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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 14  |  Issue : 3  |  Page : 250-254

Coronavirus disease in a renal allograft recipient: A case report


Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Submission24-Jun-2020
Date of Acceptance05-Aug-2020
Date of Web Publication30-Sep-2020

Correspondence Address:
Prof. Narayan Prasad
Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_63_20

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  Abstract 


Coronavirus disease-19 (COVID-19) affected everyone on the globe, including renal transplant recipients who are at increased risk of infection. The clinical manifestations, immunosuppressive modifications, and treatment protocol are not well defined. We are reporting a case of renal transplant recipient and reviewed all case reports and series (a total of 100 patients) published to date to comprehend the clinical manifestations, immunosuppression modifications, treatment given, and outcomes of the patients. A 57-year-old male kidney transplant recipient had a fever, headache, weakness, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. He became asymptomatic with the treatment of hydroxychloroquine, azithromycin, and oseltamivir. However, he remained persistently positive by reverse transcriptase-polymerase chain reaction for SARS-CoV-2 for 4 weeks and became negative only after Ivermectin therapy, a safer medicine than antivirals/antiretrovirals used for COVID therapy in renal transplant recipients. Of the 100 patients review of case series, fever was noted in 85%, cough 71%, diarrhea 10%, and radiographic abnormalities in 75% of cases. Only in 3% of cases, steroid was stopped, and in the rest of the cases, 63% either continued in the same doses or changed to methylprednisolone in 34%. Calcineurin inhibitors were temporarily stopped in 42% of cases, reduced in 9% of cases, and continued in the same doses in 49% of cases. The anti-metabolites were discontinued in 83%, reduced in 9% of cases, and not changed in 8% of cases. SARI was observed in 18% and acute kidney injury (AKI) in 26% of cases. Of all the AKI, 11% required renal replacement therapy. Mortality was observed in 21% of cases. COVID in renal transplant recipients may show an unusually longer positivity. Ivermectin may be used in the absence of any conclusive SARS-CoV-2 antivirals. Mortality is high in renal transplant recipients.

Keywords: Acute kidney injury, coronavirus disease, outcomes, renal transplant recipients, severe acute respiratory infection


How to cite this article:
Gulati Y, Prasad N, Behera MR, Patel MR, Bhadauria D, Kaul A, Yachha M, Kushwaha R, Gupta A. Coronavirus disease in a renal allograft recipient: A case report. Indian J Transplant 2020;14:250-4

How to cite this URL:
Gulati Y, Prasad N, Behera MR, Patel MR, Bhadauria D, Kaul A, Yachha M, Kushwaha R, Gupta A. Coronavirus disease in a renal allograft recipient: A case report. Indian J Transplant [serial online] 2020 [cited 2020 Oct 23];14:250-4. Available from: https://www.ijtonline.in/text.asp?2020/14/3/250/296899




  Introduction Top


Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has been declared as a pandemic by the World Health Organization (WHO) in March 2020. The pandemic began in Wuhan city of China in the late months of 2019 and directly or indirectly affected everyone on the globe; therefore, patients on renal replacement therapy (RRT), including kidney transplant recipients (KTR).

A KTR is at a significantly higher risk of acquiring COVID-19 because of long-term maintenance immunosuppression. They have the propensity to develop opportunistic infections, including respiratory tract infections, which simulate with clinical manifestations of COVID.[1],[2] The preimmunosuppressed state and the other comorbidities influence the outcomes of COVID-19 patients. The clinical manifestations of COVID in KTRs on immunosuppression are not well defined. The protocols of immunosuppression modifications and the use of anti-COVID therapy in KTRs are not standardized.[3],[4],[5] It kept the transplant specialists in a quandary. The experiences of anti-COVID treatment in KTRs from literature are small. In this brief review, we report a case who had a persistent infection for more than a month and finally responded to ivermectin therapy. We have also analyzed and summarized all the reports published to date to present a comprehensive review of the clinical manifestations, renal involvement, and outcomes of COVID 19-infected renal allograft recipients, which will guide the therapy in such patients.


  Case Report Top


A 57-year-old male KTR, who had kidney transplantation in January 2015, developed fever, headache, and weakness for 3 days. The course of the patient is shown in [Figure 1]. The patient did not have any chest pain, shortness of breath, nausea, vomiting, or diarrhea. The patient denied any travel history, contact with COVID-19-positive person, and participation in any public gatherings.
Figure 1: Course of the patient during the hospital stay

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He had the end-stage renal disease secondary to chronic glomerulonephritis. He had been on triple immunosuppression with tacrolimus 0.5 mg twice a day (trough level varying from 4 to 6 ng/ml), mycophenolate mofetil (MMF) 1.5 g/day, and prednisone 7.5 mg daily. He had a normal graft function with a serum creatinine of 1.03 mg/dl and tacrolimus levels of 6.2 ng/ml 3 months ago. There was no history of any rejections in the past. Other home medications included ramipril, metoprolol, pantoprazole, and calcium carbonate.

