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Aftermath of fortnightly universal testing for severe acute respiratory corona virus‐2 infection in maintenance hemodialysis patients

Abstract Introduction Asymptomatic maintenance hemodialysis patients with acute respiratory corona virus‐2 (SARS‐COV‐2) are missed with pre‐dialysis screening without testing. The possible ideal strategy of testing each patient before each shift with reverse transcription polymerase chain reaction (RT‐PCR) is not feasible. We aimed to study the effectiveness of fortnightly screening with RT‐PCR for SARS‐CoV‐2 in curbing transmission. Methods Between July 1, 2020 and September 30, 2020, all 273 patients receiving hemodialysis were subjected to fortnightly testing for SARS‐Cov‐2 in the unit to detect asymptomatic patients. The cost and effectiveness of universal testing in preventing transmission were analyzed using susceptible‐infectious‐removed (SIR) modeling assuming R 0 of 2.2. Results Of 273 MHD patients, 55 (20.1%) found infected with SARS‐CoV‐2 over 3 months. Six (10.9%) were symptomatic, and 49 (89.1%) asymptomatic at the time of testing. Six (10.9%) asymptomatic patients develop symptoms later, and 43 (78.2%) remained asymptomatic. A total of seven (6.1%) HCWs also tested positive for the virus. Fortnightly universal testing is cost‐effective, and SIR modeling proved effective in preventing person‐to‐person transmission. Conclusions Repeated universal testing in maintenance hemodialysis patients detected 89% of asymptomatic SARS‐CoV‐2 patients over 3 months and appeared to be an effective strategy to prevent person‐to‐person transmission in the dialysis unit.

Nevertheless, the continuation of uninterrupted dialysis services is essential for the survival of this cohort of patients. A recent study revealed that many patients missed dialysis or died due to a lack of dialysis during the COVID pandemic. 4 Many professional societies have issued guidelines to prevent transmission of SARS-CoV-2 in dialysis units to protect both the patients and the dialysis staff from getting the infection. [5][6][7] In addition to strict universal droplet and contact precautions, the guidelines suggested pre-dialysis screening for the temperature and other symptoms of COVID 19. The testing for SARS-CoV-2 of nasopharyngeal specimens by RT-PCR and isolation of infected individuals became essential components for preventing nosocomial transmission.
Recent reports have shown that a significant proportion of patients on MHD that tested positive for SARS-CoV-2 had no symptoms. 8,9 Pre-dialysis screening for symptoms of COVID-19, followed by RT-PCR testing, will miss the asymptomatic MHD patients infected with the virus. The latter may spread the infection to fellow patients and staff in the unit leading to an outbreak.
Hence, the ideal strategy would be identifying and early isolation of both symptomatic and asymptomatic SARS-CoV-2 infected individuals minimizing the potential for nosocomial transmission.
However, the data of the repeated universal testing of the MHD patients and its outcomes are lacking. This study describes the outcomes of the early implementation of dialysis unit-specific infection control measures, including repeated universal testing of all MHD patients by RT-PCR.

| METHODS
The study was conducted at a tertiary care institute in the northern part of India between July 1, 2020 and September 30, 2020. The dialysis unit has 273 MHD patients and 114 health care staff, including physicians, nurses, dialysis technicians, allied health, and environmental services personnel. The institute ethics committee approved the study and was conducted as per the Declaration of Helsinki. Informed consent for the study was taken from patients and staff.

| Structural changes and testing policy in the dialysis unit with reference to COVID 19
A dialysis unit-specific protocol for preventing nosocomial transmission of SARS-CoV-2 was developed after discussions with the hospital infection control committee (Table S1). The dialysis unit has 54 dialysis stations, 48 in the main unit, and 6 in the isolation unit, designed for hepatitis and HIV positive patients. Physical partitioning of the main dialysis unit created nine isolated cubicles, each having six dialysis stations. The distance between dialysis stations was increased minimum to 1 m. Both patients and staff were allocated to fixed dialysis cubicles. Universal masking, frequent hand hygiene with 70% alcohol-based sanitizers, and physical distancing inside the dialysis unit were enforced on all patients.
Patients with symptoms were tested for the SARS-CoV-2 by nasopharyngeal swab RT-PCR. Universal droplet and contact precautions with N95 mask with face shield and surgical gown were made mandatory for all dialysis staff during dialysis. Before entering the dialysis unit, everyone was screened for forehead temperature and a questionnaire (i.e., symptoms of COVID-19, residence, or travel to COVID-19 "hot spots" and contact history with persons or family members with known COVID-19). Those failing screening or with COVID-19 suspect symptoms were not allowed to enter the dialysis unit and were sent for SARS-CoV-2 RT-PCR test. Pending test reports, patients were dialyzed in the "holding area" dedicated to the COVID suspect patients. In addition to testing those with symptoms or pre-dialysis screening suggestive of COVID-19, testing was also done following a high-risk exposure with a confirmed positive case and before any elective intervention/surgery.

