Assessment of Prevalence and Clinical Features of COVID-19 in Patients Undergoing Maintenance Hemodialysis: Reports from Two Hemodialysis Centers in Iran

Introduction

In December 2019, Wuhan, Hubei Province, China, encountered many pneumonia cases of unknown origin. Deep analysis of underlying respiratory samples revealed the presence of a new virus called 2019 novel coronavirus (2019-nCoV) (1). Prodromal 2019-nCoV symptoms such as fever, dry cough, and malaise are non-specific. Laboratory findings include lymphopenia and bilateral ground-glass consolidation on chest CT scan (2). The spread of disease depends on many health and economic factors. Studies show that the Global mortality rate is approximately 3.2%. (3, 4) Studies reveal that the mortality rate was higher among men aged 50 and patients who suffered from NCDs such as hypertension, diabetes, and cardiovascular diseases. The causes of death were mostly multiple organ failure, and respiratory failure, acute respiratory distress syndrome, and cardiac arrhythmias (5). The mortality risk is higher among ESKD patients who develop COVID-19 (6). Several factors contribute to this increased risk, including reduced immune function from uremia, frequent contact with healthcare settings, and comorbidities such as hypertension and diabetes (7). Numerous studies evaluate presentations, characteristics, clinical course, and outcomes of COVID-19 in ESKD Patients on Maintenance Hemodialysis (MHD) (8, 9). A systematic review and meta-analysis by Nopsopon et al., examined the prevalence and case fatality rate (CFR) of COVID-19 in ESKD patients. The pooled prevalence of COVID-19 in ESKD patients was 3.10%, and the CFR was 18.06% (10). In brief, the clinical presentation of COVID-19 in hemodialysis patients can be different from the general population, and the risk of contracting COVID-19 and the severity of the disease appears to be higher in these patients compared to the general population. It is essential to implement strict infection control measures and provide appropriate treatment and support to mitigate the impact of COVID-19 in this vulnerable population. So, we aim to gain more awareness of this emerging infection to increase this importance.

Methods

Study area

Abadan is a city located in the southwest of Iran, specifically in the Khuzestan province. It is bordered in the East by the Bahmanshir outlet of the Karun River (the Arvand Rood), and in the West by the Arvand waterway near the Iraq-Iran border. The population of Abadan is around 350,000 people. The weather in this city varies greatly throughout the year, with temperatures ranging from 53 C in summer to - 4 C in winter. The mean temperature in Abadan is 25.5 C, with an average relative humidity of 45% and mean annual precipitation of 153.3 mm. (https://en.wikipedia.org/wiki/Abadan,_Iran)

Study design and population

In this retrospective study, we enrolled all hemodialysis patients from Shahid Beheshti and Vali-Asr Hospitals affiliated to Abadan University of Medical Sciences from March 02, 2020, to September 21, 2020 (a total of 240 patients). Finally, we included 44 patients who confirmed COVID-19 pneumonia. The inclusion criteria were: age more than 18 years old, having fever and respiratory symptoms such as cough and shortness of breath with the presence of pneumonia symptoms related to COVID-19 in CT scans of patients or the positivity of the RT-PCR test - as the main diagnostic test for Covid-19. Also, as the exclusion criteria, each COVID-19 positive test patient undergoing hemodialysis can refuse to participate in the study with their personal opinion. Likewise, patients with acute kidney disease (AKI) are excluded from the study.

In our two centers, a real-time reverse transcriptase-polymerase chain reaction test (rRT-PCR) for SARS-CoV-2 has been performed in 39 patients on samples from pharyngeal swabs, nasal swabs, and sputum. In addition, we took blood samples from all patients to check the C reaction protein (CRP). As another diagnostic criterion, we used CT scans only for patients admitted to the hospital. So, the presence of ground-glass opacities and consolidation areas were defined as the COVID-19 disease findings. We hospitalized patients who were in a more critical condition, and those who had milder symptoms and suspected them, we dialyzed in an isolated room and only recommended home quarantine.

