key: cord-0685212-fquuvav5
authors: Ma, Becky Mingyao; Hung, Ivan Fan Ngai; Chan, Gary Chi Wang; Tam, Anthony Raymond; Chan, Samuel Shung Kay; Wong, Bonnie Chun Kwan; Fukuda, Kenichiro; Ohno, Takanori; Yuen, Kwok Yung; Chan, Tak Mao
title: Case of “relapsing” COVID‐19 in a kidney transplant recipient
date: 2020-09-28
journal: Nephrology (Carlton)
DOI: 10.1111/nep.13786
sha: 90503c504ac1c1cbad9f951995da28b0ba39d644
doc_id: 685212
cord_uid: fquuvav5

Clinical outcomes of COVID‐19 vary considerably between patients. Little was known about the clinical course and optimal management of immunosuppressed patients infected with SARS‐CoV‐2. We report a kidney transplant recipient with COVID‐19 who presented with pneumonitis and acute kidney injury (AKI). She improved after reduction of immunosuppressive treatment and had two consecutive negative reverse transcription polymerase chain reaction (RT‐PCR) tests. Her respiratory tract samples turned positive again afterwards, and she was treated with lopinavir‐ritonavir. She had satisfactory virological and clinical response after a prolonged disease course. This case illustrates the risk of relapse or persisting shedding of SARS‐CoV‐2 in immunosuppressed patients, the important role of viral load monitoring in management, the challenges in balancing the risks of COVID‐19 progression and transplant rejection, and the pharmacokinetic interaction between immunosuppressive and antiviral medications.

with no prior episodes of rejection. On 16 February 2020 (day 0), while on-board a cruise-ship in Japan, she had low-grade fever and was mildly dyspneic, and tested positive for SARS-CoV-2 in nasopharyngeal swab and throat swab (NPS/TS) specimens, which were collected in a single aliquot. She was hemodynamically stable and her oxygen saturation was 96% on ambient air. Prednisolone dose (5 mg/D) was unaltered, while the daily dose of tacrolimus (Prograf) was reduced from 2 mg to 1 mg (0.5 mg BD), and mycophenolate mofetil MA Becky Mingyao and Hung Ivan Fan Ngai contributed equally to this work.

(Cellcept) from 750 mg to 500 mg (250 mg BD). Fever and dyspnoea subsided on day 4 and C-reactive protein (CRP) also normalized (Table 1) . SCr fluctuated between 2.45 and 3.02 mg/dL during hospitalization, and tacrolimus level was 10.5 μg/L on day 10. After two consecutive negative NPS/TS results on day 18, she returned to Hong Kong with the reduced immunosuppression. When she attended scheduled investigations on day 20, she reported new onset of mild myalgia and a lowgrade fever (37.8 C) was noted. She did not complain about respiratory symptoms but admitted that she also had new onset of mild dry cough upon direct questioning. Physical findings and oxygenation were normal. Table 2) . Lopinavir-ritonavir was stopped after 21 days, when the rectal swabs were also negative for SARS-CoV-2. sCr improved to 2.48 mg/dL and tacrolimus level to 6.1 μg/L upon discharge. There were no antibiotics administered. She remained seronegative for IgG antibodies against internal nucleoprotein (anti-NP) and surface spike protein receptor binding domain (anti-RBD). Her latest sCr on 24 April was 1.88 mg/dL.

The clinical course for COVID-19 in renal transplant populations remains to be investigated. shown to be significantly more sensitive in vitro than other assays, including COVID-19-S, COVID-19-N and RdRp-P2. 6 Unfortunately, we were unable to obtain details of the test kit and viral load data in Japan.

Another possibility could be that the NPS/TS results were falsely negative, which could have resulted from improper specimen collection, handling, transport, or presence of amplification inhibitors, or viral load infection. Its use in SARS was associated with a milder disease course, and it inhibits MERS-CoV. 11 in organ transplant recipients is the interaction between lopinavirritonavir and calcineurin inhibitors, which can raise the plasma levels of both to dangerously high levels, resulting in liver, kidney and immune dysfunctions and prolonged viral shedding. 16 Both tacrolimus and cyclosporine are metabolized by CYP3A enzymes and are subject to transport by p-glycoproteins, while protease inhibitors are potent inhibitors of CYP3A4 and inducers of p-glycoproteins. The marked increase of tacrolimus in bile and its reabsorption from the gut can result in persistently elevated plasma level despite cessation of dosing, as occurred in the patient. 17 Both tacrolimus and cyclosporine have strong inhibitory effect on the growth of SARS-CoV and HCoV-229E in vitro, 18 suggesting that viral replication is dependent on the immunophilin pathway, but the clinical impact remains to be investigated.

The patient also showed AKI, with subsequent improvement in renal function upon viral clearance. It has been postulated that SARS-CoV-2 enters cells through angiotensin converting enzyme-2 (ACE2), which are highly expressed in the kidneys. In an autopsy study of a COVID-19 patient with oligouric AKI, intracellular viral arrays within proximal tubular epithelial cells were identified by electron microscopy, indicating direct kidney infection. 19 

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The authors declare no competing interests.

All authors contributed to the clinical management, data collection, data interpretation, literature search and preparation of the manuscript. All authors reviewed and approved the final version of the report.

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