key: cord-0970157-714jbplw
authors: Goicoechea., Marian; Sánchez Cámara, Luis Alberto; Macías, Nicolás; Muñoz de Morales, Alejandra; González Rojas, Ángela; Bascuñana, Arturo; Arroyo, David; Vega, Almudena; Abad, Soraya; Verde, Eduardo; García Prieto, Ana María; Verdalles, Ursula; Barbieri, Diego; Felipe Delgado, Andrés; Carbayo, Javier; Mijaylova, Antonia; Pérez de José, Ana; Melero, Rosa; Tejedor, Alberto; Rodriguez Benitez, Patrocinio; de José, Ana Pérez; Rodriguez Ferrero, Maria Luisa; Anaya, Fernando; Rengel, Manuel; Barraca, Daniel; Luño, José; Aragoncillo, Inés
title: COVID-19: Clinical course and outcomes of 36 maintenance hemodialysis patients from a single center in Spain.
date: 2020-05-11
journal: Kidney Int
DOI: 10.1016/j.kint.2020.04.031
sha: 2b64cf2cdb8e3552b24b71341507a45af7442629
doc_id: 970157
cord_uid: 714jbplw

SARS-CoV-2-pneumonia emerged in Wuhan, China in December 2019. Unfortunately, there is lack of evidence about the optimal management of novel coronavirus disease 2019 (COVID-19), even less in patients on maintenance hemodialysis (MHD) therapy than in the general population. In this retrospective observational single-center study we analyzed the clinical course and outcomes of all MHD patients hospitalized with COVID-19 from March 12(th) to April 10(th), 2020 as confirmed by real time polymerase chain reaction. Baseline features, clinical course, laboratory data, and different therapies were compared between survivors and non-survivors to identify risk factors associated with mortality. Among the 36 patients, 11 (30.5%) died and 7 could be discharged within the observation period. Clinical and radiological evolution during the first week of admission were predictive of mortality. Among the 36 patients, 18 had worsening of their clinical status, as defined by severe hypoxia with oxygen therapy requirements greater than 4 Liters/minute and radiological worsening. Significantly 11 out of those 18 patients (61.1%) died. None of the classical cardiovascular risk factors in the general population were associated with higher mortality. However, a longer time on hemodialysis (hazard ratio 1.008(95% confidence interval 1.001-1.015) per year), increased LDH levels (1.006(1.001-1.011), and lower lymphocyte count (0.996 (0.992-1.000) one week after clinical onset were all significantly associated with higher mortality risk. Thus, the mortality among hospitalized hemodialysis patients diagnosed with COVID-19 is high. Lymphopenia and increased LDH levels were associated with poor prognosis.

The impact of this virus on patients with chronic kidney disease (CKD) is poorly understood [17] [18] [19] .

Given the advanced age and comorbidity of these patients, mortality could be higher than in general population, especially in patients on dialysis therapy. There is good quality data related to preventive and isolation measures that must be carried out in hemodialysis (HD) units to prevent the spread of the virus [17] [18] [19] , but we still do not know the specific characteristics of the disease in this population. To date, only isolated observations or small case series on prevalence and mortality rate have been reported [20] [21] [22] [23] [24] .

The objectives of this observational study were to describe the clinical manifestations of SARS-CoV-2 infection in maintenance HD (MHD) patients, identify prognostic factors and analyze the impact of different treatment schemes on mortality.

Thirty-six MHD patients out of 282 followed in two reference HD units were hospitalized with confirmed COVID-19 starting on March 12 th , 2020. Age was 71±12 years (range: 29-90) and 64% were male. Coexisting conditions are shown in Table 1 . Most patients had hypertension (97%), diabetes mellitus (64%) and dyslipidemia (67%). The most common symptoms at admission were fever (67%) and cough (44%) followed by fatigue (25%) and diarrhea (17%).

Poor oxygen saturation (<95%) breathing room air was observed in 22 out of 36 patients (61%).

All patients that had positive rRT-PCR test were hospitalized. Three cases did not have typical symptoms at the time of diagnosis of SARS-CoV-2 infection: one had an episode of intradialytic hemodynamic instability, another had an isolated fever peak during a HD session, and the third patient had a nosocomial transmission. There were three documented nosocomial transmissions.