 Data collection

All clinical information, demographic features of the patients (age, sex), vascular access(catheter, AV fistula, AV graft), history of dialysis, duration of dialysis, hospitalization days, comorbidities (diabetes mellitus, hypertension, heart failure, airway disease and malignancy), symptoms at baseline (cough, fever, diarrhea, vomiting, nausea, dyspnea, and abdominal pain), and laboratory data included C-reactive protein, hemoglobin, , platelet and WBC count, albumin ,BUN, Cr, Sodium, Potassium, calcium, phosphorus and chest radiography findings, type of medication regimen prescribed.

In order to evaluate the serum parameters of hospitalized patients, the results of the patient's routine tests are collected after admission to the hospital (first day of admission), and their value is calculated to be recorded in the questionnaire. The results of the latest tests taken in the dialysis center are used to examine the variables for patients who are in home quarantine and are not hospitalized. Also, the results of the radiological tests (By Siemens Somatom scope, made in Germany) of the hospitalized patients are also taken from the hospital system information department (HIS) to examine the CT scan images of the patient's lungs. At the end of the study, after registering in the checklist, the data will be handed over to the statistical consultant for analysis and review.

Statistical Data Analysis

This study will calculate descriptive indices such as mean and standard deviation for quantitative variables and number and percentage for qualitative variables. Also, Pearson's correlation test or its non-parametric equivalent, i.e., Spearman's correlation test, will be used to check the relationship between quantitative variables. Pearson's correlation test will be used to investigate the relationship between the prevalence of COVID-19 and the severity of the disease with laboratory factors such as White blood cell count, Neutrophil count, Lymphocyte count, Platelets, hemoglobin-serum level, albumin, Serum creatinine, Serum calcium, Serum phosphorus, Serum sodium, Serum potassium and KT/V during last month. SPSS version 20 software will be used for data analysis. A significant level in all tests will be considered less than 0.05.

Results

Basic demographic and clinical characteristics of patients

Out of 240 MHD patients, we enrolled 44 patients, comprising 26 men (59.09%) and 18 women (40.9%). The average age of the participants was 54.5±16.00 years. Of the patients, 15 (34.09%) tested positive for RT-PCR, while 5 (11.36%) were not tested. On average, the patient’s dialysis vintage was 4.5 years. A total of 41 cases (93.18%) had underlying diseases, including diabetes mellitus in 27 (61.36%), hypertension in 23 (52.27%), cardiovascular disease in 11 (25%), which included heart failure (13.63%), history of open-heart surgery (9.09%), pericardial tamponade (2.27%), history of cerebrovascular disease (4.54%), and cancer in 1 (2.27%). The most prevalent initial symptoms were fever (36.36%), shortness of breath (34.09%), cough (25%), and fatigue (13.63%). 18.18% of the patients were asymptomatic. the dialysis access of patients was catheter in 24 (54.54%), arterial venous fistula (AVF)in14 (31.81%) and 6 (13.63%) had an arteriovenous graft (AVG). Table 1 shows the demographic and clinical characteristics of the 44 patients.

Table 1. Basic demographic data and clinical parameters of participants

Laboratory parameters and chest CT-scan findings

Upon admission, Table 2 displays all laboratory and radiological data. Of the 35 patients analyzed, 80% had high C-reactive protein (CRP) levels. The mean white blood cell count ranged from 4.5-16.2 ×109/L. Approximately 22.7% of patients had leucocytes levels above the normal range (<10×10⁹/L). The mean neutrophil count was 4.38 (3.85–7.06). The mean count of lymphocytes was 0.93 ×10³/μL, the mean range of platelets was 180.2 ± 49.8 ×10³/μL, and the mean range of serum creatinine was 7.28 ± 2.8 mg/dL. Additionally, 11.36% of patients had serum albumin levels below the normal range (NL: 3.4 to 5.4 g/dL). The mean serum sodium level was 137±5 mg/dL, potassium was 4.00 mg/dL, calcium was 8 mg/dL, and phosphorus was 4.00±1 mg/dL. Furthermore, 31 patients underwent CT scans, and 28 (63.63%) had abnormal images related to COVID-19 infection. These pulmonary lesions were ground-glass opacity or patchy opacity (54.83%), consolidation (48.38%), pleural effusion (29.03%), atelectasis (4.5%), and crazy-paving (4.5%). Pulmonary involvement in 5 (12.5%) cases was bilateral, and 70.96% of these lesions were peripheral.

