key: cord-279158-dsnniuo6
authors: Luo, Y.; Li, Y.; Dai, J.
title: Low blood sodium increases risk and severity of COVID-19: a systematic review, meta-analysis and retrospective cohort study
date: 2020-05-22
journal: nan
DOI: 10.1101/2020.05.18.20102509
sha: 
doc_id: 279158
cord_uid: dsnniuo6

Background Novel coronavirus (SARS-CoV-2) infects human lung tissue cells through angiotensin-converting enzyme-2 (ACE2), and the body sodium is an important factor for regulating the expression of ACE2. Through a systematic review, meta-analysis and retrospective cohort study, we found that the low blood sodium population may significantly increase the risk and severity of SARS-CoV-2 infection. Methods We extracted the data of serum sodium concentrations of patients with COVID-19 on admission from the articles published between Jan 1 and April 28, 2020, and analyzed the relationship between the serum sodium concentrations and the illness severity of patients. Then we used a cohort of 244 patients with COVID-19 for a retrospective analysis. Results We identified 36 studies, one of which comprised 2736 patients.The mean serum sodium concentration in patients with COVID-19 was 138.6 mmol/L, which was much lower than the median level in population (142.0). The mean serum sodium concentration in severe/critical patients (137.0) was significantly lower than those in mild and moderate patients (140.8 and 138.7, respectively). Such findings were confirmed in a retrospective cohort study, of which the mean serum sodium concentration in all patients was 137.5 mmol/L, and the significant differences were found between the mild (139.2) and moderate (137.2) patients, and the mild and severe/critical (136.6) patients. Interestingly, such changes were not obvious in the serum chlorine and potassium concentrations. Conclusions The low sodium state of patients with COVID-19 may not be the consequence of virus infection, but could be a physiological state possibly caused by living habits such as low salt diet and during aging process, which may result in ACE2 overexpression, and increase the risk and severity of COVID-19. These findings may provide a new idea for the prevention and treatment of COVID-19.

Clinical research findings have demonstrated that the infection and transmission of this virus has a wide range of susceptibility in populations, but also highlights some of the following characteristic: [1] [2] [3] [4] [5] [6] [7] the elderly and people with basic diseases and underlying conditions such as cardiovascular diseases, diabetes, chronic kidney diseases and obesity, etc., are prone to develop to be severe/critical situations after infection; the young and middle-aged people after infection usually have mild symptoms and less chance of forwarding to the severe/critical conditions; the minors are less likely to be infected and onset; there are asymptomatic virus carriers; the mortality rate is related to countries, regions and races. 8 Up to now, the exact reasons and mechanisms that cause such epidemic characteristic have not been clear, and no specific therapeutic drugs and reliable vaccines have been developed and used. Therefore, it is very important to find the key susceptible factors for the prevention and control of this deadly epidemic disease.

The gene sequence of SARS-CoV-2 is highly homologous with that of SARS-CoV. 9 , 10 Previous studies have found that such types of viruses mainly enter host cells through the receptor angiotensin-converting enzyme 2 (ACE2), 11, 12 and then replicates and releases new viruses from the host cells, resulting in virus overload in the body, and finally leading to different degree of damage to tissues and organs, especially in lung, through a series of complex pathophysiological mechanisms.

A large number of epidemiological studies have demonstrated that low salt diet plays a role in the prevention and reduction of cardiovascular and cerebrovascular diseases. [13] [14] [15] [16] [17] [18] [19] Therefore; it is widely promoted as a healthy diet habit in developed countries and some developing countries. In animal studies, it was found that the decrease of salt intake can upregulate the expression of ACE2 through the activation of the renin-angiotensin-aldosterone system (RAAS). 20, 21 Therefore, we could speculate that the long-term low salt diet or the condition of sodium insufficiency may result in the low body sodium and the overexpression of ACE2 in lower respiratory tract cells, which could increase the susceptibility and pathogenicity of SARS-CoV-2 infection. In this study, we aimed to find a key risk factor for SARS-CoV-2 epidemic by investigating the relationship between the blood sodium concentration and the severity of patients with COVID-19 through a systematic reviews, meta-analysis and retrospective cohort study.

For the systematic review and meta-analysis, median or mean values of serum sodium, chloride and potassium concentrations from each report were considered as an independent variable for statistical analysis, and an unpaired t-test was used to compare the differences between the groups related to the severity of disease. For the retrospective cohort study, one-way ANOV, followed by Tukey's multiple comparisons test, was used to compare the differences among groups or an unpaired t-test was used if necessary. To assess the association between sodium, chloride or potassium concentration, and the severity of patients with COVID-19, Spearmann's rank correlation coefficient was used. P<0.05 was defined as showing statistical significance of differences. All analyses were performed by using GraphPad Prism 7 software.

