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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

COVID-19: Yet another coronavirus challenge in transplantation

  • Saima Aslam
    Affiliations
    Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California
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  • Mandeep R. Mehra
    Correspondence
    Reprint requests: Mandeep R. Mehra, MD, MSc, Center for Advanced Heart Disease, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115. Telephone: +1-617-732-8534. Fax: +1-617-264-5265.
    Affiliations
    Center for Advanced Heart Disease, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
      See Related Article, page 418
      A novel coronavirus, severe acute respiratory syndrome–coronavirus-2 (SARS-CoV-2), causing a severe acute respiratory syndrome with its disease designated as COVID-19, emerged from its epicenter in Wuhan, China, in December 2019 and is now a global pandemic. As of March 11, 2020, COVID-19 has been confirmed in 114 countries and involves 118,381 cases globally with 4,292 deaths.

      World Health Organization. Rolling updates on coronavirus disease (COVID-19). Available at:https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen.

      Most reported infections are in China, followed by Italy, Iran, Republic of Korea, and the European Union.

      World Health Organization. Rolling updates on coronavirus disease (COVID-19). Available at:https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen.

      Italy went into lockdown as a country on March 9, 2020, whereas in other countries such as the United States of America, several states have declared emergencies, focal biocontainment territories have been placed on lockdown, and cases are being reported to increase at an alarming rate.

      Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19) in the U.S. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-in-us.html.

      The rapid increase is owed to the fact that more widespread testing is now slowly becoming available; however, this virus uniquely is more efficient in its rate of transmissibility, with an individual capable of spreading to 1 to 3 others.
      • Li Q
      • Guan X
      • Wu P
      • et al.
      Early transmission dynamics in Wuhan,China, of novel coronavirus–infected pneumonia.
      The presentation of illness mimics that of a flu-like illness with fever and respiratory symptoms as common presenting complaints, and bilateral patchy infiltration is typically noted on computed tomography (CT) scans.

      Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2020 in China. [e-pub ahead of print]. N Engl J Med. doi:10.1056/NEJMoa2002032. Accessed March 11, 2020. PMID:32109013.

      Most COVID-19 cases (87%) occur between 30 and 79 years of age, and most (81%) are mild. The remaining 14% present with severe symptoms, whereas 5% require care in an intensive care unit.

      Wu Z, McGoogan JM.Characteristics of and important lessons from the coronavirus Disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. [e-pub ahead of print]. JAMA. doi:10.1001/jama.2020.2648. Accessed March 11, 2020. PMID:32091533

      The case-fatality rate has been touted to be 2.3% overall (although this is likely overestimated because of the lack of widespread testing); however, death rates climb in those aged ≥80 years (15%) and in nearly half of those requiring critical care.

      Wu Z, McGoogan JM.Characteristics of and important lessons from the coronavirus Disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. [e-pub ahead of print]. JAMA. doi:10.1001/jama.2020.2648. Accessed March 11, 2020. PMID:32091533

      Those with cancer receiving chemotherapy as well as patients with multiple comorbidities are distinctively at a higher risk for severe illness.

      Wu Z, McGoogan JM.Characteristics of and important lessons from the coronavirus Disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention. [e-pub ahead of print]. JAMA. doi:10.1001/jama.2020.2648. Accessed March 11, 2020. PMID:32091533

      ,
      • Liang W
      • Guan W
      • Chen R
      • et al.
      Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
      However, information on the predilection, presentation, and prognosis of COVID-19 in solid organ transplantation is sparse and has not been adequately reported.
      Li et al.
      • Li F
      • Cai J
      • Dong N
      First cases of COVID-19 in heart transplantation From China.
      report on the presentation and outcome of 2 microbiologically confirmed COVID-19 cases in heart transplantation detected in the Hubei Province in China. These 2 patients apparently were part of a community of at least 200 heart transplant survivors in that region and presented with variable severity of disease (one mild and another with more severe manifestations requiring a prolonged hospitalization); however, both survived the event. It is important to note that the clinical presentations were not distinct from those described in non-immunosuppressed individuals, and the patient with severe disease presented with a viral prodrome, displayed the typical findings on CT scan imaging, and progressed to clinical hypoxia. The second patient presented with a fever and mild CT scan findings (this being the screening modality used in China), with resolution in a few days. The laboratory findings mirrored those observed in non-transplant patients with elevated C-reactive protein levels and lymphopenia. The treatment for the patient with severe disease included withholding baseline immunosuppression and treating with high-dose corticosteroids and pooled immunoglobulin infusions. A kitchen sink approach to the cases also included the use of a fluoroquinolone along with ganciclovir, but whether this therapy was useful cannot be determined by this limited reporting. Crucially, the patient recovered to discharge without incurring immunologic consequences on the cardiac allograft and remained rejection-free.
      Whether transplantation-related immunosuppression alters the predisposition to acquiring infection with SARS-CoV-2 or if the disease implications are modified for better or for worse remain uncertain. The novel coronavirus achieves its anchoring to the lung by using the angiotensin-converting enzyme-2 (ACE-2) receptor. The pulmonary renin–angiotensin–aldosterone system via ACE-2 has been implicated in prevention of lung inflammation.
      • Tikellis C
      • Thomas MC
      Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease.
      When this system is overpowered by SARS-CoV-2, pulmonary inflammatory infiltrates emerge expressing the COVID-19 disease phenotype. It is unknown if heart transplant recipients have differential expression of pulmonary ACE-2 because a lower expression may result in less severe illness. Similarly, the anti-inflammatory effects of immunosuppression could diminish the clinical expression of the disease as well. These speculative assumptions will require structured studies to enhance our understanding of this disease pathway and processes.
      It is likely that immunosuppressed patients may be prone to acquiring the virus at higher risk because of its high efficiency in transmission. The virus shedding has been noted not only in respiratory specimens but also in serum and stool. Viral shedding can occur for days or weeks furtively in asymptomatic carrier individuals, especially children,
      • Li Q
      • Guan X
      • Wu P
      • et al.
      Early transmission dynamics in Wuhan,China, of novel coronavirus–infected pneumonia.
      ,

      Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. [e-pub ahead of print]. Sci China Life Sci. doi:10.1007/s11427-020-1661-4. Accessed March 11, 2020. PMID: 32146694.

      ,

      Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus Disease 2019 (COVID-19) with high viral load.[e-pub ahead of print]. Clin Infect Dis. doi:10.1093/cid/ciaa201. Accessed March 11, 2020. PMID:32112082.

      and fecal shedding has been noted in patients without diarrhea.

      Kam KQ, Yung CF, Cui L, et al. A well infant with coronavirus Disease 2019 (COVID-19) with high viral load.[e-pub ahead of print]. Clin Infect Dis. doi:10.1093/cid/ciaa201. Accessed March 11, 2020. PMID:32112082.

      Significant environmental contamination has been noted, including wash basin, toilet bowl, and air outlet fan surfaces, in hospitalized patients.

      Ong SWX, Tan YK, Chia PY, et al. Air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient. [e-pub ahead of print]. JAMA. doi:10.1001/jama.2020.3227. Accessed March 11, 2020. PMID: 32129805.

      Thus, it is prudent to advise transplant recipients to ardently practice mitigation strategies such as social distancing, sanitization, hand hygiene, and avoidance of areas known to harbor potentially infected individuals. These recommendations extend to their care providers as well.
      Therapy for manifest disease is gravely lacking at this time, although promise is on the horizon. Although several molecules are under investigation, remdesivir (an adenosine analog that incorporates into viral RNA chains and results in premature termination) and chloroquine (an anti-malarial drug that prevents viral cell fusion and interferes with glycosylation of cellular receptors of SARS-CoV) appear to have early in vitro evidence in support of their potential activity against SARS-CoV-2.
      • Dong L
      • Hu S
      • Gao J
      Discovering drugs to treat coronavirus disease 2019 (COVID-19).
      ,
      • Wang M
      • Cao R
      • Zhang L
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      Other drugs, such as ribavirin, interferon, lopinavir-ritonavir, and corticosteroids that have been used in patients with the 2003 SARS or the 2012 Middle Eastern Respiratory Syndrome, are candidates for investigation. The reason is that the novel coronavirus belongs to the Betacoronavirus family, which also contains SARS-CoV and Middle Eastern Respiratory Syndrome–CoV.
      • Dong L
      • Hu S
      • Gao J
      Discovering drugs to treat coronavirus disease 2019 (COVID-19).
      Hyperimmune globulin that contains targeted antibodies against SARS-CoV-2, derived from the plasma of recovered individuals and thus capable of providing passive immunity, may also be therapeutic.
      • Mair-Jenkins J
      • Saavedra-Campos M
      • Baillie JK
      • et al.
      The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.
      Ultimately, control of this outbreak will require the development of a vaccine.
      An important area of significant concern to transplant clinicians will involve the testing of donors, decisions on organ suitability from those recently exposed or infected, and the implications of recovery of such organs by procurement teams. This will need to be debated and studied rapidly as more widespread testing becomes available. At this time, it would be prudent to avoid transplanting organs from donors with a history of contact with someone at risk or diagnosed with COVID-19, as well as those with recent travel to an area with high density of infection.
      In summary, the novel coronavirus and its disease, COVID-19, require thoughtful approaches for the prevention, mitigation, timely detection, and appropriate therapeutic intervention for our vulnerable patients.

      Disclosure statement

      Dr Aslam reports consulting fees from Merck, unrelated to this manuscript; Dr Mehra reports no direct conflicts pertinent to the development of this editorial. Other general conflicts include consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus, and Triple Gene. Dr Mehra is also Editor in Chief of the Journal of Heart and Lung Transplantation. This paper should be considered to be the personal opinion of the authors and not the official stance of the International Society of Heart and Lung Transplantation.

      References

      1. World Health Organization. Rolling updates on coronavirus disease (COVID-19). Available at:https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen.

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