key: cord-1049325-rpyoeg9n
authors: Alberici, Federico; Delbarba, Elisa; Manenti, Chiara; Econimo, Laura; Valerio, Francesca; Pola, Alessandra; Maffei, Camilla; Possenti, Stefano; Lucca, Bernardo; Cortinovis, Roberta; Terlizzi, Vincenzo; Zappa, Mattia; Saccà, Chiara; Pezzini, Elena; Calcaterra, Eleonora; Piarulli, Paola; Guerini, Alice; Boni, Francesca; Gallico, Agnese; Mucchetti, Alberto; Affatato, Stefania; Bove, Sergio; Bracchi, Martina; Costantino, Ester Maria; Zubani, Roberto; Camerini, Corrado; Gaggia, Paola; Movilli, Ezio; Bossini, Nicola; Gaggiotti, Mario; Scolari, Francesco
title: A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection.
date: 2020-05-08
journal: Kidney Int
DOI: 10.1016/j.kint.2020.04.030
sha: 849007b889c400765a793516e5fc97a40b51481b
doc_id: 1049325
cord_uid: rpyoeg9n

Abstract The SARS-CoV-2 epidemic is pressuring health care systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience of four dialysis centers of the Brescia Renal COVID task force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70) and dyspnea at presentation were associated with the risk of developing ARDS whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis.

The impact of the SARS-CoV-2 epidemic in subgroups of patients has yet to be determined. In

Brescia. Italy we have developed a standardized protocol when approaching patients on maintenance haemodialysis (MHD) and kidney transplant recipients, respectively (1) . Reports would suggest a more severe disease course in patients with CKD(2) although outcomes in MHD patients is still unclear with earlier small case series suggesting a milder course (3) .

Management of MHD patients in the context of an epidemic poses several challenges: this group of patients usually requires caregiver assistance, transportation from home to the dialysis units as well as spending periods of time in crowded waiting areas before and after treatment (4) . Moreover, MHD patients are usually old and affected by several comorbidities that are known to be associated with high risk of poor outcomes in patients with COVID-19.

The Lombardy region in general and Brescia in particular have been severely hit by the SARS-CoV-2 epidemic and this has generated several logistical and clinical challenges for the dialysis units of the "Brescia Renal COVID task force". Here, we describe the characteristics and outcomes of the MHD patients affected by COVID-19 and followed in four dialysis units that are a part of the "Brescia Renal COVID task force".

Ninety-four patients tested positive for RT-PCR within the overall population of 643 (15%) ( Table 1) .While 3 centers limited the viral testing only to patients showing symptoms suggestive for SARS-CoV-2 infection, the center of Brescia performed RT-PCR in its entire MHD population (patients with symptoms and patients without symptoms). The positivity rates were not substantially different between these approaches (14% versus 16%, respectively). Patients testing positive were either triaged to the hospital or back to their dialysis facility based on the clinical judgement of the caring physician according mainly to the severity of the symptoms shown. The main clinical characteristics of the overall MHD population with SARS-CoV2 infection and the subgroups managed as outpatient or in hospital are shown in Table 2 . The median time from symptoms onset to positive RT-PCR was 2 days (IQR 0-3). Patients that needed to be admitted showed a higher proportion of symptoms compared to the ones not requiring hospitalisation (46% vs 14%).

Thirty-seven out of 94 (39%) patients were managed as outpatients, for a median follow-up of 8 days (IQR 6-11). Among the group managed as outpatient, 18/37 (49%) were asymptomatic at disease diagnosis, while the remaining patients experienced mild symptoms. Among the asymptomatic patients, in 13/18 (72%) the chest x-ray was negative, while unilateral and bilateral infiltrates were detected respectively in 3/18 (17%) and 2/18 (11%). Detailed patient characteristics are shown in Table 2 . Antiviral therapy and/or hydroxychloroquine were employed in 28/37 (76%) patients for a median duration of 4 days (IQR 3-8). Antibiotics were employed in 25/37 (68%): macrolides in 56%, cephalosporins in 48%, carbapenems in 8%, glycopeptides in 8%, aminoglycosides in 8%, beta-lactams in 4% and fluoroquinolones in 4%. 4/37 (11%) received prophylactic heparin and 3/37 (8%) were on ACEi or ARBs.

One patient had to withdraw hydroxychloroquine due to vomiting. No other adverse event due to the treatment was documented in this patient group.

