key: cord-336252-e92omqyr
authors: Chen, Tracy Yixin; Farghaly, Sara; Cham, Samantha; Tatem, Luis Lantigua; Sin, Jonathan H.; Rauda, Roberto; Ribisi, Maria; Sumrani, Nabil
title: COVID‐19 pneumonia in kidney transplant recipients: Focus on immunosuppression management
date: 2020-07-06
journal: Transpl Infect Dis
DOI: 10.1111/tid.13378
sha: 
doc_id: 336252
cord_uid: e92omqyr

BACKGROUND: The coronavirus disease of 2019, also known as COVID‐19, has been declared a global pandemic. Significant controversies exist regarding treatment modalities for this novel disease, especially in immunocompromised patients. Experience with management of COVID‐19 in kidney transplant recipients is scarce; effects of this virus on immunosuppressed individuals are not well understood. METHODS: We identified 30 renal transplant recipients with confirmed COVID‐19 pneumonia who were admitted to inpatient between March 2020 and April 2020. All patients received a 5‐day course of hydroxychloroquine and azithromycin; half of the patients received methylprednisolone. During hospitalization, calcineurin inhibitors and antimetabolites were held; prednisone was continued. RESULTS: Clinical presentation of flu‐like symptoms was similar to those in the general population. Hyponatremia, lymphopenia, acute kidney injury, and elevated inflammatory markers were common. Over the course of follow‐up, 23 have been discharged home with a functioning allograft and in stable condition; 4 experienced acute kidney injury requiring renal replacement therapy; 7 patients were intubated, and 6 expired. The mortality rate in our cohort was 20%. CONCLUSION: Our findings described the characteristics and outcomes of this highly fatal illness in a multi‐ethnic kidney transplant cohort, with insights on immunosuppression management that could further our understanding of this unique disease in immunocompromised populations.

RNA betacoronavirus that binds to angiotensin-converting enzyme 2 (ACE2) receptors, abundant on alveolar cells but also present in kidney, heart, small intestine, and vascular endothelium. 3 Patients may have flu-like symptoms such as fever, shortness of breath, and cough. As the infection advances, viral replication and inflammation of the lung become evident; patients develop viral pneumonia and possibly hypoxia. The most advanced disease manifests as respiratory failure leading to cardiopulmonary collapse.

Transplant recipients are in a vulnerable position in this potentially fatal pandemic. The immunocompromised state predisposes patients to greater susceptibility to infections, more rapid progression to pneumonia, and greater disease severity. 4 inpatient mortality rate across all organ types, with the immunosuppression reduction strategy of reducing or holding antimetabolites. 5 A brief correspondence on kidney transplant recipients hospitalized with COVID-19 pneumonia reported 35% mortality rate, withholding only antimetabolites primarily. 6 Another similar cohort in which all baseline immunosuppression was withdrawn and only methylprednisolone was administered reported 25% mortality rate. 7 Electronic medical records were utilized to obtain demographic information including age, sex, race, year and type of transplant, cause of end-stage renal disease (ESRD), relevant comorbidities, and baseline immunosuppression regimen. We also collected last known calcineurin inhibitor levels (on admission or prior to), signs and symptoms of COVID-19 infection, and duration of symptoms prior to presentation. Baseline laboratory values including serum sodium, serum creatinine, albumin, alkaline phosphatase, aspartate transaminase, alanine transaminase, brain natriuretic peptide, creatine kinase, white blood cell count, absolute neutrophil count, and absolute lymphocyte count were recorded. If present, inflammatory Leukocytosis was uncommon. Inflammatory markers, including LDH, CRP, ferritin, D-dimer, and ESR that are commonly elevated in the general population, were also elevated in this transplant cohort (Table 2) .

Ninety percent of patients required oxygen supplementation during admission. Urine and blood cultures were negative in all patients except two patients who were critically ill on mechanical ventilation, received appropriate antibiotic treatment for positive blood cultures, and expired shortly afterward due to respiratory failure.

Of the 30 patients included in this cohort, seven patients required mechanical ventilation but none were extubated successfully; 23 patients have been discharged home in stable clinical condition, three of which required home oxygen. Among the seven patients who required mechanical ventilation, two were intubated en route to or in the emergency department, and five required intubation on average 3.4 days after admission; six patients expired on average 2.8 days after intubation due to respiratory failure, and one remains intubated. The overall mortality rate was 20%.

Four patients experienced acute kidney injury requiring renal replacement therapy during admission, two of which were chronic kidney disease (CKD) stage 5 at baseline, one was CKD stage 3, and one was CKD stage 2 and is currently intubated. Two cases of ischemic stroke occurred in our patient cohort; one was present on admission; the other patient developed ischemic stroke on sequential compression device only. Repeat viral RT-PCR was performed on several patients, and all returned positive at as far as 21 days after symptom onset; we elected not to retest patients for negative PCR but instructed them to self-quarantine for minimum 14 days at discharge. Patients were followed up in the outpatient clinic 3-5 days after discharge without issues, at which point immunosuppression was resumed. Among discharged patients, their average length of stay was 9 days.

