COVID-19

COVID-19 overview

The rapid worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to the ongoing coronavirus disease 2019 (COVID-19) pandemic. In the absence of a vaccine or approved therapy, the pandemic has had a considerable impact on the number of hospitalisations, ICU admissions and deaths worldwide. Those who are particularly vulnerable to severe COVID-19 appear to be those who are older and those with underlying health conditions such as hypertension and diabetes¹.

Solid organ transplantation patients who are on immunosuppressive treatments may be considered a vulnerable patient group for SARS-CoV-2 infection². Patients on the waiting list for transplant procedures may also face additional risks from infected donor organs. These risks are increasing, particularly as the global COVID-19 pandemic progresses; however, risks will vary depending on local infection rates. Healthcare professionals also face additional challenges that relate to infection control including the availability of clearly separated infrastructure that allow for safe patient admission pathways and resources such as personal protective equipment (PPE) and SARS-CoV-2 PCR testing. These requirements have led to major changes in organ procurement, patient admission pathways, the number of transplantation procedures taking place and patient management guidance.

Dr Saima Aslam, the Chair of the International Society of Heart and Lung Transplant COVID-19 taskforce shares some of the ways in which the COVID-19 pandemic has changed her clinical practice, including her experience with telemedicine. She also signposts to some of the recent guideline changes for managing solid organ transplantation patients.

COVID-19 manifestations

COVID-19 has a wide degree of severity, from patients being asymptomatic to those with severe or critical disease that requires hospitalisation³. Details of each phase are discussed in more detail below:

• Early or mild: Symptomatic patients experience symptoms such as a dry cough, fever and malaise. This phase is associated with viral replication and establishment, particularly affecting the respiratory system, but also the small intestine and vascular epithelium that express the angiotensin-converting enzyme 2 (ACE2) receptor for SARS-CoV-2 binding. Assessment at this stage may involve PCR testing for SARS-CoV-2, chest imaging, complete blood counts and liver function tests⁴.
• Mild to moderate: Involves established pulmonary disease characterised by localised inflammation in the lung. These patients should be hospitalised for observation and management. They show continued viral reproduction, fever, and cough with evidence of viral pneumonia, and in some cases, hypoxia (defined as PaO₂/FiO₂ < 300 mm Hg)⁴. Chest imaging highlight bilateral infiltrates or ground glass opacities, and blood tests reveal increasing lymphopenia⁴. Patients at this stage who experience hypoxia are likely to progress to severe disease requiring mechanical ventilation.
• Severe phase: Manifests as extrapulmonary systemic hyperinflammation syndrome, with high levels of systemic inflammation markers including IL-2, IL-6, IL-7, granulocyte colony-stimulating factor, macrophage inflammatory protein 1-α and tumour necrosis factor-α⁴. This stage may involve shock, vasoplegia, respiratory failure, systemic organ involvement, myocarditis and cardiopulmonary collapse⁴. Patients who experience severe disease are likely to progress to a critical state and death. Treatment that subdue the hyperinflammatory state is therefore a key focus of clinical trials for COVID-19.

COVID-19 in solid organ transplantation patients

Dr Saima Aslam explains the two critical stages of the immune response to COVID-19 and points out that the impact of immunosuppressive treatments on the immune response to COVID-19 is currently unclear.

The impact of immunosuppressive treatments given to solid organ transplantation patients who contract SARS-CoV-2 is currently unclear, and paradoxical in nature. Immunosuppressive treatments may lead to an increased risk of initial infection; however, it is thought that immunosuppressive treatments may benefit patients who experience moderate or severe COVID-19. Currently, the evidence suggests that a benefit in solid organ transplant patients is unlikely, particularly since there is a higher rate of COVID-19 associated mortality in these patients. Whilst comparative studies are lacking, mortality rates for kidney transplant patients, for example, vary from 20–28% for those admitted to hospital, which appears to be higher than the mortality rates for the general population^5–7.

Here, Dr Federico Alberici talks about his single-centre study on 20 kidney transplant patients with COVID-19 in Italy, 25% of whom died⁶. He highlights the main findings related to this study and discusses the management of these patients.

The high mortality rate observed in kidney transplant patients admitted to hospital may be due to a combination of risk factors, including underlying chronic kidney disease and unrelated issues including diabetes, hypertension and age. Altogether, the data indicate that solid organ transplantation patients should at least be managed with additional considerations.

COVID-19 treatments

There are currently over 600 clinical trials that are investigating treatments for COVID-19. Investigative agents include antiviral treatments which aim to address the early phase of SARS-CoV-2 infection and anti-inflammatory or immunosuppressive agents that aim to subdue the over-reaction of the immune response to infection, a later phase response that is associated with severe or critical COVID-19^8,9.

