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      COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal

      , MD, MSCR, , MD, MSc *

      The Journal of Heart and Lung Transplantation

      International Society for Heart and Lung Transplantation.

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          Abstract

          The onslaught of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19) has gripped the world in a pandemic and challenged the culture, economy and healthcare infrastructure of its population. It has become increasingly important that health systems and their clinicians adopt a universal consolidated framework to recognize the staged progression of COVID-19 illness in order to deploy and investigate targeted therapy likely to save lives. The largest report of COVID-19 from the Chinese Centers for Disease Control and Prevention summarized findings from 72, 314 cases and noted that while 81% were of a mild nature with an overall case fatality rate of 2.3%, a small sub-group of 5% presented with respiratory failure, septic shock and multi-organ dysfunction resulting in fatality in half of such cases, a finding that suggests that it is within this group that the opportunity for life saving measures may be most pertinent. 1 Once the disease is manifest, supportive measures are initiated with quarantines; however a systematic disease modifying therapeutic approach remains empirical. Pharmacotherapy targeted against the virus holds the greatest promise when applied early in the course of the illness, but its usefulness in advanced stages may be doubtful. 2 , 3 Similarly, use of anti-inflammatory therapy applied too early may not be necessary and could even provoke viral replication such as in the case of corticosteroids. 4 It appears that there are two distinct but overlapping pathological subsets, the first triggered by the virus itself and the second, the host response. Whether in native state, immunoquiescent state as in the elderly, or immunosuppressed state as in heart transplantation, the disease tends to present and follow these two phases, albeit in different levels of severity. The early reports in heart transplantation suggest that symptom expression during the phase of establishment of infection are similar to non-immunosuppressed individuals; however, in limited series the second wave determined by the host-inflammatory response appears to be milder, possibly due to the concomitant use of immuno-modulatory drugs. 5 , 6 Similarly, an epidemiological study from Wuhan in a cohort of 87 patients suggests that precautionary measures of social distancing, sanitization and general hygiene allow heart transplant recipients to experience a low rate of COVID-19 illness. 7 We do not of course, know if they are asymptomatic carriers, since in this survey-based study universal testing during the early 3 months was not employed. One interesting fact in this study was that many heart transplant recipients have hematological changes of lymphopenia due to the effects of immunosuppressive therapy which may obfuscate the laboratory interpretation of infection in such patients should they get infected. Much confusion abounds in the therapeutic tactics employed in COVID-19. It is imperative that a structured approach to clinical phenotyping be undertaken to distinguish the phase where the viral pathogenicity is dominant versus when the host inflammatory response overtakes the pathology. In this editorial we propose a clinical staging system to establish a standardized nomenclature for uniform evaluation and reporting of this disease, to facilitate therapeutic application and evaluate response. We propose the use of a 3-stage classification system, recognizing that COVID-19 illness exhibits three grades of increasing severity which correspond with distinct clinical findings, response to therapy and clinical outcome (Figure ). Figure 1 Classification of COVID-19 Disease States and Potential Therapeutic Targets Figure 1 The figure shows 3 escalating phases of disease progression with COVID-19, with associated signs, symptoms and potential phase-specific therapies. ARDS = Acute respiratory distress syndrome; CRP = C-reactive protein; IL = Interleukin; JAK = Janus Kinase; LDH=Lactate DeHydrogenase; SIRS = Systemic inflammatory response syndrome. Stage I (mild) – Early Infection The initial stage occurs at the time of inoculation and early establishment of disease. For most people, this involves an incubation period associated with mild and often non-specific symptoms such as malaise, fever and a dry cough. During this period, SARS-CoV-2 multiplies and establishes residence in the host, primarily focusing on the respiratory system. Similar to its older relative, SARS-CoV (responsible for the 2002-2003 SARS outbreak), SARS-CoV-2 binds to its target using the angiotensin-converting enzyme 2 (ACE2) receptor on human cells. 