key: cord-0887487-zbipirhd authors: Wang, Aileen X.; Quintero Cardona, Orlando; Ho, Dora Y.; Busque, Stephan; Lenihan, Colin R. title: Influence of Immunosuppression on Seroconversion Against SARS‐Cov‐2 in Two Kidney Transplant Recipients date: 2020-07-23 journal: Transpl Infect Dis DOI: 10.1111/tid.13423 sha: 2f8e1bb3b6790963b22958d9476b4f915f9b8cbe doc_id: 887487 cord_uid: zbipirhd Solid organ transplant recipients are at risk for infectious complications due to chronic immunosuppression. The outbreak of Coronavirus Disease 2019 (COVID‐19) in United States has raised growing concerns for the transplant patient population. We seek to add to the current limited literature on COVID‐19 in transplant recipients by describing the clinical course of two kidney transplant recipients with SARS‐Cov‐2 infection monitored by both RT‐PCR and serology. Through careful adjustment of their immunosuppression regimen, both patients had excellent recovery with intact graft function and development of anti‐SARS‐Cov‐2 antibodies. The novel coronavirus (SARS-Cov-2), which first led to an outbreak of acute severe respiratory disease in Wuhan, China, has since spread across the globe. In the United States, the first case was identified on January 22, 2020 and has since increased to 2,545,250 confirmed cases, leading to 126,369 deaths as of June 29, 2020. 1 Solid organ transplant recipients may be at greater risk for severe complications due to immunosuppression and a high prevalence of comorbidities. While more data on in solid organ transplant recipients have been made available recently, 2,3 the optimal management remains unclear especially in light of the disease's high mortality in transplant recipients. 2 Here we describe the clinical course of SARS-Cov-2 infection in two kidney transplant recipients, both of whom recovered and seroconverted against SARS-Cov-2. This article is protected by copyright. All rights reserved A middle-aged female, who underwent deceased donor kidney transplant 2 months prior, presented for post-transplant clinic follow-up with fatigue, loss of appetite, and temperature of 37.3 °C for one week. Laboratory testing was notable for new onset leukopenia to 2.1 K/uL (absolute lymphocyte count 0.13 K/uL). She had no respiratory symptoms and no gastrointestinal symptoms. Her past medical history included end stage renal disease from chronic pyelonephritis, almost 10 years of hemodialysis, sleeve gastrectomy and type 2 diabetes. She was highly allosensitized and received a flow crossmatch negative deceased donor kidney transplant with a low level preformed donor specific antibody. Immunosuppression consisted of anti-thymocyte globulin induction (5 mg/kg) and maintenance therapy of tacrolimus, mycophenolate (MMF) and prednisone. Her post-transplant course was complicated by three weeks of delayed graft function. She received cytomegalovirus (CMV) and pneumocystis jiroveci pneumonia prophylaxis with valganciclovir and trimethoprimsulfamethoxazole respectively. In clinic, she underwent SARS-Cov-2 RT-PCR testing by nasopharyngeal swab (developed by Stanford Clinic Virology Laboratory 4, 5 ) and went home with instructions to self-isolate pending results. Serological testing was not performed at the time since it was not yet available to our institution. The following morning SARS-Cov-2 RT-PCR resulted positive. She remained minimally symptomatic with fatigue and low-grade fever. She was instructed to stop MMF. The next day she reported new-onset cough, rhinorrhea and dyspnea. At presentation to emergency department she was hypoxic on minimal exertion, with an O 2 saturation of 85% on room air. Chest X ray revealed diffuse bilateral patchy opacification. Her laboratory testing during hospitalization is summarized in Table 1 . She was admitted with diagnosis of SARS-Cov-2 pneumonia. She was maintained on 1-3 L of oxygen via nasal cannula with O 2 saturations of 91-94%. Tacrolimus was continued but dose adjusted to a lower target level of 4-7 ng/mL and prednisone was maintained at 5mg daily. She did not receive antibiotics or antivirals. On day 3 of hospitalization (diagnosis day 4, symptom onset day 11), she had worsening fever (38.6 °C) and increasing dyspnea. CT chest showed extensive bronchovascular "crazy-paving" with associated regions of consolidation and regions of lobular sparing ( Figure 1 ). In light of her clinical deterioration, hydroxychloroquine was initiated. By hospital day 7 she no longer required supplemental oxygen and on day 11 (diagnosis day 12, symptom onset day 19) she was well enough to be discharged home. On day of discharge IgM and IgG antibodies to the SARS Cov-2 spike