| Universal testing for SARS-CoV-2 by RT-PCR
Testing all patients visiting the hospital irrespective of symptoms was made mandatory by the hospital infection control committee from May 15, 2020. The policy of fortnightly universal testing for MHD patients was adopted. The first universal testing of all MHD patients was done on July 1-3, 2020, and subsequently, universal serial testing was continued fortnightly till the end of the study. Staff was only tested if they developed any COVID-19-related symptoms and after incidental exposure without protective gear.

| Clinical characteristics of the patients
Clinical data, including age, gender, body mass index (BMI), native kidney disease, comorbidity, viral serology, and dialysis-related variables (i.e., vintage, vascular access, frequency, and modality), were noted. Exposure characteristics like public transport, use of waiting area, residence in COVID "hot spots," exposure history with a confirmed positive case, and family member positivity were noted.
Information about RT-PCR testing (i.e., indication, date, and the result of the test) and dialysis session details (i.e., dialysis station, cubicle, day, and shift) was collected prospectively. Those testing positive for SARS-CoV-2, information regarding symptoms, date of symptom onset, and recent exposure with other patients and staff were noted. Patients were classified as symptomatic if they had symptoms at the time of testing, pre-symptomatic if they did not have symptoms at the time of testing but later developed any symptoms, and asymptomatic if they did not exhibit symptoms at any time till the end of the study period. The first available laboratory parameters (e.g., white blood count, percentage Lymphocyte/ Neutrophil, C-reactive protein, ferritin, procalcitonin, fibrinogen, fibrinogen degradation products, D-Dimer, and albumin) after confirmation of SARS-CoV-2 infection were noted.

| Statistical analyses
Data were expressed as the mean (± standard deviation) or median (range) for continuous variables and number (%) for categorical variables. The Student's t-test or one-way analysis of variance (ANOVA) was used to compare continuous variables, and the Pearson chi-square test was used to compare categorical variables.
Susceptible-infectious-removed (SIR) modeling was performed to show the effectiveness of universal testing. The detailed description of SIR modeling has been shown in Zhang et al 10

| Patients related outcomes
Of 273 hemodialysis patients, 55 (20.1%) got infected with SARS-CoV-2 over 3 months ( Figure 1, Table 1). The indications of testing of the patients and health care personnel (HCPs) are shown in Table 1.
The clinical characteristics of SARS-CoV-2 positive and negative MHD patients are shown in Table 2. Out of 273, 39 (14.2%) patients were elderly (≥65 years), and 224 (82.0%) of the patients had one or more comorbidity. There was no significant difference in age, gender, ESRD cause, and comorbidities between the two groups. At the time of testing for SARS-CoV-2, only six (10.9%) patients were symptomatic, and 49 (89.1%) patients were asymptomatic for COVID-19. Of the asymptomatic patients, six (10.9%) became symptomatic during follow-up (i.e., pre-symptomatic; median, 5 days; range, 3-10 days), and 43 (78.2%) patients remained asymptomatic through their course of illness. The universal testing identified 41 (74.5%), whereas predialysis screening identified 6 (10.9%) positive patients. One patient (1.8%) tested positive on pre-operative testing done before arteriovenous fistula angioplasty and another one (1.8%) after a high-risk exposure with a symptomatic patient in the waiting area. A significantly higher proportion of positive patients had family members positive for COVID-19 (7.2% vs. 1.3%, P = 0.013) and were using a common waiting area (16.3% vs. 6.8%, P = 0.026) as compared to negative patients. However, there was no correlation with contact history with confirmed positive case (P = 0.548), or use of public transport (P = 0.663), and residence in COVID "hot spots" (P = 0.429).
Clinical and laboratory characteristics of symptomatic, presymptomatic, and asymptomatic patients are shown in Table 3.
Serum ferritin (P = 0.121) and fibrinogen (P = 0.118) levels were similar among the three groups. All the positive patients were hospitalized with a stay of 22.8 ± 9.9 days (range, 6-52 days). The entire three groups had a similar length of hospitalization (P = 0.559). Six (10.9%), three (5.4%), and three (5.4%) patients had mild, moderate, and severe COVID-19 disease, respectively. Four (7.2%, two symptomatic and two asymptomatic) patients had required mechanical ventilation during hospitalization, and three (5.4%, two symptomatic and one pre-symptomatic) had died.
F I G U R E 1 From July 1, 2020 to September 30, 2020, a total of 55 hemodialysis patients tested positive for SARS-CoV-2. Patients were tested either because of symptoms suggestive of COVID-19 (red), after failing pre-dialysis screening (green), after a high-risk exposure (violet), before an elective operative procedure (brown). All patients were also tested every fortnight as part of the universal testing protocol (blue) [Color figure can be viewed at wileyonlinelibrary.com]