8 These receptors are abundantly present on human lung and small intestine epithelium, as well as the vascular endothelium. As a result of the airborne method of transmission as well as affinity for pulmonary ACE2 receptors, the infection usually presents with mild respiratory and systemic symptoms. Diagnosis at this stage includes respiratory sample PCR, serum testing for SARS-CoV-2 IgG and IgM, along with chest imaging, complete blood count (CBC) and liver function tests. CBC may reveal a lymphopenia and neutrophilia without other significant abnormalities. Treatment at this stage is primarily targeted towards symptomatic relief. Should a viable anti-viral therapy (such as remdesivir) be proven beneficial, targeting selected patients during this stage may reduce duration of symptoms, minimize contagiousness and prevent progression of severity. In patients who can keep the virus limited to this stage of COVID-19, prognosis and recovery is excellent. Stage II (moderate) - Pulmonary Involvement (IIa) without and (IIb) with hypoxia In the second stage of established pulmonary disease, viral multiplication and localized inflammation in the lung is the norm. During this stage, patients develop a viral pneumonia, with cough, fever and possibly hypoxia (defined as a PaO2/FiO2 of <300 mmHg). Imaging with chest roentgenogram or computerized tomography reveals bilateral infiltrates or ground glass opacities. Blood tests reveal increasing lymphopenia, along with transaminitis. Markers of systemic inflammation may be elevated, but not remarkably so. It is at this stage that most patients with COVID-19 would need to be hospitalized for close observation and management. Treatment would primarily consist of supportive measures and available anti-viral therapies such as remdesivir (available under compassionate and trial use). It should be noted that serum procalcitonin is low to normal in most cases of COVID-19 pneumonia. In early stage II (without significant hypoxia), the use of corticosteroids in patients with COVID-19 may be avoided. 4 However, if hypoxia ensues, it is likely that patients will progress to requiring mechanical ventilation and in that situation, we believe that use of anti-inflammatory therapy such as with corticosteroids may be useful and can be judiciously employed. Thus, Stage II disease should be subdivided into Stage IIa (without hypoxia) and Stage IIb (with hypoxia). Stage III (severe) – Systemic Hyperinflammation A minority of COVID-19 patients will transition into the third and most severe stage of illness, which manifests as an extra-pulmonary systemic hyperinflammation syndrome. In this stage, markers of systemic inflammation appear to be elevated. COVID-19 infection results in a decrease in helper, suppressor and regulatory T cell counts. 9 Studies have shown that inflammatory cytokines and biomarkers such as interleukin (IL)-2, IL-6, IL-7, granulocyte-colony stimulating factor, macrophage inflammatory protein 1-α, tumor necrosis factor-α, C-reactive protein, ferritin, and D-dimer are significantly elevated in those patients with more severe disease. 10 Troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) can also be elevated. A form akin to hemophagocytic lymphohistiocytosis (sHLH) may occur in patients in this advanced stage of disease. 11 In this stage, shock, vasoplegia, respiratory failure and even cardiopulmonary collapse are discernable. Systemic organ involvement, even myocarditis, would manifest during this stage. Tailored therapy in stage III hinges on the use of immunomodulatory agents to reduce systemic inflammation before it overwhelmingly results in multi-organ dysfunction. In this phase, use of corticosteroids may be justified in concert with the use of cytokine inhibitors such as tocilizumab (IL-6 inhibitor) or anakinra (IL-1 receptor antagonist). 11 Intravenous immune globulin (IVIG) may also play a role in modulating an immune system that is in a hyperinflammatory state. Overall, the prognosis and recovery from this critical stage of illness is poor, and rapid recognition and deployment of such therapy may have the greatest yield. The first open-label randomized controlled clinical trial of antiviral therapy was recently reported. 3 In this study, 199 patients were randomly allocated to the antiviral agents lopinavir–ritonavir or to standard of care and this regimen was not found to be particularly effective. One reason for this may have been that the patients were enrolled during the pulmonary stage with hypoxia (stage IIb) when the viral pathogenicity may have been only one lesser dominant aspect of the overall pathophysiology, and host inflammatory responses were the predominant pathophysiology We believe that this proposed 3-stage classification system for COVID-19 illness will serve to develop a uniform scaffold to build structured therapeutic experience as healthcare systems globally are besieged by this crisis, in patients with or without transplantation. Disclosure Dr. Siddiqi has nothing to declare. Dr. Mehra reports no direct conflicts pertinent to the development of this paper. Other general conflicts include consulting relationships with Abbott, Medtronic, Janssen, Mesoblast, Portola, Bayer, NupulseCV, FineHeart, Leviticus and Triple Gene.