No differences in pre-existing comorbidities or clinical presentation were observed between survivors and non-survivors. Lung abnormalities on initial chest X-ray were observed in 29 patients (80%). Peripheral ground glass opacities, the typical radiological pattern, were bilateral in 22 patients and unilateral in 7 patients. Seven out 36 patients had a normal x-ray at admission.

Twenty-seven patients (75%) received lopinavir/ritonavir for antiviral therapy.

Hydroxychloroquine was administered in all patients but one. Azithromycin was administered in 23 patients (64%), corticosteroids in 17 (47%), interferon β in 13 (36%) and tocilizumab in 2 (5%). Drugs, dosages and treatment schemes are described in Supplementary table 1.

All patients were included in MHD programs with a median time on dialysis therapy of 29 months (1 week-285 months). Nineteen patients had an arteriovenous fistula and 17 patients a permanent central venous catheter. During admission, convective volume ranged from 22 to 32 L per session.

By April 10 th , 7 patients were discharged and 11 (30.5%) patients died during hospitalization, all due to respiratory failure. The median time until discharge was 13 days after symptom onset and 11.4 days after admission, and the median time of death was 9.3 days after symptom onset and 7.2 after admission.

One week after admission, we observed mild worsening of anemia, increased serum lactate dehydrogenase (LDH) levels, and a reduction in serum total protein and albumin levels ( Table   2 ). Lymphocyte count was the lowest on day 7 after illness onset in non-survivors [0.38±0.14 vs 0.76±0.48 (x10 9 /µL), p=0.040]. In addition, on day 7, in comparison with patients who survived, non-survivors had higher LDH (490±120 vs 281±151 U/L, p= 0.008) and higher C-reactive protein serum levels (18.3±13.7 vs 8.1±8.1 mg/dL, p=0.021) (Figure 1a , 1b and 1c).

All patients developed radiological uni or bilateral pulmonary consolidation or infiltrates on xray examination during hospitalization including the 7 patients that had normal chest x-rayfeatures at admission.

Radiological improvement during the first week was observed in only 2 patients out of 36, 16 remained stable and 18 had radiological worsening. The worst x-ray scores were seen 7 days after initial onset of symptoms with 85.7% prevalence of bilateral pneumonia. Lung abnormalities were still present in 6 out of 7 patients at the time of discharge.

Peripheral oxygen saturation at room air was 94±4% at admission. During hospitalization, all patients required oxygen supplement therapy: 24 (67%) through nasal cannula (up to 4 L/min) and 12 (33%) through face mask with oxygen reservoir bag (5 -20 L/min). 12 patients (33%) required assisted mechanical ventilation but only one patient was admitted to the ICU, due to severe comorbidities in the other 11 patients that limited invasive measures. Clinical and radiological worsening during the first week of admission associated with mortality such that 11 out of 18 patients (61.1%) that worsened eventually died (logRank 10.918, p = 0.001).

Established risk factors in general population such as age, diabetes, obesity, coronary heart disease or chronic obstructive lung disease were not associated with higher mortality in this cohort ( 

The primary aim of the report is to provide descriptive information including clinical features, pneumonia [13] [14] [15] . Limited studies suggest early treatment of corticosteroids could decrease the need for mechanical ventilation in these patients, and therefore decrease mortality 15, 16 . The probable beneficial effects of azithromycin or corticosteroid treatment in patients on maintenance hemodialysis must be confirmed in clinical trials with an adequate sample size.

The mortality rate (30.5%) was much higher than that observed in the general population (1.4 -8%) 1-3 , and even higher than the 26% ICU mortality rate reported by Grasselli The mortality rate in our cohort was higher than that reported by Yiqiong et al, 30.5% vs.

16.2%, but the patients in the Chinese cohort were also younger than those in our series, albeit only minimally (66 vs. 71 years) 22 . Mortality reported in two other series from Italy are much closer to our findings, Scarpioni et 23 al found a mortality rate of 41% in Piacenza, Italy (n=41)

and Albertici et al. 24 reported a mortality rate 25% in Brescia, Italy (n=21).