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors (JD and YL) had full access to all the data in the study and had final responsibility for the decision to submit for publication.

For the systematic review and meta-analysis, we identified 682 papers published between Jan 1 and April 28, 2020. After removing unsuitable studies (duplicates, not relevant, inappropriate reviews, inadequate information and case reports), 36 studies had adequate data that were represented in the dataset (Table S1) (Table S1 ).

We found that the serum sodium concentrations in patients with COVID-19 on admission presented the characteristic as follows (Table 1, Figure 2 ): regardless of the disease severity, the mean serum sodium concentration was 138.6 mmol/L (138.6±2.5, n=31), which was significantly lower than the median level (142.0) of normal reference range (137.0-147.0); the mean serum sodium concentration in severe/critical patients was 137.0 mmol/L (137.0±2.02, n=25), close to the lower level of normal range, and was significantly lower than those in mild (140.8±4.0, n=7) and moderate (138.7±2. 35, n=23) patients (P=0.0019 and P=0.0141, respectively), but there was no significant difference between the mild and moderate patients (P=0.0927) (Table 1, Figure 2A) ; some studies showed that the serum sodium concentrations in patients who died after admission were even lower than that in recovered patients ( Figure 2B , r=-0.4558, p=0.0005).

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 2 ) and significant lower than the mean level of control patients (138.9±2.77, n=59, p=0.0443, Figure 3D ); the mean serum sodium concentration in 60 years and older patients was 136.6 mmol/L (136.6±4.62, n=120), which was significant lower than that in patients under 60 years (138.3±3.411, n=124, P=0.0019, Table 2, Figure 3B ); there was significant difference between male and female in the mean serum sodium concentrations (136.7±4.25 and 138.3±3.82, P=0.0021, Table 2 , Figure 3C ), however, there were no difference in gender and age (<60 years and ≥60 years) in control patients (Table 2) ; the mean serum sodium concentrations in the mild, moderate and severe/critical patients were 139.2 mmol/L (139.2±2.72, n=65), 137.2 mmol/L (137.2±3.72, n=61), and 136.6 mmol/L (136.6±4.66, n=118), respectively, and the differences between the mild and moderate groups as well as the mild and severe/critical groups were significant (p=0.0330 and p=0.0003, respectively) , but there was no significant difference between the moderate and severe/ critical groups (p=0.7886) (Table 2, Figure 3D ); The serum sodium concentrations were significantly correlated to the illness severity of patients (Table 2, Figure 3E , r=-0.2462, p=0.0001).

We also analyzed the serum chloride and potassium concentrations in all patients and there were no significant differences in gender (male vs female) and age (≥ 60 vs <60 years) in the non-COVID patients ( Table 2 ). The mean serum chlorine concentrations in all, mild, moderate and severe/critical Figure 3F ). The serum chloride concentrations were significantly correlated to the severity of patients (Table 2, Figure 3G , r=-0.1753, p<0.0060). The mean serum potassium concentrations in all, All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 22, 2020. . https://doi.org/10.1101/2020.05.18.20102509 doi: medRxiv preprint mild, moderate and severe/critical patients were 4.00 mmol/L (4.00±0.56, n=244), 4.10 mmol/L (4.10±0.41, n=65), 3.96 mmol/L (3.96±0.65, n=61) and 3.97 mmol/L (3.97±0.65, n =118), respectively, and there were no statistical differences between the groups (Table 2, Figure 3H ). The serum potassium concentrations were slightly correlated to the severity of patients (Table 2, Figure 3I , r=-0.1394, p=0.0419). There was no differences in serum potassium and chlorine concentrations between the 60 years and older patients (3.99±0.59 and 101.6±4.7 mmol/L, respectively, n=120) and the patients under 60 years old (4.02±0.53 and 102.5±3.57 mmol/L, respectively, n=124) (Table 2, Figure 3B ).