In this video, Dr Saima Aslam talks to the possible utility of these investigative agents in transplantation patients and points out noteworthy drug-drug interactions with immunosuppressive treatments used to treat solid organ transplant recipients.

Antiviral agents under investigation include remdesivir and the HIV treatments lopinavir-ritonavir. When considering antiviral agents for solid organ transplant patients, it is important to note that some of these agents, such as lopinavir-ritonavir display drug-drug interactions with some immunosuppressant treatments. Anti-malaria drugs such as chloroquine or hydroxychloroquine in combination with azithromycin are also under investigation, though it is important to note that these therapies are associated with a higher risk of QT interval prolongation^8,9. Anti-inflammatory treatments under investigation include tocilizumab (anti-IL-6 antibody), sarilumab (anti-IL-6R antibody), sirolimus and corticosteroids^8,9.

Throughout the following sections, you will hear insights from both Dr Saima Aslam and Dr Federico Alberici on topics including organ procurement, considerations for transplant procedures and the management of existing transplant recipients, and those infected with SARS-CoV-2.

Organ procurement

Local guidelines from regions around the world are changing continuously as the COVID-19 pandemic progresses. In the USA, the American Society of Transplantation Infectious Disease Community of Practice has revealed new recommendations regarding organ donor testing, which is subject to change as more information becomes available¹⁰. The recommendations include epidemiological screening (travel and exposure history of the donor), clinical screening (symptoms of COVID-19 such as fever, cough, flu-like symptoms) and laboratory testing (nucleic acid testing/PCR testing for SARS-CoV-2 infection) of both live and deceased organ donors¹⁰.

Dr Saima Aslam says that the introduction of screening questionnaires and PCR-based testing for SARS-CoV-2 infection in both live and deceased organ donors play an important role in mitigating the risk of COVID-19 transmission. For lung donors, additional assessments should be considered including bronchoalveolar lavage (BAL) PCR testing for SARS-CoV-2 infection.

Another change to donor procurement in the USA relates to the pathway for transporting donor organs to hospital sites for transplantation procedures. The minimum number of personnel should be employed, preferably by a local delivery team who are equipped with personal protective equipment including masks¹¹. On-site personnel should follow all the appropriate hospital protocols and should not enter isolation rooms of potential donors who have pending COVID-19 testing¹¹.

Solid organ transplant procedures

The beginning of the COVID-19 pandemic saw a significant reduction in the number of transplantation procedures being carried out. The halting was mainly related to the lack of pathways, guidance and resources (for example, PCR tests for detecting SARS-CoV-2) for infection risk avoidance. Globally, guidelines are now constantly emerging and changing as new data becomes available, mainly related to the mitigation of SARS-CoV-2 infection risks for living donors, transplant recipients and healthcare workers. Whilst other factors have impacted on the ability to restart, including local spread, these changes have been key to the restart of many transplantation programmes.

During the COVID-19 pandemic, transplant programmes have had to make decisions to continue or cease procedures based on a variety of considerations including:

• risk of introducing immunosuppressive treatments in patients
• risk versus benefit for postponing transplantation for individual patients
• availability of healthcare resources
• the ability to provide a clearly separated hospital area for transplant patients
• the local risk of COVID-19 transmission

Here, we ask Dr Saima Aslam to tell us about the key considerations when preparing a patient for a transplant procedure, and whether changes have been made to the perioperative care of these patients.

In centres that can carry out solid organ transplantation procedures, patient preparation now involves minimising SARS-CoV-2 infection risk prior to the procedure taking place. This involves providing information to the patient on social distancing and carrying out screening questionnaires to better understand risk. To reduce the infection risk to healthcare providers, patients should undergo PCR testing prior to the procedure taking place, and all healthcare personnel should ensure that personal protective equipment (PPE) is appropriately used and disposed of.

At the time of interview, Dr Federico Alberici pointed out that transplant procedures were taking place in a few designated transplant centres in the Lombardy region in Italy; however, that his own centre situated in Brescia was yet to reopen. He points out that restarting the programme can be considered once there is a clean path between the wards and operating theatre, and that a clear physical separation is needed between patients who are infected, and those who are uninfected.  

Managing existing transplant recipients

Existing solid organ transplant patients who are not infected with COVID-19 are not treated any differently in terms of immunosuppressant treatments; however, there have been significant changes in the management of these patients. These changes relate mainly to reducing the risk of SARS-CoV-2 infection. This primarily involves patient management using telemedicine, which reduces the need for patients to travel, and their chances of exposure to SARS-CoV-2.

