key: cord-0814426-f6hl1hgi
authors: Wang, Tianyu; Qiu, Tao; Yuan, Yan; Chen, Zhongbao; Ma, Xiaoxiong; Zhang, Long; Jin, Zeya; Zou, Jilin; Zhang, Yalong; Zhou, Jiangqiao
title: Summary report of seven cases of COVID-19 infection in renal transplant recipients
date: 2021-08-10
journal: Transpl Immunol
DOI: 10.1016/j.trim.2021.101445
sha: 428288f76ba9466518d327eec73510427bdaa4e2
doc_id: 814426
cord_uid: f6hl1hgi

The coronavirus disease 2019 (COVID-19) has swept the world, posing a serious threat to people's lives and health. Several cases of COVID-19 infection in renal transplant recipients (RTRs) have been reported, but the treatment and prognosis have not been fully elucidated. We followed-up with RTRs infected with SARS-CoV2 in our center and classified them as five clinical types—asymptomatic, mild, moderate, severe, and critical. The immunosuppressive agents were not adjusted in asymptomatic carriers and mild patients, the former was mainly treated by isolation, and the latter was treated by low-dose intravenous immunoglobulin (IVIG) to enhance immunity. For moderate or severe patients, the immunosuppressive agents were largely reduced or even interrupted, low-dose IVIG was adopted, and low-dose methylprednisolone (MP) was used to inhibit inflammation and rejection. Immunosuppressants were discontinued early in critical patients; IVIG, high-dose MP, and antibiotics were used. Meanwhile, all patients received at least one antiviral drugs. After aggressive treatment, three patients developed acute kidney injury, and two showed reversal, while the remaining one lost the allograft kidney; one patient died, while other patients were discharged. For different clinical types of RTRs infected with COVID-19, personalized therapies were essential, Meanwhile, patients with COVID-19 infection may have different outcomes due to their different clinical manifestations.

In December 2019, an outbreak of Coronavirus Disease 2019 (COVID-19) was identified in the world. This epidemic rapidly spread globally, and the World Health Organization (WHO) declared COVID-19 to be a pandemic in early March 2020 [1] .

As of June 15, 2020, more than 6 million cases and 400 000 deaths have been confirmed worldwide. According to the WHO guidelines, while the overall population is generally susceptible, elderly patients and those with chronic underlying conditions have a poorer prognosis than young, healthy adults [2] . Owing to long-term use of immunosuppressive agents, recipients of renal transplantation comprise an immunocompromised population that are prone to all kinds of opportunistic infection [3] . According to the theory, renal transplant recipients (RTRs) should be susceptible to infection with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2), which can easily progress to critical type COVID-19 and cause poor prognosis [4] .However, based on multiple reports, the COVID-19 infection rate of transplant recipients is similar to that of the general population, most of whom had a good prognosis in Wuhan [5, 6] . Moreover, the clinical manifestations of COVID-19 vary widely among patients, from asymptomatic carrier to the most critical type. To 

Epidemiological history (≤14 days): travel to or residence in Wuhan and its surrounding areas, or other communities where COVID-19-positive cases had been found; contact with COVID-19 patients or contact with patients with fever or respiratory symptoms and from Wuhan and its surrounding areas, or from communities where COVID-19 has been found; clustered cases.

Clinical symptoms: fever and/or respiratory symptoms; normal or decreased white blood cell (WBC) count, normal or decreased lymphocyte count; imaging characteristics of COVID-19.

Any one criteria of epidemiological history plus any two clinical symptoms, or all three clinical symptoms were considered as suspected cases. A confirmed case of COVID-19 was made based on the suspected cases with etiological or serological evidence: (1) RT-PCR positivity in respiratory specimens for SARS-CoV-2 or (2) serological evidence with specific IgG or IgM.

According to the diagnosis and treatment guidelines of the national health commission of China (7 th edition), all COVID-19 confirmed cases were classified into different types [2] . The classification criteria are described below:

Asymptomatic infected people: no related clinical symptoms such as fever, cough, or sore throat and no evidence of pneumonia on computed tomographic (CT) images, but positive nucleic acid test or specific antibody. Critical type; Needs mechanical ventilation or shock or complicated with other organ failure and requiring ICU admission.

The mean age of the seven RTRs who developed COVID-19 pneumonia was 52 years (range: 37-64 years, four male and three female). The transplant length covered from 10 days to 80 months after renal transplantation. Seven patients were associated with one or more of the following diseases: hypertension (n=6), myocardial infarction (n=1), and polycystic kidney disease (n=1). The maintenance immunosuppression regimen was MMF +Tacrolimus (FK)+prednisone. Serum creatinine and eGFR was maintained at normal levels during follow-up. In terms of epidemiology, all seven patients lived in Wuhan, but only one family member was infected with SARS-CoV-2. Table 1 .