In this study, we found that the patients infected by SARS-CoV-2 on admission have presented the low blood sodium levels (hyponatremia) that were related to the disease severity. The occurrence of such a condition may not be the consequence of virus infection, but should be a physiological state being existed in the body before virus infection. There were no clear reasons that could cause such a significant reduction of blood sodium concentration because diarrhea and vomiting occurred only in a small number of patients. The fever, a main symptom of patients with CIVID-19, may lead to dehydration and then should increase, but not reduce the blood sodium concentration. Therefore, we could boldly speculate that the low blood sodium population, especially the elderly and people with underlying diseases, may increase the risk and illness severity to SARS-CoV-2 infection, and one possible explanation is that the people companied with long-term hyponatremia may increase the expression of ACE2 in tissue cells, especially in lung cells, through the RAAS. 20, 21 Hyponatremia is closely related to the incidence and severity of community-acquired pneumonia and perforated acute appendicitis in children. [24] [25] [26] Clinical studies have showed that the elderly are more susceptible to SARS-CoV-2 infection and become more severe than the young and middle aged people, which may be due to the lower blood sodium levels in the elderly population. One of the reasons may be the decrease of the regulation mechanism of sodium ion in the elderly, including the decrease of renal reabsorption function for sodium ion during aging process; however, another key reason may be the result of long-term low sodium diet. For a long time, especially in the developed countries, the strategy of low sodium diet being actively implemented by physicians, medical organizations and public health agencies has played an important role in preventing and controlling hypertension and related diseases, 27,28 however, some recent evidence suggests that very low sodium intake may actually have adverse effects on human health, which may also preset a very unfavorable state in certain population against SARS-CoV-2 infection. In this study, we found that some young severe patients with CODIV-19 had serious hyponatremia, reinforcing our interpretations. In addition, the low susceptibility of SARS-CoV-2 infection to the minors suggests that the relative high levels of blood sodium may play a role in fighting against the virus infection. Whether an age-dependent change in blood sodium levels is related to increasing expression of ACE2 in human tissue cells, in particular in alveolar cells, remains to be experimentally confirmed.

The presence of high concentration of extracellular sodium ions in lower aquatic organisms, even reaching to 440 mmol/L in squid, may be a natural means for them to fight against various microbial infections besides the realization of physiological functions such as nerve action potential. The blood sodium concentration with an average level of 146.0 mmol/L in bats that can coexist with multiple coronaviruses in vivo is indeed much higher than that in human beings. 29 In addition, it was found that All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. North American bat populations, if its blood sodium level was significantly reduced during hibernation, would increase their infection to fungal and develop white nose syndrome causing widespread death of bats. 30 Such a finding may provide a physiological mechanism for an explanation of coexisting with various coronaviruses in bats, and also indicate a possibility that many asymptomatic SARS-CoV-2 carriers may hold higher blood sodium levels and have lower expression of ACE2 in lower respiratory tract cells.

Three studies from the United States have showed that the median levels of serum sodium in COVID-19 patients were approximately 136.0 mmol/L, which was much lower than an average level of approximately 138.0 mmol/L as reported in most studies from China. It remains to be clarified whether such a difference could provide an explanation for the higher mortality rate after SARS-CoV-2 infection in US as compared to that in China.

There exist two limitations in this study. The data from the systematic review and meta-analysis were mainly extracted from the observational studies in a preprint form due to an unexpected, fast and short-period SARS-CoV-2 pandemic, which would not allow the research works to be published immediately through a traditional review way. However, it could be recognized that the standardization and automatic detection methods for serum electrolytes used in the modern hospitals could ensure the reliability of extracted data from the identified studies. In addition, for the retrospective cohort analysis, although a small cohort of 59 non-COVID-19 inpatients as control have provided very useful control data, however, it would be benefit to our conclusion if a normal control population matched with age and sex, etc.; during the SARS-CoV-2 epidemic period.

In conclusion, we found that people with low serum sodium (hyponatremia) may be related to the susceptibility of SARS-CoV-2 infection and the development of severity of disease. This finding may provide an important idea to prevent the widespread prevalence of this virus or even other types of coronavirus, and to treat the patients. In the epidemic stage, it may be of great significance to properly provide enough sodium intake or maintain blood sodium at a reasonable level for the susceptible population in order to reduce the virus infection, and treat patients through therapeutic sodium supplementation (such as infusion) to prevent from the development of severe condition of disease.

JD had the idea for and designed the study. JD collected the data for systematic review and meta-analysis. YL (first author) and YL collected the data for retrospective cohort study. JD and both of YL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. JD drafted the paper, and JD and both of YL agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

We declare no competing interests.

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The copyright holder for this preprint this version posted May 22, 2020. . https://doi.org/10.1101/2020.05. 18.20102509 doi: medRxiv preprint This work was partially supported by the research funds of South-Central University for Nationalities (XTZ15014 and CZP 18008). 

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 15. Xu-wei Hong, Ze-pai Chi, Guo-yuan Liu, Hong Huang, Shun-qi Guo, Jing-ru Fan, Xian-wei Lin, Liao-zhun Qu, Rui-lie C hen, Ling-jie Wu, Liang-yu Wang, Qi-chuan Zhang, Su-wu Wu, Ze-qunPan, Hao Lin, Yu-hua Zhou, Yong-hai Zhang.

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