Table 2. Laboratory results and chest CT scan findings

Treatment and outcomes

All patients underwent MHD in an isolated room with negative pressure. 45.45% of the patients (20 people) were admitted to the COVID-19 treatment ward at the hospital, while the remaining patients received supportive treatment in isolated rooms at the dialysis center. Antibiotics, such as vancomycin (7+), ciprofloxacin (4+), ceftazidime (4+), clindamycin (3+), and meropenem (1+) were administered to patients according to infectious disease specialist consultation. For antiviral treatment, 45.4% of patients received lopinavir/Ritonavir tablets, 20.4% received hydroxychloroquine, 9.09% received oseltamivir, 6.81% received ribavirin, 6.81% received Daclatasvir/sofosbuvir, and 2.27% received interferon β-1a. Additionally, six patients (13.63%) were given corticosteroids like methylprednisolone or dexamethasone. Patient follow-up continued until September 21, 2020, during which eight (18.1%) people passed away, 5 of them (45.4%) were due to COVID-19 infections; Six patients among hospitalized died, while the remaining hospitalized patients recovered and were discharged at the end of the study. The mean duration of hospitalization was 8.1 days, and all discharged patients were in good health. Also, among the twenty hospitalized patients, two needed intensive care unit (ICU) support.

Discussion

The prevalence of COVID-19 in patients undergoing maintenance hemodialysis in different centers and regions is different (from 4.8% to 41.5%). (11-13) Flythe et al., conducted a retrospective cohort study that examined the clinical progress and outcomes of patients with pre-existing kidney disease and COVID-19 who were admitted to intensive care units (ICUs) in the United States. Patients with pre-existing maintenance dialysis-dependent kidney failure had the highest risk of in-hospital death compared to those without pre-existing CKD (8). A study conducted by Kazmi and colleagues included 43 such patients and found that 25.6% of them died. The study also found that older age, leukocytosis, lymphopenia, hypoalbuminemia, and high lactate dehydrogenase (LDH) levels were significantly associated with mortality. Hemodialysis patients experience a pro-inflammatory state and impaired immune cell function, which puts them at a higher risk of contracting COVID-19 and dying from it (between 20% and 30% in the short term) (14, 15).

Risk factors such as older age, male sex, longer duration of dialysis, diabetes mellitus (DM), and cardiovascular diseases are known to be poor prognostic (16). In general population studies, severe COVID-19 disease requiring intensive care or death is associated with leukocytosis, lymphopenia, and increased CRP. In this study, 80% of patients had high CRP and 22.7% leukocytosis. Some studies investigated that CRP levels are increased in 30- 50% of MHD patients, and it is an indicator of atherosclerosis and cardiovascular disease. So, we cannot consider it only as a reflection of ongoing COVID-19 infection and inflammation in our patients (11, 17-19). Also, Serum creatinine levels have been found to be significantly high. In this study, the mean serum Cr level was 7.00±2 mg/dL, which is higher than the normal range (20). Additionally, the mortality rate due to COVID-19 was found to be 11.36%. On the other hand, as in the present study, the amount of serum albumin in patients has decreased in previous studies. These studies show that albumin and creatinine levels significantly differed between deceased and living individuals. Also, follow-ups show that the albumin took 2-3 months to return to normal (21).

According to the HEMO study, researchers have found that a decrease in serum albumin levels by more than 0.3g/dL that lasts for six weeks indicates lower albumin synthesis. This response is linked to the activation of acute phase reaction or inflammation. The study further highlights that inflammation is the primary cause of decreased serum albumin in well-dialyzed patients, while the role of protein intake is insignificant (22).

According to the mean level of KT/V, 1.10±0.39 (0.8 – 1.24), and the mean level of albumin (2g/dL) in our patients, the significant role of inflammation due to COVID-19 infection in our patients should be taken to account. In previous studies, individuals with COVID-19 undergoing hemodialysis were reported to have lower-than-normal potassium levels (18). The current study found that the potassium level was within the normal range. Previous studies have shown mixed results regarding the difference in lymphocyte levels between surviving and deceased patients. Some studies have found no significant difference, while others have reported lower levels of lymphocytes and higher neutrophil/lymphocyte ratios in deceased patients (23, 24). Also, in our study, lymphocyte level was lower in patients under hemodialysis. In our study, the mean serum calcium level of the patients (8 mg/dL) is lower than the normal range (8.5-10 or 10.5mg/dL) (25), consistent with some previous studies. However, this value has been reported differently in different studies and is not considered a reliable factor (26-28).