According to the diagnosis criteria and clinical classification method, patient 1 and patient 2 were confirmed as asymptomatic carrier and mild type respectively, patient 3 was moderate type, patients 4 and 5 were severe type, and patients 6 and 7 were critical type. Laboratory results showed that seven patients had normal WBC and reduced lymphocyte counts, and four patients had significantly elevated levels of C-reactive protein (CRP). All patients had normal procalcitonin levels. Chest CT was Table 2 . The chest CT image of all patients were characterized by typical COVID-19 image features including multiple patchy ground glass shadows in the pulmonary peripheral zone ( Figure 2A ). However, If the patients were accompanied by other basic diseases or in different periods of the course of the COVID-19, the chest CT images were not typical ( Figure 2B ).

For the asymptomatic patient 1, we did not adjust the immunosuppressive regimen. In the case of mild COVID-19, the patient's dose of immunosuppressant remained unchanged. We choose the IVIG, and umifenovir (Arbidol) for antivirus therapy. For patients with moderate-and severe-type patients, the immunosuppressive agents were first largely reduced and then interrupted if symptom or CT lesion worsen.

A low-dose IVIG (2.5-10 g/d) was administered to restore immune function for fighting infection, and low-dose methylprednisolone (20-40 mg/d) was used to inhibit inflammation and prevent rejection. The patients were given common antiviral drugs including Arbidol, lopinavir/ritonavir, and chloroquine phosphate. These patients were only prescribed one of the above drugs at a given time. For patients 6 and 7 with critical type illness, the treatment regimen included interruption of immunosuppressive agents, cefoperazone sodium+sulbactam sodium to fight infection, high-dose IVIG (10-20 g/d) to enhance immune function, and methylprednisolone (40-80 mg/d) to inhibit inflammation and prevent rejection. The antiviral regimen included Arbidol or lopinavir/ritonavir tablets.

The timeline of clinical characteristic, key treatment, and outcome of RTRs infected with COVID-19 were shown in figure 2. The asymptomatic patient was discharged after 6 days of isolation. The patient's renal function returned to normal and a series of NAT and chest CT images were negative for COVID-19. The mild type patient was cured after 2 weeks of therapy. In addition, the series of NAT and J o u r n a l P r e -p r o o f chest CT images were negative, the antibody test was also negative upon evaluation for the next two months.

The moderate-type patient's fever disappeared after 2 weeks of treatment, and CT image showed that the lesion was gradually absorbed. AKI which was defined as increase of serum creatinine ≥26.5 μ mol/L within 48 hours appeared during the treatment. Based on the clinical symptom and doppler ultrasound results, the clinical rejection was diagnosed, so the renal function was restored to normal after MP shock therapy. The patient was cured after 24 days of treatment.

After the first 10 days of symptom aggravation and evidence of progression on chest CT images, both patients with severe-type illness recovered very smoothly, and the renal function was always maintained at normal levels. After a month of oxygen therapy and antiviral therapy, the lung lesions were gradually absorbed, and the patients were discharged. Both patients developed protective IgG antibodies.

The two critical patients were admitted to the intensive care unit (ICU) for further treatment. Patient 6 developed acute heart failure and fast ventricular rate of atrial fibrillation causing AKI; the patient's serum creatine level was elevated to 305 µmol/L. A series of treatments including furosemide diuresis, sodium bicarbonate, and continuous renal replacement therapy (CRRT) were administered to improve the heart failure. The further synchronized cardioversion was provided to reverse atrial fibrillation to a sinus rhythm. The patient gradually recovered from heart failure and renal insufficiency, and finally, the pneumonia symptoms and pulmonary infection lesions also gradually disappeared. After two consecutive negative NAT results, the patient was discharged after 40 days treatment. During the most recent one-month follow-up, the renal function of both patients remained normal, and there was no indication of heart failure. The SARS-CoV2 antibody was positive 

In our hospital, there was currently nearly 1,200 renal transplantation recipients being followed-up, and COVID-19 infection was detected in seven patients. While the overall incidence was similar to the confirmed incidence reported in Wuhan, there was no large-scale outbreak of COVID-19 among transplant recipients.

The clinical manifestations of the transplant recipients were consistent with the general population [4] [5] [6] [7] [8] [9] . In our current reported cases, fever was the most common symptom, accompanied by other respiratory symptoms such as cough, expectoration, and myalgia. The low level of blood lymphocytes is most likely because of the viral infection and long-term use of antiproliferative drugs to inhibit lymphocyte proliferation. Acute kidney injury appeared in some patients to an extent, the causes of which include various drugs' side effects, acute rejection, and kidney injury possibly caused by the virus [10] . Although the SARS-CoV2 binding receptor, ACE2, is highly expressed in the kidney, studies have differing views on whether it directly causes renal pathological changes [11, 12] .

The CT images of recipient patients infected with COVID-19 showed similar typical lesions as the general population, characterized by bilateral, multiple peripheral patchy shadows [13, 14] . However, in case of complications such as kidney dysfunction, heart failure, the CT images were not typical. To illustrate, the CT findings of a critical type patient showed pulmonary edema, while that of another patient with critical type showed early Cytomegalovirus (CMV) pneumonia; the superposition of the two images resulted in an atypical presentation.

