key: cord-0889702-wwqnarq0
authors: Krishna, Vinay Narasimha; Ahmad, Masood; Overton, Edgar T.; Jain, Gaurav
title: Recurrent COVID-19 in Hemodialysis: A Case Report of 2 Possible Reinfections
date: 2021-03-17
journal: Kidney Med
DOI: 10.1016/j.xkme.2021.02.004
sha: 02d8e7a61d17f344659fbcedda7f305366df3972
doc_id: 889702
cord_uid: wwqnarq0

Patients receiving in-center hemodialysis are at a high risk of infections, due to relative immunosuppression as well as to limited ability to physically distance and frequent encounters with the health care setting; this has been particularly evident during the COVID-19 pandemic. We describe two patients with suspected recurrent COVID-19 infection, each with documented clearance of virus between episodes. The duration between a negative RT-PCR for SARS-CoV-2 and symptomatic reinfection was 31 and 55 days, respectively, in the two patients. A higher risk for infection with COVID-19 and poor outcomes if infected, including a 20% or higher short term mortality risk, is worrisome in this patient population. Continued measures, such as infection prevention, community outreach and early testing may play a role in establishing protocols to protect the vulnerable dialysis population.

As the COVID-19 pandemic evolves, the possibility of reinfection among patients who have recovered from COVID-19 infection is being recognized [1] . Recent data confirm that patients with mild COVID-19 disease often fail to mount a humoral response to the virus [2] . Even those with a robust antibody response may experience rapid decline in SARS-CoV-2 specific antibodies up to undetectable levels by three months post-infection [3] . There are now several reports of reinfection in the literature [1, 4, 5] . Certain patient groups are likely at higher risk for reinfection due to poor immune response against the SARS-CoV-2 virus, including persons with immunosuppression from medications or underlying medical conditions. Dialysis centers are a high-risk environment for transmission of certain infectious diseases, including those caused by respiratory viruses, and dialysis patients may have more severe disease due to multiple co-morbid conditions. The dialysis population, particularly those receiving in-center hemodialysis, assumes particular significance due to unique exposure risks, namely: 1.

Recurrent exposure to medical personal and other patients thrice a week in the dialysis units; 2. Lower ability to mount a stronger immune response [6] ; and 3. Frequent additional confounding exposures, such as residing in nursing homes, long term acute care, and rehabilitation facilities. For example, the reported incidence of COVID-19 in dialysis patients was 3.3 % compared to 0.2% in the general population in the French National Cohort of dialysis patients [7] . There is also concern for much higher mortality in the dialysis population affected by COVID-19, with rates of 20% as compared to 4% in the general population [7, 8] [9] .

J o u r n a l P r e -p r o o f Currently, our understanding of the ability to prevent reinfection after the first episode of COVID-19 infection is limited, but certain factors have been linked to a greater vulnerability, including the strength and duration of immunity, as well as differences in the underlying immune system of certain patient populations. Although studies among primates suggest acquired immunity prevents COVID-19 recurrence, responses in humans are currently being investigated [10] . Some studies suggest declining titers of SARS-CoV-2 Immunoglobulin G (IgG) antibodies in humans in the ensuing months post infection [11] . Reports of persistently positive RT-PCR results in patients after symptom resolution has been well described, and most patients, including those with severe infection, are not infectious after a period of 20 days [12] [13] [14] [15] . The Centers of Disease Control and Prevention (CDC) has set guidance for the general population to quarantine for 10 days after the onset of symptoms based on data that ambulatory patients with COVID-19 no longer shed viable virus after day 9 of symptoms [16] . However, immunocompromised patients and those with severe illness have been demonstrated to shed for longer and should remain in quarantine for 20 days [17, 18] . Many centers are using serum IgG antibodies to assess COVID-19 status, and utilize this test as a measure of immunity, but it remains unclear if an elevated IgG antibody titer affords subsequent protection given reports of short-lived immunity and COVID-19 recurrence in the medical literature [2] . This debate assumes special importance in the clinical management of dialysis patients, given the inherent risks of re-exposure and well-described inability to mount and sustain immune responses in this population, similar to other populations with extensive comorbid conditions [9, 19] .

