The results of the current study suggest that the evolution of both hypovolemic or euvolemic hyponatremia during the hospitalization of the patients with COVID-19 pneumonia is linked to their inflammatory status. Indeed, the decrement of IM levels during hospitalization was accompanied by an increase in SNa and a reduction in the rate of hyponatremia at the same time. This permits us, therefore, hypothesize that the presence of hyponatremia in COVID-19 patients, either hypovolemic or euvolemic, could depend of the inflammation generated in these patients.
As in pneumonia caused by other infections(11,12), hyponatremia is also a risk factor for a poor hospital prognosis in patients with COVID-19 pneumonia(4,5,9,13). In fact, a lower SNa at admission have been related with a higher risk for mortality(5). The current study found similar results. Although most of the patients in our cohort had mild hyponatremia, with no patient with SNa below 125 mmol/L, we observed that per each increment in mmol/L of SNa at admission, the risk of mortality reduced by a 57%. However, the mechanisms behind the impact of the decreased SNa levels or hyponatremia on hospital mortality are totally elucidated.
A common discussion is about whether hyponatremia, especially when mild, is a direct cause for increased mortality risk or whether it is only another “indicator” of a worse clinical situation. Based on our results, we hypothesize that the latter would be the most probable setting, and some findings of our study support that idea. First, we observed a parallel decrement of the rate of hyponatremia as IM levels were decreasing. This suggests that an inflammatory status could predispose to the development of hyponatremia and that the degree of hyponatremia could be a reflection of the degree of the inflammation. Thus, when inflammation decreases, a recovering in the water/sodium balance would be expected, as did in our cohort. Inflammatory pathways via different cytokines, such as tumoral-necrosis factor-α, IL-1 or IL6, are involved in a non-osmotic release of arginine-vasopressin(14). In fact, it has been reported that the risk of hyponatremia is higher in the setting of an acute inflammatory phase, especially when patients are receiving hypotonic fluids(15,16), indicating an inadequate antidiuresis. Beukhof et al. in a case-control study of patients with hyponatremia, observed that those who developed hyponatremia had a coincident increase in C-reactive protein levels(16). Likewise, IL-6, a usual IM, has been strongly corelated with arginine-vasopressin concentrations in blood, and directly related with the development of SIADH, both in children (17) and adults (18,19). Recently, Berni et al. (9) found an inverse moderate correlation between IL-6 levels and SNa in 29 COVID-19 patients. Furthermore, they observed a significative increment of SNa when hyponatremic patients with elevated IL-6 levels were treated with tocilizumab (humanized monoclonal antibody against the IL-6 receptor). Second, we found that patients who remained hyponatremic during hospitalization were not at high risk of death. This is in contrast with the expected if mild hyponatremia could induce a direct damage and therefore increases the mortality risk. And third, the early death of the patients, with only 3/7 of them with hyponatremic at the 2nd -3th hospitalization day, suggests that the clinical severity was principally caused by COVID-19 pneumonia itself rather than hyponatremia. Therefore, in agreement with Berni et al., we suspect that hyponatremia is another sign of a major severity in COVID-19 patients, which is depending of the inflammatory involvement affecting respiratory function. In fact, higher respiratory rates(4,5)and lower oxygen levels(4) have been reports as more frequent in hyponatremic than eunatremic COVID-19 patients.
However, we cannot deny that even mild hyponatremia could impair the metabolic cellular response to inflammation in different tissues, and therefore, perpetuate the damage already stablished by the inflammation itself. Thus, the role of hyponatremia seems to be more complex. In fact, in the HOPE-COVID-19 study(5) -with a predominantly mild hyponatremia cohort- hyponatremia was also associated with a higher risk for sepsis. Furthermore, in that study the combination of sepsis with hyponatremia increased the mortality risk of these patients(5). Sepsis, as an inflammatory status, can cause Na + and Ca + + channel dysfunction (20). Hyponatremia itself can also alter the normal function of Na + and Ca + + channels (21,22).A combination of both factors could thus harm the mechanisms of voltage-dependent cellular conduction and therefore impair several cellular functions, which can lead to organ/tissue dysfunction (e.g., in the kidney(23)) and consequently induce multi-organ failure. Therefore, we encourage physicians to properly correct hyponatremia in all clinical situations.
One would expected that SIADH, an euvolemic hyponatremia is the main cause of hyponatremia in COVID-19 patients, as some authors have proposed (8). Furthermore, it would be in accordance with the commented above. However, we find a similar rate of hypovolemic and euvolemic hyponatremia. Unfortunately, our study lacked the power to determine specific etiologies of hyponatremia, since nor adrenal axis nor the withdrawal of SIADH-related drugs, nor urine ions studies, nor data of clinical losses of volemia were fully evaluated and registered in the clinical records of our cohort. Nevertheless, the fact that the IM levels were similar between hypovolemic and euvolemic, both at admission and at 7th -10th hospitalization day, indicates that in both types of hyponatremia, the inflammatory status played a similar role. Therefore, although other factors may be involved in the development of hyponatremia depending on whether it is hypovolemic or euvolemic, it is a fact, in our opinion, that the inflammatory status of patients with COVID-19 pneumonia would favor its presence.
A weakness of the study is the size of the series. Other is the lack of a more detailed information about hospital treatment of the patients. However, at that moment of the pandemic, different protocols were used in different hospital, so these data would have been heterogeneous and biased. Nevertheless, the current data was enough to permit the main objective to be evaluated. Unfortunately, IL-6 was not measured in all patients, which decreased the statistical potency to assay this variable. Likewise, no hypervolemic hyponatremia was encountered in our registry, therefore whether hypervolemic hyponatremia has the same inflammatory characteristics than hypovolemic or euvolemic hyponatremia remains unknown. The main strength is that this study highlights the role of hyponatremia as a clinical marker of severity and inflammation in COVID-19 patients, which could help physicians stratify patient risk in order to take clinical decisions.
In conclusion, in our COVID-19 series, the evolution of admission hyponatremia during the hospitalization coincided with the improvement of IM levels. This evolution was similar in both hypovolemic and euvolemic hyponatremia. Therefore, the implication of the inflammatory status on the development of hyponatremia in COVID-19 patients is proposed.