Nucleic acid detection can identify the virus, but nucleic acid detection often shows false negative results [15] . Hence, the test should be repeated, and multi-site nucleic acid detection should be used. At the same time, serum antibody should be used as a supplementary basis for diagnosis of the virus. However, some patients did not produce antibodies against SARS-CoV2 for a long time despite positive NAT results [16] . Of the seven patients we followed-up, only five produced antibodies. (Table 3) .

Transplant recipients are an immunocompromised population, and physicians initially considered reducing the dose of or discontinuing immunosuppressant drugs after pneumonia [17] . However, this increases the risk of organ rejection, which will lead to kidney damage and possible irreversible failure. As described in a patient with moderate-type illness, we discontinued immunosuppressants; after a continuous fever for 10 days thereafter, the first signs of organ rejection appeared, and MP shock therapy was administered to reverse this rejection. Fortunately, the patient's renal function recovered, and she recovered from COVID-19. Thus, in the case of mild and moderate type COVID-19 illness, it is not recommended to reduce the J o u r n a l P r e -p r o o f immunosuppressant use. For severe and critical types, we suggest to discontinue MMF and reduce CNI. If the immunosuppressant drugs have been stopped for long term, possible rejection reactions should be closely monitored and CNI drugs restarted in a timely manner. In addition, moderate immunosuppressive agents can avoid inflammatory factor storm and alleviate the progression of lung infection; hence, it is necessary to detect inflammatory factors in the treatment of COVID-19 and choose tocilizumab therapy depending on the severity of the inflammatory storm [18] [19] [20] .

Whether MP therapy is beneficial for the COVID-19 infection, there is a big dispute, while the Chinese and WHO guidelines do not advocate the use of MP, except in the case of progressive deterioration of oxygenation indicators, rapid disease progression verified by imaging, and excessive activation of inflammatory response in the body. Even then, the MP dose should not exceed 1-2 mg/kg [21] . The main concern is that hormone-induced immunosuppression slows virus clearance. According to our case summary, patients with mild and moderate COVID-19 do not need to use MP, while those with the severe and critical type with MMF and CNI reduction can use a low dose of MP for short term.For low-dose hormone, we use 40-80mg per day. In case of pulmonary edema, excessive exudation and fever, we recommend using low-dose hormone for 5-10 days in the early stage. When the symptoms improve, we can reduce it to 20mg per day.

Another preferred treatment choice for transplant physicians is reconstruction of immune function. The theoretical basis for this is the long-term immunosuppression in cellular immunity and humoral immunity function in recipients with impaired cellular and humoral immune function [22] . Therefore, IVIG was widely used to treat infection among transplant recipients, especially for the severe or critical type patient.

There is no standard for the dosage and course of IVIG treatment, For critically ill patients, IVIG in our center is used 5-10g per day for 5-10 consecutive days. [19] .

Several existing drugs have been recommended for antiviral treatment and written into the national guide, such as Arbidol, chloroquine phosphate, and oral J o u r n a l P r e -p r o o f lopinavir/ritonavir [23] .Arbidol was mostly chosen for antiviral treatment for transplant recipients of COVID-19, as this drug is cheaper and easier to obtain than others.

Several doctors have tried other drugs such as colchicine, which inhibit inflammation in transplant patients and reduce the production of IL-6, leading to recovery [4] . Overall, there is no conclusive evidence to control the development of severe pneumonia.

However, it is preferable to not routinely use more than three antiviral drugs at a given time and/or use them for more than ten days. The use of these drugs is not an issue for transplant patients, as it is important to consider the risk of renal function damage as well as the interaction with CNI drugs. 

Characteristics of and Important Lessons From the

COVID-19) Outbreak in China: Summary of a Report of

Cases From the Chinese Center for Disease Control and Prevention

Dynamic changes of Chest CT follow

Coronavirus Disease-19 (COVID-19) pneumonia: relationship to clinical typing

Coronavirus Disease 2019 Pneumonia in Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan

COVID-19 in kidney transplant recipients

Identification of Kidney Transplant Recipients with Coronavirus Disease

Immunosuppressed Renal Transplant Recipients: A Summary of 10 Confirmed Cases in Wuhan, China

Recommendations on management of the SARS-CoV-2 coronavirus pandemic (Covid-19) in kidney transplant patients

Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression

COVID-19 in a Kidney Transplant Patient

Acute kidney injury in SARS-CoV-2 infected patients

Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020

Earliest cases of coronavirus disease 2019 (COVID-19) identified in solid organ transplant recipients in the United States

Novel Coronavirus (2019-nCoV) Pneumonia

Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States

Diagnostic accuracy of an automated chemiluminescent immunoassay for anti-SARS-CoV-2 IgM and IgG antibodies: an Italian experience

Kidney transplant programmes during the COVID-19 pandemic

Tocilizumab treatment in COVID-19: A single center experience

High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease

Covid-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine

Interpretation of the 7th edition of the "diagnosis and treatment guidelines of coronavirus disease 2019 in China

Successful treatment of plasma exchange followed by intravenous immunogloblin in a critically ill patient with 2019 novel coronavirus infection