During follow-up, 7/37 (19%) patients experienced a new onset/a worsening of the interstitial pneumonia, 3/37 (8%) died, 2/37 (5%) developed ARDS and 2/37 (5%) had to be hospitalized. In addition, 5/37 patients (14%) developed cough, 5/37 (14%) myalgia, 4/37 (11%) fever and 3/37 (8%) gastrointestinal symptoms during follow up.

Patients who were asymptomatic at baseline, compared to the symptomatic ones, were less likely to develop ARDS (0/18 vs 2/19), to develop a new onset or a worsening of pneumonia (1/18 vs 6/19) and less likely to die (0/18 vs 3/19).

Fifty-seven patients were admitted after a median time from symptom onset and from positive RT-PCR test results of 4 (IQR 1-7) and 2 days (IQR 1-3), respectively. Median followup was 8 days (IQR 4. [8] [9] [10] [11] [12] [13] [14] [15] . Detailed characteristics of this population are shown in Table 2 .

Antiviral therapy was employed in 45/57 (79%) with 13/45 patients (29%) experiencing adverse events: 7 diarrhoea, 4 increase in liver enzymes, 3 prolongation of QTc interval, 2 atrial fibrillation, 1 gastrointestinal bleeding, 1 coagulation alterations and 1 skin rash. The median duration of lopinavir/ritonavir or darunavir + ritonavir and hydroxychloroquine treatments were 7 days (IQR 5-12) and 5 days (IQR 3-7), respectively. Antibiotics were administered in 55/57 patients: macrolides in 40%, cephalosporins in 49%, carbapenems in 15%, glycopeptides in 20%, aminoglycosides in 7%, beta-lactams in 25% and fluoroquinolones in 24%. Thirty one out of 57 (54%) received prophylactic heparin and 11 out of 57 (19%) were on ACEi or ARBs.

Forty-five out of 57 patients (79%) developed ARDS; 24/57 (42%) died after a median of 6 days (IQR 3.8-9.5) from admission and a median of 9 days (IQR 7-10) from onset of symptoms. Eleven out of 57 (19%) patients were discharged after a median of 8 days (IQR 6.5-13) from admission and 15 days (IQR 12.5-17.5) from onset of symptoms. Among the patients who died, the cause of death was respiratory failure secondary to ARDS in 15/24 (63%), bacterial sepsis in 4/9 and sudden death of unknown origin in 5/9.

Serial chest x-rays were performed in 27/57 (47%) patients; among those patients 20/27 (74%) showed chest x-ray worsening compared to baseline.

Dexamethasone was administered to 18/57 (32%) patients due to respiratory deterioration; 2 out of 18 of these patients also received tocilizumab. In this group, 5 out of 18 patients (28%) died. Out of 9 patients whose response to glucocorticoids was assessable at the moment of data analyses, 2/9 showed stabilisation of the pO2/PIF ratio or chest x-ray improvement, while the remaining patients did not improve. Regarding the two tocilizumab treated patients, response was assessable only in one with no improvements in chest x-ray or lung function.

In univariate analyses, cardiac failure (OR 6.22 (95%CI 1.85-28.6), p=0.007), ischemic heart disease (OR 5.61 (95%CI 1.65-25.9), p=0.01), fever at disease diagnosis (18.2 (95%CI 5.6-82.44), p=0.000013), shortness of breath at disease diagnosis (18.17 (95%CI 4.8-119.5), p=0.0002), myalgia or fatigue at disease diagnosis (OR 5.6 (95%CI 1.65-25.9), p=0.01), infiltrates at the baseline chest X-ray (OR 4.4 (95%CI 1.67-13), p=0.004), higher AST levels (OR 2.81 (95% 1.08-7.6), p=0.04) and higher CRP levels (OR 4.68 (95%CI 1.83-12.7), p=0.002) were associated with the risk of developing ARDS. Ischemic heart disease (OR 3.11 (95%CI 1.02-9.6), p=0.05), fever at disease diagnosis (OR 18.7 (95%CI 3.62-343), p=0.005), cough at disease diagnosis (OR 3.5 (95%CI 1.28-9.7), p=0.01), shortness of breath at disease diagnosis (OR 5.3 (95%CI 2-15), p=0.001) and higher CRP at disease diagnosis (OR 6 (95%CI 2.1-19), p=0.001) were associated with the risk of death (Table 3) .