Presently, global mortality from COVID-19 is reported at 4.7%, ranging widely from 0.7% to 10.8% by location and population. 8 In comparison with recently published case series in transplant patients, our cohort shows similar but not higher case mortality. Not only that all patients were diagnosed with COVID-19 pneumonia based on bilateral patchy infiltrates on radiographic imaging, but the highly prevalent baseline comorbidities such as hypertension, diabetes, vascular diseases, and obesity in our cohort have contributed to the 20% case mortality due to inability to overcome COVID-19 pneumonia. Counter-intuitively, immunosuppression has been proposed as a therapeutic option or "protective factor" by tampering the immune response that contributes to hyperinflammatory injury to the lungs from elevated cytokines. 4, 23 The COVID-19 pandemic has being referred to as a gerolavic (from Greek, géros "old man" and epilavís, "harmful") infection because of substantially higher infection rates, severity, and lethality in the elderly population known to have immunosenescence. 24 If a suppressed or senescent immune system is "protective" from inflammatory injury, one would argue that the elderly population should be less susceptible to COVID-related mortality, contrary to reality. Similarly, our results have shown that while all patients were taking immunosuppression prior to admission, their COVID infections uniformly advanced to moderate-to-severe disease with confirmed diagnosis of pneumonia, while seven of the 30 patients required intubation and 20% died, cautioning the use of immunosuppression especially during the earlier phase of infection when viral suppression by the immune system is key to halt disease progression. Direct cytopathic changes of alveolar cells by the virus have also been reported, suggesting injury etiology beyond inflammation alone. 25, 26 The use of high-dose corticosteroids warrants individualized assessment. In our cohort, 40% patients did not receive any methylprednisolone and continued low-dose prednisone only, while the rest received methylprednisolone doses ranging between 40 mg and 455 mg. The decision to use high-dose methylprednisolone (40-125 mg per dose, given per daily assessment) was based on significantly elevated inflammatory markers as well as worsening radiographic imaging. In several patients, significant improvement in previously worsening chest X-ray was observed after receiving cumulative doses of methylprednisolone 250-375 mg, while other patients continued disease progression, seemingly due to the already established advanced pneumonia, for which no interventions appeared effective. While we attempted to describe our usage of corticosteroids in COVID-19 pneumonia, we acknowledge that the practice was based on little evidence. It remains unclear which patients would benefit most from steroids and when to initiate steroids in those who rapidly progressed, due to unclear association between response to steroids, timing of steroids, baseline laboratory values, and stage of disease progression.

Hypotension, hyponatremia, and rising serum creatinine were noted to be the most common initial presentation related to allograft dysfunction; AKI was common. Dehydration due to diarrhea, decreased oral intake, and increased insensible losses from the viral infection was the most common cause for hypovolemic hyponatremia; hypotension also contributed to AKI due to decreased autoregulation in renal allograft. Continuous intravenous infusion of normal saline was administered to all patients until volume status was normalized, and serum creatinine decreased noticeably. Despite the widely debated topic of continuing versus stopping rennin-angiotensin-aldosterone system (RAAS) inhibitors in COVID-19 infections, hypotension precluded the use of these agents.

In the general population, various pathways for kidney damage were proposed in COVID-related AKI, including cytokine damage, direct cytopathic effect, lung-kidney crosstalk, and systemic effects. 27, 28 Although these factors can certainly exert negative effects on allograft function as pneumonia progresses in advanced stages, when AKI is present on admission, majority is reversible with fluid resuscitation. Resolution of AKI was associated with recovery of COVID-19. 

The authors of this study would like to thank the many healthcare professionals who have devoted to providing best possible care for all patients during the COVID-19 pandemic.

The authors of this manuscript have no conflicts of interests to disclose.

TYC is responsible for the conception, development of methodology, data collection and analysis, writing, review, and revision of this manuscript. SF and SC contributed to data collection, analysis, writing, and revision of this manuscript. LLT and JHS contributed to review and revision of manuscript. RR contributed to data collection and writing of this manuscript. MR contributed to approval of institutional review board for exempt review. NS is responsible for review and revision of this manuscript.

pdf?sfvrs n=18969 76f_2. Accessed

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

Novel Coronavirus-19 (COVID-19) in the immunocompromised transplant recipient: #Flatteningthecurve

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia

Covid-19 and kidney transplantation

The COVID-19 Pandemic in the US

Effectiveness and safety of two different antithymocyte globulins used in induction therapy in kidney transplant recipients: a single-center experience

Polyclonal anti T-lymphocyte antibody therapy monitoring in kidney transplant recipients: comparison of CD3+ T cell and total lymphocyte counts

Monitoring of CD3(+) T-cell count in patients receiving antithymocyte globulin induction after cadaveric renal transplantation

Effect of rabbit antithymocyte globulin on acute and chronic active antibody-mediated rejection after kidney transplantation

Direct antiviral mechanisms of interferon-gamma

Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic

Cyclosporin A and tacrolimus reduce T-cell polyfunctionality but not interferon-γ responses directed at cytomegalovirus

Pathogen-specific T cell polyfunctionality is a correlate of T cell efficacy and immune protection

T cell exhaustion during persistent viral infections

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19)

Fighting COVID-19 exhausts T cells

Dysregulation of Immune Response in Patients With Coronavirus

Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome

Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?

Immunosuppression drug-related and clinical manifestation of Coronavirus disease 2019: A therapeutical hypothesis

Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections

Identification of coronavirus isolated from a patient in Korea with COVID-19. Osong Public Health Res Perspect

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

COVID-19 and kidney failure in the acute care setting: our experience from Seattle

Kidney involvement in COVID-19 and rationale for extracorporeal therapies

COVID-19 pneumonia in kidney transplant recipients: Focus on immunosuppression management