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          Most cited references 3

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          COVID-19: Yet another coronavirus challenge in transplantation

          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. 1 Most reported infections are in China, followed by Italy, Iran, Republic of Korea, and the European Union. 1 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. 2 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. 3 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. 4 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. 5 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. 5 Those with cancer receiving chemotherapy as well as patients with multiple comorbidities are distinctively at a higher risk for severe illness. 5 , 6 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. 7 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. 8 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, 3 , 9 , 10 and fecal shedding has been noted in patients without diarrhea. 10 Significant environmental contamination has been noted, including wash basin, toilet bowl, and air outlet fan surfaces, in hospitalized patients. 11 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. 12 , 13 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. 12 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. 14 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.
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            EPIDEMIOLOGICAL AND CLINICAL CHARACTERISTICS OF HEART TRANSPLANT RECIPIENTS DURING THE 2019 CORONAVIRUS OUTBREAK IN WUHAN, CHINA: A DESCRIPTIVE SURVEY REPORT

            BACKGROUND The epidemiological and clinical characteristics of heart transplant (HTx) recipients during the SARS-CoV-2 epidemic remains unclear. We studied the characteristics of HTx recipients during Dec 20, 2019 and Feb 25, 2020 in an effort to understand their risk and outcomes. METHODS All accessible HTx recipients were included in this single-center, retrospective study. We collected information on the recipients using a web-based questionnaire as well as the hospital database. RESULTS We followed 87 HTx recipients (72.4% were men and average age was 51 years). 79 recipients resided in Hubei, and 57 recipients had a Wuhan related history of travel or contact. The majority took precautionary measures while in contact with suspicious crowds. 96.6% of the families and communities undertook prevention and quarantine procedures. 4 upper airway infection were reported, and 3 of them tested negative for SARS-CoV-2 (the 4th recovered and was not tested). All cases were mild and successfully recovered after proper treatment. Laboratory results of 47 HTx cases within the last 2 months were extracted. 21.3% recipients had pre-existing lymphopenia and 87.2% of recipients had therapeutic tacrolimus concentration (5-12ng/ml). 5 and 6 recipients had liver and kidney insufficiency respectively. CONCLUSION HTx recipients that practiced appropriate prevention measures had a low rate of infection with SARS-CoV-2 and transition to COVID-19. These early data will require confirmation as the pandemic establishes around the world.
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              Dysregulation of immune response in patients with COVID-19 in Wuhan, China

               C Qin,  L ZHOU,  Z HU (2020)
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                Author and article information

                Contributors
                Journal
                J Heart Lung Transplant
                J. Heart Lung Transplant
                The Journal of Heart and Lung Transplantation
                International Society for Heart and Lung Transplantation.
                1053-2498
                1557-3117
                20 March 2020
                20 March 2020
                Affiliations
                Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
                Author notes
                [* ]Corresponding Author: Mandeep R. Mehra, 75 Francis Street, Boston, MA 02115, Fax: 617-264-5265; Tel: 617-732-8534 MMEHRA@ 123456BWH.HARVARD.EDU @ 123456MRMehraMD
                Article
                S1053-2498(20)31473-X
                10.1016/j.healun.2020.03.012
                7118652
                © 2020 International Society for Heart and Lung Transplantation. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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