso EY-K, Liu R, Chung TW-H, Chu M-Y, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395: 1695–1704.
- Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19. 15 May 2020 [cited 25 Aug 2020]. Available: https://www.who.int/news-room/commentaries/detail/multisystem-inflammatory-syndrome-in-children-and-adolescents-with-covid-19
- RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020. doi:10.1056/NEJMoa2021436
- Department of Communications, WHO Global. Corticosteroids for COVID-19. World Health Organization; 2020 Sep. Report No.: WHO REFERENCE NUMBER: WHO/2019-nCoV/Corticosteroids/2020.1. Available: who.int/publications/i/item/WHO-2019-nCoV-Corticosteroids-2020.1
- Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117: 10970–10975.
- Coomes EA, Haghbayan H. Interleukin-6 in Covid-19: A systematic review and meta-analysis. Rev Med Virol. 2020; e2141.
- A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia. In: ClinicalTrials.gov [Internet]. 31 Jul 2020 [cited 7 Sep 2020]. Available: https://clinicaltrials.gov/ct2/show/NCT04320615
- Genentech Provides an Update on the Phase III COVACTA Trial of Actemra in Hospitalized Patients With Severe COVID-19 Associated Pneumonia. 28 Jul 2020 [cited 7 Sep 2020]. Available: https://www.gene.com/media/press-releases/14867/2020-07-28/genentech-provides-an-update-on-the-phas
- Focosi D, Anderson AO, Tang JW, Tuccori M. Convalescent Plasma Therapy for COVID-19: State of the Art. Clin Microbiol Rev. 2020;33. doi:10.1128/CMR.00072-20
- Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020 [cited 29 Mar 2020]. doi:10.1001/jama.2020.4783
- Ahn JY, Sohn Y, Lee SH, Cho Y, Hyun JH, Baek YJ, et al. Use of Convalescent Plasma Therapy in Two COVID-19 Patients with Acute Respiratory Distress Syndrome in Korea. J Korean Med Sci. 2020;35: e149.
- Joyner MJ, Bruno KA, Klassen SA, Kunze KL, Johnson PW, Lesser ER, et al. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020;95: 1888–1897.
Author: Dr Wu Tak Chiu
Consultant and Head, Division of Infectious Diseases, Department of Medicine, Queen Elizabeth Hospital