Two multivariate analyses were performed, one for each outcome of interest (ARDS and death). In the first model, the characteristics found to be associated with the risk of ARDS were history of ischemic heart disease (OR 7.5 (95%CI 1.6-36.2), p=0.04), fever at disease diagnosis (OR 17 (95%CI 4.5-64), p=0.0009), age at symptoms onset (OR 1.1 (95%CI 1-1.15), p=0.03) and shortness of breath at disease onset (OR 20, (95%CI 3.6-79.3), p=0.004). In the second model, the characteristics associated with the risk of death were fever at disease diagnosis (OR 18.7 (95%CI 2.4-146), p=0.02), cough at disease diagnosis (OR 4 (95%CI 1.02-17.6), p=0.05) and higher serum CRP at disease diagnosis (OR 5.6 (95%CI 1.6-23.5), p=0.01) ( Table 4 ).

SARS-CoV-2 infection is challenging health care systems around the world. The predictions regarding Covid-19 associated mortality are changing as new information is gathered although comorbidities such as cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension and cancer are consistently associated with worse prognosis(5, 6). We have reported recently that hospitalized kidney transplant recipients tended to have a poor prognosis with a mortality rate of 25% (7), while another group observed that when such patients did not require hospital admission they experienced a more favourable outcome (8) .

The prognosis of haemodialysis patients with COVID-19 is still unclear and more data are desperately needed. In our cohort including four centers of the "Brescia Renal COVID task force", we have identified 94 patients with SARS-CoV-2 infection. As expected, infected MHD patients not requiring hospital admission experienced a better disease course compared to patients who required hospitalisation. Nevertheless, 5% of the patients treated in the outpatient setting subsequently required admission. There was also substantially less use of antiviral medications in patients managed in the outpatient setting although the proportion of patients receiving hydroxychloroquine was similar between the two groups. This should be taken into account when interpreting the results since it was the managing physicians decision to start medications. While the lower rate of antiviral use was associated with lower incidence of adverse events in the outpatient group, whether this may be the result of less frequent antiviral use rather than a better overall disease profile needs to be clarified. Finally, in our cohort, only a few patients were treated with glucocorticoids and tocilizumab, which does not allow us to draw any conclusions on the potential efficacy of these treatments.

The disease severity of the SARS-CoV-2 infection is highly variable and a significant proportion of infected patients appear to experience only mild disease or no symptoms at all in our cohort. Notably, the overall case fatality rate of our population was higher compared to the general Italian and Chinese population (28% vs 7.2% vs 2.3%) (9, 10) . The finding of worse outcome of hemodialysis patients with SARS-CoV-2 infection may be explained by high prevalence of comorbidities as well as other risk factors related to end stage renal disease per se (2).

Our study also provides some preliminary information on factors associated with the risk of ARDS and death. The presence of CVD and severe inflammation were predictive of worse outcomes. Notably, these factors are not specific for the haemodialysis population since cardiac comorbidities, fever and older age have been already described as prognostic factors in the general population with SARS-CoV-2 infection (11, 12) .

Our results should be interpreted with some caution. Median follow-up was 8 days, center bias cannot be ruled out, symptoms severity was not collected, and the relatively small sample size of our cohort may have impacted on the generalizability of our analyses. The strengths of our study include a shared management approach characterized by relative data homogeneity and detailed data collection made possible by an unprecedented commitment of the members of our task force.

In conclusion, SARS-CoV-2 infection in maintenance haemodialysis patients presents with a wide range of symptoms. The data represented herein suggest a strikingly higher mortality rate compared to the general population although the risk factors for disease severity are similar. Further data collection and follow up is necessary to have a complete picture of the spectrum of COVID-19 in maintenance dialysis patients. Considering the well-known potential of lopinavir/ritonavir and hydroxychloroquine for increasing QTc, a baseline EKG was performed before therapy commencement and, afterwards, every 2-3 days; in case of QTc prolongation a reduction or discontinuation of treatment was considered in a case-by-case manner.

Acute respiratory distress syndrome (ARDS) and cardiac failure have been defined as reported by others (13, 14) . The decision whether or not admitting a patient was taken by the attending physician according to symptoms severity or signs of respiratory failure.

Ethical approval for this study was obtained according to Italian regulations.

Statistical analysis was performed using R software (https://www.r-project.org) and GraphPad Prism 7. Results are expressed as the number and percentage for categorical variables and the median (interquartile range [IQR]) for continuous variables.

Changes in variables were compared by a related sample Wilcoxon test, proportions of patients were compared using a chi-squared or Fisher test, as appropriate.

Univariate and multiple logistic regression models were used to assess the ability of some predefined clinical characteristics to predict the risk of ARDS or death. All the statistically significant predictors at univariate analysis were entered in a multivariate model (15) . Finally, the best multivariate model was identified by adopting a stepwise selection approach. Odds ratios (ORs) and their 95% CIs were estimated from logistic regression analysis. P values less than 0.05 (2-tailed) were considered significant. 

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