In this cohort, the main parameters that predicted mortality were dialysis vintage and two laboratory findings: low lymphocyte count and high LDH levels 7 days after clinical onset, in accord with previous reports, although our analysis did not reach the level of statistical significance with regards to lymphocyte count [1] [2] [3] [4] [5] [20] [21] [22] [23] [24] . LDH has been shown to have prognostic value in Pneumocystis jirovecii pneumonia 30 , which could be also applicable to COVID-19.

Interestingly no laboratory findings at baseline were predictors of mortality. D-dimer levels,

which are shown to be associated with outcomes in general population are probably not good predictors of mortality in this population, since elevated levels have been described in MHD patients in stable conditions, and there is evidence of D-dimer clearance with dialysis therapy affecting its concentration independent of disease states. The cause of death in all our patients was the respiratory distress syndrome due to Covid-19, as it was in the Italian cohorts 23, 24 . This data contrasts with the Wuhan´s cohort where the main cause of death was a cardiovascular event 22 .

Our study has some limitations. First, due to the retrospective study character, laboratory tests such as IL-6 and serum ferritin were not done in all patients. Therefore, their role could not be evaluated in predicting in-hospital death. Second, we do not know the incidence of SARS-CoV-2 infection in our dialysis facility because rRT-PCR test could only be performed in symptomatic patients. Third, at the time of publication of these results, several patients are still hospitalized, which could be a bias in the interpretation of our findings. Fourth, the elevated mortality rates observed with the first "steroid-free" treatment schemes might be related to other confounding factors not related to treatment modifications (e.g. better clinical experience, improved logistical conditions or, perhaps, a virulence reduction over time). Lastly, interpretation of our findings might be limited by the small sample size.

In conclusion, mortality among hospitalized maintenance hemodialysis patients diagnosed with Covid-19 infection is strikingly high. Lymphopenia and increased LDH levels at day 7 after hospital admission are parameters associated with poor prognosis.

Study design: Observational, analytical, retrospective, single-center study.

Inclusion criteria: All patients on MHD therapy admitted to hospital with positive real time reverse transcriptase PCR testing for SARS-CoV-2 (rRT-PCR) from 2020 March 12th to 2020

April 10th.

Data collection: Demographic and clinical features, laboratory and radiological data, treatment schemes and mortality rates were registered.

Laboratory procedures: Methods for laboratory confirmation of SARS-CoV-2 infection have been described elsewhere 27 . Routine blood examinations included complete blood count, coagulation profile and serum biochemistry (including liver function tests, creatine kinase, LDH, total proteins and albumin). Laboratory parameters were measured at admission, one

week after clinical onset and at the discharge or before death.

Clinical and radiological evolution: Clinical improvement, stability or worsening were defined based on the need for oxygen therapy at admission, one week after clinical onset, and at discharge or before death. Radiological improvement, stability or worsening were evaluated by successive chest X-ray results collected at admission, one week after clinical onset, and at discharge or before death. Unfavorable evolution was defined as severe hypoxia with oxygen therapy requirements greater than 4 l/min and worsening or appearance of x-ray pulmonary infiltrates.

Throughout the outbreak the treatment scheme was modified according to a decision of our Hospital Commission. Patients were initially treated with lopinavir/ritonavir plus hydroxychloroquine and interferon beta. In a second phase, starting 21st March, patients were treated patients were treated with lopinavir/ritonavir plus hydroxychloroquine or azithromycin with hydroxychloroquine, and methylprednisolone was administered in cases of radiological worsening. Tocilizumab was indicated for cases with radiological and clinical worsening and IL-6 levels > 40 pg/mL in patients who meet criteria for ICU admission.

The study was approved by the local Research Ethics Committee.

During admission, all patients received three four-hour dialysis sessions per week with similar dialysis prescription: post-dilution on-line hemodiafiltration with auto-substitution control system (AutoSub Plus®, FMC, Bad Homburg-Germany) in 5008 dialysis monitors, dialyzer surface 1.8 m2 (helixone or triacetate membranes depending on history of hypersensitivity).

Dialysis prescription was individualized according to patient previous regimes and evolution during admission.

Qualitative Cox proportional hazard models were used to determine the influence of different treatments adjusted for age. All statistical analyses were performed with SPSS 21.0 software (SPSS;

Chicago, IL, USA). Statistical significance was considered as a two-sided P-value <0.05.

CONFLICT OF INTEREST STATEMENT None declared.

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