The difference in the severity of the disease of COVID-19 is determined by lung function, which CT-scan measures. In the current study, 28 people out of 31 people under CT-scan had an abnormal appearance; these findings are consistent with the study of Yonglong Min et al., Pulmonary lesions in the majority of patients are shown as ground glass opacity and patchy (60%), consolidation (53.5%), or pleural effusion (32.1%). 60% of the patients had bilateral pulmonary involvement, and a large volume (78.5) of these lesions were peripheral. In the Yonglong Min et al., study, 76.2% of the lesions were bilateral, and in about half of the patients (52.3%), different lesions were seen simultaneously in the lungs. On the other hand, the patients under study are undergoing hemodialysis, and therefore, fluid overload can affect their CT-scan results, especially in patients with ground glass appearance (29, 30).

Patients were treated with antibiotic, antiviral, and corticosteroid drugs. Although there is no evidence of the effect of antibiotics on the recovery of COVID-19, antibiotics are prescribed because of co-infections that are common in the disease of COVID-19 (15). The current study, like other studies, used vancomycin, ciprofloxacin, ceftazidime, clindamycin, and meropenem in the category of antibiotics, lopinavir/ritonavir, hydroxychloroquine, and interferrone β-1a in the category of antivirals. In the category of corticosteroids, both methylprednisolone and dexamethasone have been used (12, 31, 32).

Limitations

The present study has some limitations that should be considered. For instance, the patients selected were only from a small group who agreed to undergo hemodialysis treatment, meaning those who refused treatment were not included in the study. Moreover, while the study covers patients treated in Abadan city, it may not entirely represent the entire Khuzestan population in Iran. Therefore, a study with a more extensive and more diverse population could yield more complete results. Another limitation of this study is that CT-scan information before the disease was unavailable as it was almost impossible to know who would get the disease. As a result, CT scan abnormalities cannot be directly attributed to COVID-19.

Conclusion

Our study has found that patients who are critically ill and in intensive care or those who are dying tend to have higher levels of CRP and white blood cells. Additionally, they tend to have lower levels of serum albumin than the normal range. However, it should be noted that there is still controversy surrounding the amount of calcium present in COVID-19 patients, and it cannot be used to accurately predict the disease's prognosis. It is also worth mentioning that most patients had abnormal CT scan findings, many of which were bilateral. However, as many of these patients were in fluid overload due to dialysis, the CT scan results may have been affected. Another downside that must be considered is less availability of RT-PCR testing across the nation in low-middle-income countries (LMIC) like Iran.

Authors’ contributions

M.M. Sh and T. EF and F. P and AA. A wrote the original manuscript and prepared Tables 1 and 2. R. YS collected and interpreted the patients' information. S.H and S.M and Sh. S were in charge of the management and treatment of the patients at the time of hospitalization in the centers under our study, and they performed the necessary consultations in line with the hypotheses and objectives of the study. And also, they did the design of the study. M.HF performed imaging, analysis, interpretation, and radiological consultations of patients when they were hospitalized. F.M performed the statistical analysis. All authors read and approved the final manuscript.

Acknowledgments

The authors would like to thank all the medical staff of Shahid Beheshti Hemodialysis Ward and Taleghani Hospital for all their efforts in perfectly assisting patients’ medical management.

Conflicts of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research project has been financially supported by the Abadan University of Medical Sciences (Grant No.1399-U856). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and was ultimately responsible for deciding to submit it for publication.

Ethics statement

The ethical considerations of this study are based on the Declaration of Helsinki. All subjects voluntarily agreed to participate in this research project. A signed written informed consent was obtained from all participants. The study protocol has received approval from the Abadan University of Medical Sciences Ethical Committee (IR.ABADANUMS.REC.1399.100).

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Data availability

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AKI              Acute kidney disease

CRP           C-reactive protein

DM              Diabetes mellitus

ESKD          End-Stage Kidney Disease

ICU             Intensive care unit

LDH            High lactate dehydrogenase

LMIC           Low-middle-income countries

rRT-PCR     Reverse transcriptase polymerase chain reaction