| DISCUSSION
In this study, 20% of the MHD patients became infected with SARS-CoV-2 over 3 months. Initial reports from China estimated the prevalence of SARS-CoV-2 infection in hemodialysis units of 9.6% based on RT-PCR or IgM/G antibodies and 17% based on CT-based screening. 12,13 Studies from Spain, the United Kingdom, and Italy report the prevalence of SARS-CoV-2 infection as 19%, 22%, and 26%, respectively. 11,14,15 In our study, most (89%) of the SARS-CoV-2 infected patients were asymptomatic at the time of testing, and the majority (78%)  One patient tested positive after a high-risk exposure in the waiting area with another patient who was symptomatic and later tested positive; one staff tested positive after a high-risk exposure with the positive index staff. b One patient tested positive when tested before AV fistula angioplasty; one staff tested positive when tested before an elective dental procedure. c Universal testing of all patients was done by RT-PCR every fortnightly; universal testing of staff was not done.
remained asymptomatic throughout the follow-up period. Few (11%) infected patients who were initially asymptomatic later became symptomatic. Other studies also reported a high (50%-60%) prevalence of asymptomatic infection among MHD patients. 8,9 The paucity of symptoms in these patients may be attributed to immune dysfunction due to uremia or underreporting of milder symptoms. Pre-dialysis screening-based testing identified only 11% positive patients indicating either lack of typical clinical signs (i.e., fever) or atypical clinical features (i.e., fatigue), which is usually attributed/imputed to uremia.
In this study, universal testing detected the majority (74.5%) of the SARS-CoV-2 infected patients who were asymptomatic at the time of testing. Two cross-sectional studies, which tested all MHD patients following a COVID-19 outbreak in the unit, found a prevalence of SARS-CoV-2 infection of 4.6% and 8.2%, respectively. 16,17 However, universal testing was not repeated in both the studies, and follow-up testing was done only for symptomatic patients. In a skilled nursing facility experiencing a COVID-19 outbreak, weekly universal testing identified 8.4% of its inmates with SARS-CoV-2 infection. 18 We detected a significant number of asymptomatic patients with SARS-CoV-2 with universal serial testing by RT-PCR. As all the infected patients were admitted to a COVID facility, this testing strategy allowed us to isolate them early. A large proportion of infected patients can be asymptomatic, and the latter could be the source of nosocomial transmission in a hemodialysis unit. Therefore, identifying and isolating asymptomatic individuals (i.e., both patients and staff) may be prudent. It can be done by testing all with a sensitive test, preferably done at frequent intervals, for example, nasopharyngeal swabs for RT-PCR before each dialysis session. This ideal scenario is seldom possible without the cost and patient discomfort. However, it was reassuring that despite the presence of a large number of  infection of about 12%. 17 Lower incidence of staff positivity rats in our study may be due to strict droplet and contact precautions inside the dialysis unit and the policy of mandatory N95 masks throughout the hospital.
Ours is probably the first study describing the implementation and outcomes of repeated universal testing on MHD patients in a hemodialysis unit. The study showed that a significant number of asymptomatic SARS-CoV-2 infected patients could be identified on universal testing, and isolation of the latter from the dialysis unit can be implemented. However, the study remains limited because of the lack of a controlled population without universal testing.
There are several other limitations to our study. Asymptomatic

ACKNOWLEDGEMENT
We acknowledge all dialysis technicians and nurses for the helping out in carrying out the study.