key: cord-266234-lg866rnt
authors: Adrogué, A. H.; Mithani, F.; Ibrahim, H. N.; Schwartz, M.; Gaber, L.; Hebert, S. A.; Adrogué, H. E.
title: A kidney transplant recipient with COVID-19: utility of a prognostication score
date: 2020-09-03
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2020.08.041
sha: 
doc_id: 266234
cord_uid: lg866rnt

Background Cytokine release storm (CRS) is a potentially fatal, hyperinflammatory condition common to both COVID-19 and reactive hemophagocytic histiocytosis (rHLH). We present our experience with the use of a diagnostic score, developed for rHLH, in a kidney transplant recipient hospitalized with COVID-19. Methods We applied the H-Score to risk-stratify our patient to help predict his hospital course. This study was exempt from requiring specific IRB approval, but met all the criteria required by our institution for this type of study and report including consent from the patient. Results The calculated H-Score for our patient fell below the diagnostic cut-off value for rHLH. Since rHLH is characterized by CRS, we expected him to have a milder hospital course with COVID-19. Correlating with his below cut-off H-score, the patient had a more benign than expected hospital course. Conclusion Since this is only a single case, we plan to retrospectively review a series of patients to validate our initial experience: that a low H-Score may correlate with a milder hospital course in kidney transplant patients with COVID-19.

While a growing number of case reports have been published describing infections in solid organ transplant recipients, few have explored formulas to predict the hospital course of this high risk patient group. Since outcomes have ranged from mild infection 1 to death due to acute respiratory distress syndrome (ARDS) and cytokine release storm (CRS), in the severe COVID-19 cases 2 we explored the utility of a risk stratification score which could help predict outcomes in these patients. We decided to implement the H-Score, the first validated score developed for the diagnosis of reactive hemophagocytic lymphohistiocytosis (rHLH). 3 The H-Score is calculated by adding the values assigned to factors such as immunosuppression, fever, IL-6 levels, and anemia on admission to the hospital (Table 1) . Standard admission laboratory tests and clinical features of patients suspected of COVID-19 provide the majority of variables needed to calculate the H-Score. Any data points listed on the table not available when the formula is used are assigned a score of 0. A value of 169 on the H-Score is 93% sensitive and 86% specific for the diagnosis of rHLH, accurately classifying 90% of patients studied.

Additionally, the score calculator is available for free online. 4 We describe the use of this score and how it may help risk-stratify kidney transplant patients by predicting who is at higher risk of death from COVID-19.

We present a 53 year old white male whose original kidney disease was biopsy-proven focal segmental glomerulosclerosis (FSGS) who had undergone a pre-emptive kidney transplant from his 60 year old father 13 years earlier. He was induced with J o u r n a l P r e -p r o o f thymoglobulin and maintained on mycophenolate mofetil (750 mg, twice a day), and tacrolimus (3 mg, every 12 hours). He received no steroids beyond his transplantation admission. His tacrolimus level was kept between 4-5 mcg/L. He never experienced a rejection episode or a recurrence of his original disease. His past medical history included coronary artery disease, diabetes mellitus, and hypertension. He was last seen in clinic in October 2019 and was doing well with a serum creatinine of 1.8 mg/dL, a tacrolimus level of 4 ng/mL, and a normal urine protein to creatinine ratio of 0.2.

On February 4, 2020, he developed an upper respiratory infection and sinusitis. This was treated with azithromycin and he improved. On March 8, he was diagnosed with Influenza Type B and was treated with a five day course of oseltamivir. On March 18th, he was diagnosed with another bout of sinusitis and was given amoxicillin/clavulanic acid. According to his family, on March 21st, the patient was exposed to SARS-CoV-2 during a car ride with a coworker, who became acutely ill on March 22nd and tested positive for SARS-CoV-2. On March 23rd, our patient became acutely ill with fever (100.8° Fahrenheit ), headache, dry cough, myalgias, chills, and labile blood pressure J o u r n a l P r e -p r o o f Upon admission, he was put into immediate respiratory isolation in the emergency room. His initial oxygen saturation was 98% on 2L by nasal cannula. He was found positive for SARS-CoV-2 by qualitative PCR. His CXR and CT scan were consistent with patterns previously described as COVID-19-associated pneumonia. 5 He was admitted to an intermediate care unit designated for suspected or confirmed COVID-19 patients. His maintenance immunosuppression was reduced to mycophenolate mofetil 250 mg every 12 hours while continuing his tacrolimus to a goal trough level 5-8 mcg/L.

On hospital day 2, he was started on azithromycin 500 mg followed by 250 mg daily and hydroxychloroquine 400 mg daily, which he was administered for five days. On the night of hospital day 5 (symptom day 8), he developed worsening hypoxia (oxygen saturation 82%) on 2L nasal cannula. The hypoxia improved with increase of oxygen support to 3.5L nasal cannula. With his worsening clinical condition and increasing inflammatory markers (Table 2) , his mycophenolate mofetil was held and his tacrolimus continued.