On presentation, the patient was febrile with 100.1 Fahrenheit, pulse rate 110 beats/min, blood pressure 138/72 mm Hg, respiratory rate 20 breaths/min, and oxygen saturation 94% on room air. His reverse transcriptase-polymerase chain reaction (RT-PCR) for SARS-CoV-2 turned out to be positive, and he was admitted in isolation ward. Other physical examinations were unremarkable. His X-ray chest and computed tomography (CT) of the thorax were normal. The laboratory parameters are summarized in [Table 1]. His procalcitonin level, D-dimer, international normalized ratio, and activated partial thromboplastin time remained normal during the hospital stay. His 1st h erythrocyte sedimentation rate (ESR) value was 20 (normal = 0–15 mm/h) and C-reactive protein-15 mg/L (normal = 0.5–10 mg/L) value was high at presentation. He was started on hydroxychloroquine (HCQ), azithromycin, oseltamivir, and cefoperazone-sulbactam combination empirically for suspected COVID-19 and pneumonia. Electrocardiogram was done to monitor the QTc interval before HCQ and azithromycin initiation, which was within the normal limits. During the stay in the hospital, the intensity of fever tended to increase from day 3. He also developed leukopenia with lymphopenia, as depicted in [Table 1].
Table 1: Course of the patient during hospitalization

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Along with fever, he later developed a dry cough from day 3; however, an X-ray was still within the normal limits. Because of persisting leukopenia and fever, MMF was stopped on day 3. He also developed acute kidney injury (AKI) with rising creatinine values from day 3 and peak, reaching up to 1.65 mg/dl on day 14 from the baseline of 1.1 mg/dl. The trend of increase in serum creatinine values is depicted in [Table 1]. He became afebrile from day 6, although total leukocyte count remained in a declining trend. He was given a single dose of injection filgrastim subcutaneously on day 7. Subsequently, his total leukocyte count normalized. With these measures, his general condition improved and became asymptomatic, although his SARS-CoV-2 RT PCR swab was still positive on day-21. Because of persistent RT-PCR positivity, he was given 200 mcg/kg of ivermectin on day 22 and a repeat dose on the next day. After 5 days of ivermectin therapy, his two consecutive samples of SARS-CoV-2 RT PCR became negative. MMF was reinitiated at a lower dose, and the patient was discharged in stable condition.

Review of published data on coronavirus disease-19 and kidney transplant recipients

The case series and case reports published to date have been searched on PubMed and Google Scholar with reference to COVID 19 and renal transplant recipients.[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] The details of the case series and reports have been outlined in Supplementary File and the summary in [Table 2].[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] A total of 100 cases of renal transplantation with SARS-CoV-2 were reported from different case series and reports. Of the 100 patient case series, fever was observed in 85%, cough 71%, diarrhea 10%, and radiographic abnormalities 75% of cases. The prednisolone was continued in the same doses in 63%, changed to methylprednisolone in 34% cases, and stopped in 3% of cases. Calcineurin inhibitors (CNIs) were temporarily stopped in 42% of cases, reduced in 9% of cases, and continued in the same doses in 49% of cases. The anti-metabolites were stopped in 83%, reduced in 9% of cases, and not changed in 8% of cases. SARI was observed in 18% of cases. Drugs used for the treatment with different antiviral effects varied across the series and reports [Table 2] and Supplementary File] [Additional file 1]. AKI developed in 26% of cases, and 11% of them required RRT.[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14] Mortality was reported in 21% of cases.
Table 2: Review of publications in reference to coronavirus disease-19 in renal transplant recipients

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  Discussion Top


In our case report, we observed that despite the milder clinical manifestations with fever and headache without the severe acute respiratory syndrome, the case showed prolonged SARS-CoV-2 positivity till 4 weeks despite the resolution of symptoms after a week with HCQ, azithromycin treatment, and other treatments. To the best of our knowledge, this is the first case report of the use of ivermectin, an anti-parasite agent for the treatment of SARS-CoV-2 in KTR in the literature. The patient also developed mild AKI, which recovered with the resolution of clinical symptoms. It remained unclear that persistent positivity for longer period after the resolution of symptoms in the patient was a simple presence of dead virus RNA detected on RT-PCR.

However, he responded to ivermectin used in the last week; moreover, it is not clear that this effect was self-clearance of virus or the impact of ivermectin. Ivermectin exerts broad-spectrum antiviral activity against several animal and human viruses, including both RNA and DNA viruses. The antiviral activity of ivermectin may be mediated through the inhibition of importin α/β-mediated nuclear transport of viral proteins in the case of SARS-CoV-2.[15] In an animal model, a study by Caly et al., Vero-hSLAM cells were treated with ivermectin after 2 h of SARS-CoV-2 infection, resulting in ~ 5000-fold reduction in viral RNA after 48 h.[16] Ivermectin may increase the plasma concentration of co-administered drugs like tacrolimus and sirolimus used in KTR. However, dose modification is not required.[17]

Atypical presentation and course of COVID are not unexpected in a KTR because of drugs like CNIs and steroids in these patients.[1] The case series from different publications shows the illness from COVID-19 in KTR ranged from mild-to-severe disease, and a few patients develop atypical symptoms.[1],[2] A case series of 15 inpatients KTR with COVID from New York City, an epicenter of COVID in the USA[3] showed similar clinical manifestations as in the general population with fever in 87% and cough in 60% with multifocal opacities on chest X-ray in 47%, and 33% had normal radiographs. In addition, the median white blood cell count was only 4.8 × 1000/μl, with elevated inflammatory markers, including ESR, C-reactive protein, and interleukin-6 (IL-6). Similar observations were seen in an Italian cohort of 20 KTRs, in which all patients had fever, and 50% had cough[4] with half showing bilateral infiltrates, and 15% without any infiltrates on imaging. Our patient also presented with similar findings of fever with a dry cough, but the X-ray chest and CT thorax did not show any infiltrates.