receptor-binding domain tested positive while repeat (nasopharyngeal) SARS-Cov-2 RT-PCR remained positive. She was discharged on tacrolimus and prednisone with MMF held. Repeat SARS-Cov-2 RT-PCR obtained on diagnosis day 26 (symptom onset day 33) was negative, and MMF was reinitiated. An elderly female with end stage renal disease presumed due to diabetic nephropathy who was 6 years status post deceased donor kidney transplant presented to an outside hospital emergency room with a week-long history of dry cough and fevers up to 38.8 °C. Her past medical history included type 2 diabetes, hypertension and obesity. She was maintained on tacrolimus, MMF, and prednisone for immunosuppression with good kidney allograft function. Other medications include losartan 50mg daily. In the emergency department she was hypoxic and required supplemental oxygen. Chest Xray revealed bilateral interstitial infiltrates. SARS-Cov-2 RT-PCR returned positive (diagnosis day 0, symptom onset day 7). A serological test was not performed at the time. She was This article is protected by copyright. All rights reserved treated with hydroxychloroquine, ceftriaxone and azithromycin based on hospital protocol. By day 7 (symptom onset day 14) she had improved clinically and was discharged home. She continued her home immunosuppression regimen throughout hospitalization, although following consultation with us, MMF was held on day 8. Repeat SARS-Cov-2 RT-PCR on day 23 (symptom onset day 30) was negative. MMF was reinitiated. IgM and IgG antibodies to the SARS Cov-2 spike receptor-binding domain were performed on day 29 (symptom onset day 36) and both resulted positive. This article is protected by copyright. All rights reserved specific cytotoxic T lymphocytes are suppressed by MMF, which have been shown to negatively impact recovery from CMV infection. 9 Early discontinuation of MMF may have allowed for the observed expansion in peripheral B-lymphocyte population with CD19 and CD20 expression (Table 1) . Continuing tacrolimus, on the other hand, may have been protective via its anti-inflammatory effect through decreased synthesis of IL-2, which is necessary for lymphocyte activation. 10 For COVID-19 positive solid organ transplant recipients the concern lies not only in the successful clearance of the virus, but also the development of an immunologic response. This article is protected by copyright. All rights reserved completely. However, in our first patient, the detection of IgM and IgG antibodies to SARS-Cov-2 was on diagnosis day 12 (symptom onset day 19) , indicating that an immune response can be mounted rapidly under immunosuppression, with response time comparable to the observed average time of immunocompetent patients (10-13 days 21, 22 ). While detection of IgM has high false positive rate due to increased cross-reactivity between coronaviruses, thus making its diagnostic utility somewhat unclear 23 , the detection of IgG antibody is less likely to be false positive due to its higher antigen affinity. Our in-house IgG assay has a sensitivity of 100% and specificity of 97% when performed > 21 days post symptom onset, comparable to two other commercially available assays Abbott and EUROIMMUN which has specificity of 99.9% and 94.8%, and sensitivity of 93.8% and 85.4%, respectively at greater than 14 days post symptom onset. 24 The rapidity of antibody formation in our first patient may be attributed to the early discontinuation of MMF. The 26 Prolonged viral shedding has additionally been associated with male gender 25 , which may explain the increased disease severity and mortality observed in men. Women have been hypothesized to have lower susceptibility to severe COVID-19 disease due to lower viral load, less inflammation, and production of higher antibody levels that remain in circulation longer compared to men. 27 However, to what extent IgG antibodies against SARS-Cov-2 can confer protective immunity remains an area of intense research at this time. The contribution of hydroxychloroquine on our patients' clinical course is uncertain. More data is needed to help draw conclusion regarding the usefulness of hydroxychloroquine in treatment of SARS-Cov-2 in transplant recipients. In conclusion, the successful management of SARS-Cov-2 infection in kidney transplant recipients requires careful titration of immunosuppression to allow an adequate host viral immune response while maintaining adequate rejection prophylaxis. The availability of serological testing in addition to RT-PCR may be helpful in achieving this delicate balance. 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OQC, DYH: editing and review of the manuscript.