During our patient's worst clinical symptoms, his calculated H-Score was 165. This was below the 169 cut-off value used to diagnose rHLH characterized by CRS. As a result, we decided against the use of IL-6 inhibitor tocilizumab in favor of continuing supportive care. His IL-6 level later returned within the normal range consistent with minimal systemic inflammation and a better prognosis. 6 With continued supportive care including oxygen and nebulized albuterol he was successfully discharged on hospital day 12 on room air. The chronology of his vital signs and labs during his hospitalization are shown in Table 2 .

The patient continued to have close follow-up with a SARS-CoV-2 molecular test obtained after discharge. His test returned negative. While his fever and cough J o u r n a l P r e -p r o o f improved, his renal function did not. His baseline creatinine was 1.8 mg/dl and his creatinine post discharge rose to 2.3 mg/dl, which prompted a kidney allograft biopsy on 6/12/2020, two months after hospitalization. There was delay in the biopsy due to the need for two negative SARS-CoV-2 tests, spaced at least 24 hours apart, and the difficulty of performing an allograft biopsy in the setting of the pandemic. 

Based on published data for COVID-19, our patient had three of the major risk factors for increased mortality from COVID-19 infection: diabetes mellitus, coronary artery disease, and hypertension. 5, 7, 8 In an effort to predict his hospital course, we used the H-Score to risk-stratify him for treatment options. This score was previously validated in a multicenter retrospective cohort of 312 patients 3 and is the first score devoted to the diagnosis of rHLH. rHLH is a hyperinflammatory condition caused by the immune system's exaggerated response to conditions such as infection, autoimmunity, or malignancy, most commonly in the setting of chronic immunosuppression(IS). rHLH presents with fever, pancytopenia, hepatosplenomegaly and widespread histiocytic infiltration. The H-Score includes immunosuppression as a risk factor, prompting us to consider its application in the transplant population. The score is based on biologic, cytologic, and clinical variables, each with different weights ( Table 2 ).The H-Score generates the probability of rHLH. Our patient's H-Score was generated by his use of IS (18 points), fever > 103 (49 points), ferritin 4400 (35 points), AST > 30 IU/L (19 points), and triglycerides (44 points). It is important to note that while a bone marrow aspirate is part of the score, it is not needed to make the diagnosis of rHLH. Our patient did not undergo a bone marrow biopsy, so this variable was assigned a value of zero on the online calculator. The use of this score helped guide our treatment and dissuaded us J o u r n a l P r e -p r o o f 7 from using the anti-IL-6 receptor antibody mAB tocilizumab, thus conserving doses of medication for more critically ill patients.

CRS is becoming more clearly described in patients with severe cases of COVID-19. 9 CRS is an abnormal pro-inflammatory state where cytokines such as IL-6 are secreted by infected alveolar macrophages, leading to CD-4 and CD-8 positive T-cellular dysfunction. Both CRS and rHLH can manifest as ARDS and have a similarly hyperactive immune response. While APACHE II scores are useful in predicting mortality in patients in the ICU, 2 we sought a risk assessment for less critically-ill patients.

To balance worsening infection and risk of rejection, we withheld mycophenolate mofetil and increased tacrolimus. We did not use corticosteroids as these have not proven useful in treating COVID-19 lung injury. 10 Tacrolimus has been demonstrated to strongly inhibit the growth of SARS-CoV-2 in cell culture, 11 so we continued it in case it could be of benefit against SARS-CoV-2 targeting slightly higher trough levels. What is not clear is whether IS increases mortality in COVID-19 patients. Standard IS drugs are effective against naive T-cells, but do not block memory T and B cells. Tacrolimus may inhibit cytokine release initiated by the virus, 12 contributing to reduced mortality.

This kidney allograft biopsy is the only biopsy done to date in our institution. We had several discussions with our pathology group and asked that all efforts be made to see if SARS-CoV-2 viral particles were identified in the biopsy. Electron microscopy did not identify viral particles. We are in the process of validating immunohistochemistry assays to try to identify viral antigens in formalin-fixed paraffin-embedded tissue. perform autopsies on patients who die with COVID-19, thus limiting access to tissue from these patients. Respiratory-related procedures on COVID-19 infected patients are also limited from safety concerns. As we continue to learn from each patient we care for and from each other, we will all be safer from COVID-19.

In summary, the H-Score may potentially have risk-stratification value in transplant patients diagnosed with COVID-19. However, due to the extremely small sample size of this case report (n=1), it must be validated in a large series of transplant patients diagnosed with COVID-19. We plan to develop a retrospective case series to further investigate the H-Score's utility in transplant patients diagnosed with COVID-19. We report one of the first kidney biopsies in a kidney transplant recipient who had a milder case of COVID-19 but remained with acute kidney injury over two months after returning home. While his biopsy did not show SARS-CoV-2 viral particles by electron microscopic examination, it also did not show another explanation for his persistent elevation in creatinine. We acknowledge that the measurement of viral particles within the paraffin block would have been the best and most sensitive way to detect the virus.

Unfortunately, at this time, this technique is not commercially available. Additionally, we could have overlooked the virus using both light microscopy and electron microscopy due to current limitations in available technology. Our plan is to assess for viral antigens in the biopsy after validation of immunohistochemical assays with appropriate controls. 

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