Management is challenging in the absence of effective anti-SARS-Cov-2 therapy. The trials of antiretroviral drugs such as ritonavir and lopinavir[18] and remdesivir[19] on viral clearances showed negative results. In addition, these drugs pose a risk of drug interaction with a rise in CNIs level and drug toxicity and require drug level monitoring. A recent New England Journal Medicine study showed that Remdesivir, an inhibitor of the viral RNA-dependent RNA polymerase with inhibitory activity against SARS-CoV, was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection.[20] However, drug interaction with CNIs remains of concern in RT recipients, and it is not recommended for the patients with glomerular filtration rate of <30 ml/min.

Cellular immunity is the principal determinant of the course and outcome of COVID, which is suppressed in KTR due to maintenance immunosuppression. Persistent lymphopenia is associated with a grave prognosis.[21] However, our patient who responded to filgrastim and recovered despite lymphopenia. However, the role of filgrastim in such patients is not defined. High level of inflammatory cytokines, particularly IL-6, signifies an imbalance between protective and dysregulated host immune response. These dampening effects of immunosuppression on T-cell activity may decrease the severity of the cytokine storm and reduce the severity of cytokine storm associated problems in KTR.[21],[22]

In addition, CNIs modify the adaptive T cell response, which may pose the patients at increased risk of uncontrolled viral shedding and invasion in KTR. Therefore, modifications of immunosuppression become the cornerstone of the therapy. Immunosuppressive agents also inherently cause lymphopenia and impaired lymphocyte functions. The general practice is to modify immunosuppression by holding MMF and adjusting the dose of CNIs, such as tacrolimus if symptoms persist.[5] However, the exact way of modifications and immunosuppressant reduction that is required to enable the containment of SARS-Cov-2 remains unclear. We have seen in the present review that anti-metabolites should be stopped temporarily in all patients, and CNIs should be either stopped or reduced to 50% of the previous dose till patients remain symptomatic. Changing of steroid to IV methylprednisolone may be a good idea to dampen the cytokine storm and have shown beneficial effects with SARS-CoV-1 and MERS-CoV infection in the past.[23] However, WHO does not recommend the use of steroids in such a scenario.[24] Moreover, discontinuation of steroids should be discouraged as these patients are on long term steroids with the risk of adrenal suppression.

A 50% dose reduction or complete cessation of a KTR anti-metabolite on the initial diagnosis of COVID-19 appears appropriate.[25] The decision should be based on the severity of illness and the patient's risk of rejection. The appropriate time for a reduction in CNI dose is unknown; prior reports describe withholding CNI on the development of severe pneumonia.[6] We also adopted the same strategy of withholding anti-metabolites. MMF might have contributed to persisting lymphopenia in our patients, along with the inherent property of the viral illness.

The SARS-CoV-2 virus uses an angiotensin-converting enzyme (ACE) 2 to gain entry to cells,[26] leading to suggestions that ACE inhibitors and/or angiotensin receptor blockers may increase risk of COVID-19, potentially via altered expression of ACE2. However, there are no precise clinical data supporting or refuting this hypothesis, and changing the dosing of ACE inhibitors or angiotensin receptor blockers for treating SARS-CoV-2 is not recommended.[26],[27] However, in our patients, we stopped ACEI because of the development of AKI. We have observed in the reviewed literature that approximately 26% of the patients developed AKI, and 11% required RRT. AKI predisposed them to a higher risk of mortality.[4],[7] Overall death in the reviewed series was 21% and varied in literature. It is possible that mortality is underreported as mainly successful cases are reported while unsuccessful cases are not.

Limitation of the study was that it was unclear whether viral clearance was spontaneous or due to ivermectin and whether persistent viral positivity was due to the dead virus.


  Conclusions Top


Ivermectin may be used to treat SARS-CoV-2 infection in renal transplant recipients. Anti-metabolites and CNI's can be reduced and, if needed, can be suspended. Steroids should not be stopped. As there is no proven treatment or vaccine available as of now, prevention and close monitoring of the general condition of the patient, along with modification of immunosuppression, is the key to management. A renal transplant recipient may show persistent positivity of RT-PCR after the resolution of symptoms for a relatively more extended period than the general population. The persistent positivity poses challenges to follow these patients in a regular outpatient clinic.[28],[29]

Declaration of patient consent

The authors certify that patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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