Dr Saima Aslam points out that the risk of SARS-CoV-2 infection may be reduced through telemedicine and deferral of surveillance biopsies in recent solid organ transplant recipients who have not encountered problems with graft rejection. She also highlights the importance of informing existing recipients on the need for social distancing, hand washing hygiene and avoiding people who may have COVID-19.  

Dr Federico Alberici points out the importance of immunosuppressive treatments in solid organ transplant patients and reiterates that immunosuppressive treatments remain unchanged in solid organ transplant recipients who are not affected by COVID-19.  

In a situation where a solid organ transplant patient displays symptoms of SARS-CoV-2 infection, Dr Federico Alberici points to using teleconsultations to firstly assess patients, and the decisions that are taken at his centre in Italy when symptoms worsen.

SARS-CoV-2 infected transplant recipients

The management of COVID-19 infected patients is dependent on COVID-19 severity. Limited observational studies indicate that solid organ transplantation patients admitted to hospital are generally more likely to die in response to SARS-CoV-2 infection; however, the reason for this is currently unclear⁶.

Dr Alberici highlights key complications that may arise in kidney transplant patients with COVID-19 and points out how these patients are managed differently to the general population.

A key question for transplantation patients who have COVID-19 include whether to continue immunosuppressive treatment. Immunosuppressive treatments play an important role in preventing graft rejection in transplant recipients, particularly in recent recipients. Anti-inflammatory treatments are currently under clinical investigation for treating the later stages of COVID-19; however, evidence indicates that early use of corticosteroid in patients with lung injury may promote viral replication^4,12. Whilst the role for immunosuppressive treatment in COVID-19 is currently unclear, both our experts indicate that alterations to immunosuppressive treatments should be considered based on COVID-19 severity. 

Dr Saima Aslam explains the steps being taken at her centre for treating solid organ transplantation patients who have mild, moderate or severe COVID-19. She points out that patients with mild disease should be managed using telemedicine whilst they remain at home in quarantine. Patients admitted to hospital, such as those who experience worsening symptoms or complications such as acute kidney injury should be assessed on arrival to the hospital. 

Dr Federico Alberici shares his experience in treating kidney transplant patients in Italy who suffered both mild and severe COVID-19, and discusses the available evidence for withdrawal of immunosuppressant treatment in patients with severe disease, and considerations for the utility of hydroxychloroquine and antiviral treatments in these patients.

References

1. Phua J, Weng L, Ling L, Egi M, Lim CM, Divatia JV, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. The Lancet Respiratory Medicine. 2020;8(5):506–517.
2. Aslam S, Mehra MR. COVID-19: Yet another coronavirus challenge in transplantation. Journal of Heart and Lung Transplantation. 2020;39(5):408–409.
3. World Health Organisation: Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). https://www.who.int/publications-detail/report-of-the-who-china-joint-mission-on-coronavirus-disease-2019-(covid-19). Accessed 23 April 2020.
4. Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal. Journal of Heart and Lung Transplantation. 2020;39(5):405–407.
5. Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, et al. Covid-19 and Kidney Transplantation. N Engl J Med. 2020;382(25):2475–2477.
6. Alberici F, Delbarba E, Manenti C, Econimo L, Valerio F, Pola A, et al. Management Of Patients On Dialysis And With Kidney Transplant During SARS-COV-2 (COVID-19) Pandemic In Brescia, Italy. Kidney Int Reports. 2020. doi:10.1016/j.ekir.2020.04.001.
7. ERA-EDTA Registry. Covid-19 - ERA-EDTA Registry. 2020. https://www.era-edta.org/en/registry/covid-19/. Accessed 6 November 2020.
8. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). 2020. StatPearls Publishing http://www.ncbi.nlm.nih.gov/pubmed/32150360. Accessed 9 June 2020.
9. Wu R, Wang L, Kuo HCD, Shannar A, Peter R, Chou PJ, et al. An Update on Current Therapeutic Drugs Treating COVID-19. Current Pharmacology Reports. 2020;6(3):56–70.
10. United Network for Organ Sharing: 2019-nCoV (Coronavirus): Recommendations and Guidance for Organ Donor Testing. https://unos.org/covid/. Accessed 10 June 2020.
11. Association of Organ Procurement Organisations (AOPO). COVID-19 (CORONAVIRUS) BULLETIN. 2020. https://www.aopo.org/information-about-covid-19-coronavirus-is-being-released-rapidly-we-will-post-updates-as-we-receive-them/. Accessed 10 June 2020.
12. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet. 2020;395(10223):473–475.