At the University of Alabama in Birmingham, in partnership with our dialysis provider, we established a COVID cohort unit for hemodialysis in March 2020. All incenter dialysis patients followed at our medical center who were designated either as patients under investigation or as confirmed cases of COVID-19, received hemodialysis in the cohort unit, with protocol driven testing to confirm a negative RT-PCR test at 2 weeks after onset of symptoms and once asymptomatic. For patients still positive at 2 weeks, PCR testing was repeated on a weekly basis. Patients were transferred back to the "home" dialysis facility once they tested negative. It is important to note that CDC guidance using a test-based strategy recommended two negative tests before a patient could be deemed not infectious. However our organization's ability to conduct multiple tests, like many others, was limited; accordingly, to utilize resources judiciously, we relied on a single negative test. This protocol was modified in October 2020 to 

A woman in her late 50s who resides in a nursing home with additional past medical history of hypertension, hepatitis C, and heart failure receiving maintenance incenter hemodialysis tested positive by nasal swab RT-PCR (CT of 33) after prolonged close contact with a roommate with symptomatic COVID-19. The patient was asymptomatic, and, as per protocol, underwent dialysis at the COVID-19 cohort shift at the dialysis unit and was quarantined at the nursing home. Two weeks later, as per protocol for discontinuing isolation, she underwent nasal swab RT-PCR testing on days J o u r n a l P r e -p r o o f 14 and 20 after her first positive test and, both tests were negative. Isolation and cohort dialysis precautions were discontinued at this time. Fifty five days later, the patient described myalgias, low grade fevers and a sore throat to the medical team at the nursing home; her nasal swab RT-PCR for SARS-CoV-2 was positive (CT unavailable) and work up did not reveal any alternative explanation of her symptoms. She was again placed in the COVID dialysis cohort unit and quarantined at the nursing home. She did not require hospitalization and was managed conservatively. As per the testing protocol, she underwent COVID-19 testing weekly after the first 2 weeks. At day 22 of the second episode, her RT-PCR remained positive (CT of 28); she subsequently tested negative by nasal swab RT-PCR at 36 days from the onset of symptoms and was discharged back into the general dialysis population.

We describe 2 patients with chronic kidney failure dependent on in-center hemodialysis who developed symptomatic SARS-CoV-2 infection after a prior episode of COVID-19, with resolution based on negative RT-PCR testing; both patients were asymptomatic during their first episode. Although reinfection with other human coronavirus can occur, the possibility and frequency of SARS-CoV-2 reinfection is unknown [19] . While some patients have persistent shedding of SARS-CoV-2 RNA, the current consensus suggests that most patients are not infectious 20 days after the onset of symptoms [12] [13] [14] [15] [21] [22] [23] . As of September 30, 2020, thirty-six patients had dialyzed in our COVID cohort dialysis unit. Of these, 22 patients had persistently positive RT-PCR SARS-CoV-2 RNA at 2 weeks; 10 of these 22 patients continued to be persistently positive at 3 weeks and five at 4 weeks. Although, 13.3% of our patients were J o u r n a l P r e -p r o o f persistently positive with the RT-PCR test at 4 weeks after the initial test, we cannot determine whether these tests reflect replication competent virus or not.

The duration between a negative test, and then symptomatic re-infection was 31 and 55 days respectively in the two patients we describe. The first patient developed a symptomatic second infection despite having positive COVID-19 IgG antibodies.

Seroconversion of IgM and IgG antibodies usually occur in the first week after onset of symptoms, rising till the fourth week, and by the seventh week IgM is not detected in most patients, though IgG antibodies persist longer [22] . A study that performed serial IgG testing of 34 patients with mild symptoms showed that the half-life of IgG was 36 days and the decline in antibody titers was faster than that reported for SARS CoV-1 virus [2] . The antibody data needs to be interpreted with caution as commercially available serological tests may reflect a false positive result [23] . In general, the growing body of medical literature indicates that patients with mild symptoms have limited initial humoral responses to the virus and a rapid loss of IgG antibodies with a half-life of approximately 36 days and that these lower titers may not be adequate to provide immunity [2] . One other case of a dialysis patient with suspected reinfection and antibody dependent enhanced response driving severe symptoms requiring ICU care has been described [4] .

There is uncertainty regarding the best use of the RT-PCR test, especially with well described reports of prolonged positivity and of false negative tests [18, 21, 24] . It is important to differentiate between true reinfections and persistent viral shedding. In our patients, the confirmation of a negative test result between the 2 episodes, the long duration between the 2 episodes of COVID-19, the cycle threshold values and the presence of symptoms on the onset of second viral infection, suggest that these cases are true re-infection episodes. Both patients were residents of nursing homes with a high prevalence of infection at that time exposing them to risk of COVID-19. Unavailability of whole genome sequencing and serial antibody titer data are limitations of this report.

Current CDC recommendations have since evolved to suggest testing may only be warranted in patients who develop new symptoms consistent with COVID-19 during the 3 months after the date of initial symptom onset if an alternative etiology cannot be identified.

In-center hemodialysis patients are a unique population, with multiple risk factors for severe illness with COVID-19, including repeated exposures to a health care setting.

The higher incidence of infection and mortality are concerning, and call for evidencebased interventions for infection control that help mitigate the spread of COVID-19; this includes strict in-center protocols, measures during transportation of patients and education in the community [25] . We hope to continue to learn more about COVID-19 in dialysis patients as the pandemic evolves and incorporate the knowledge to develop best practices and protocols to prevent serious illness in this group of patients. 

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