Severe hyponatremia with consciousness disturbance after receiving SARS-CoV-2 mRNA vaccination

Summary There are very few reports of syndrome of inappropriate antidiuresis hormone secretion (SIADH) after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Herein, we present the case of an 84-year-old woman who developed severe hyponatremia following the second administration of the SARS-CoV-2 mRNA vaccine. The patient presented with nausea, vomiting, and headache. Laboratory tests showed a plasma sodium level of 119 mmol/L. After receiving 500 mL of intravenous saline over a 2-h period, her plasma sodium level raised to 121 mmol/L, but her symptoms persisted. Considering that rapid plasma sodium correction was necessary, we started 3% saline solution overnight. Her plasma sodium level raised to 132 mmol/L and her symptoms completely resolved. Clinical and laboratory findings were consistent with a diagnosis of SIADH. In the absence of any other triggering factors, we concluded that the condition was likely associated with the vaccination. Clinicians should be aware of the potential for hyponatremia, particularly SIADH, associated with SARS-CoV-2 mRNA vaccination. Learning points Reports of syndrome of inappropriate antidiuresis hormone secretion after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination are limited. If nausea, headache, and confusion are observed immediately after SARS-CoV-2 vaccination, clinicians should consider the presence of hyponatremia. As similar case reports to date have presented with severe hyponatremia, prompt treatment may be required.


Summary
There are very few reports of syndrome of inappropriate antidiuresis hormone secretion (SIADH) after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Herein, we present the case of an 84-year-old woman who developed severe hyponatremia following the second administration of the SARS-CoV-2 mRNA vaccine. The patient presented with nausea, vomiting, and headache. Laboratory tests showed a plasma sodium level of 119 mmol/L. After receiving 500 mL of intravenous saline over a 2-h period, her plasma sodium level raised to 121 mmol/L, but her symptoms persisted. Considering that rapid plasma sodium correction was necessary, we started 3% saline solution overnight. Her plasma sodium level raised to 132 mmol/L and her symptoms completely resolved. Clinical and laboratory findings were consistent with a diagnosis of SIADH. In the absence of any other triggering factors, we concluded that the condition was likely associated with the vaccination. Clinicians should be aware of the potential for hyponatremia, particularly SIADH, associated with SARS-CoV-2 mRNA vaccination.
Correspondence should be addressed to T Kumagai Email tamtam6546@gmail.com

Learning points
• Reports of syndrome of inappropriate antidiuresis hormone secretion after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination are limited.
• If nausea, headache, and confusion are observed immediately after SARS-CoV-2 vaccination, clinicians should consider the presence of hyponatremia.
• As similar case reports to date have presented with severe hyponatremia, prompt treatment may be required.

Background
Severe hyponatremia, defined by serum sodium level below 120 mmol/L, is a potentially lethal condition that can lead to neurological complications. While there have been several reported cases of severe hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, the relationship between vaccination and SIADH remains unclear. We present a case of severe hyponatremia following SARS-CoV-2 mRNA vaccination that improved with the administration of a 3% saline solution.

Case presentation
An 84-year-old woman presented to our department with nausea, vomiting, and headache after receiving the second dose of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine two days before. The first dose, also from Pfizer-BioNTech, was administered three weeks prior to the second dose. Her symptoms gradually worsened, leading to lethargy and impaired responsiveness to questions and commands. Physical examination revealed a body temperature of 36.8°C, blood pressure of 143/75 mmHg, pulse rate of 93 beats per minute, respiratory rate of 20 per minute, and oxygen saturation of 98% on ambient air. She was lethargic and did not respond to questions or commands well. Her mouth was slightly dry but otherwise unremarkable. Her comorbidities were hypertension and atrial fibrillation. She had no significant medical history. Her medications were candesartan 4 mg and apixaban 5 mg; no diuretics were included.

Investigation
Laboratory tests revealed a plasma sodium level of 119 mmol/L, chloride level of 84 mmol/L, and plasma osmolality of 253 mOsm/L. Urine sodium level was 69.6 mmol/L and urine osmolality was 439 mOsm/L. Results of liver biochemistry, renal function, basal cortisol, and thyroid function were within the normal range (Table 1). Chest x-ray and brain CT scan were unremarkable.

Treatment
Medical records revealed that the patient had a normal plasma sodium level in the previous year (Na: 140 mmol/L). The patient was diagnosed with acute symptomatic hyponatremia and was initiated 500 mL of intravenous saline to exclude decreased extracellular fluid volume. Subsequently, her plasma sodium level slightly increased to 121 mmol/L. At this point, her plasma AVP level was 1.1 pg/mL and her plasma osmolality was 268 mOsm/L, compatible with SIADH. As her symptoms persisted, we changed to a 3% saline solution at a rate of 20 mL/h overnight. The following day, the patient was symptom free and her plasma sodium level raised to 132 mmol/L. We changed the fluid to 0.3% NaCl (Na+: 50 mEq/L, K+: 20 mEq/L, Cl−: 50 mEq/L) to avoid osmotic demyelination syndrome because the correction rate of sodium was faster than expected. On hospital day 4, the patient was free from fluid therapy and was discharged with a plasma sodium level of 138 mmol/L (Fig. 1).

Outcome and follow-up
As there were no other triggering factors apart from vaccination, we considered that SIADH was associated with previous vaccination. Five days after discharge, her plasma sodium level was 141 mmol/L, and symptoms have not recurred to date. She continues to visit the primary care clinic.

Figure 1
Changes in plasma sodium level and infusion during the clinical course. Clinical course: The patient initially presented with plasma Na of 119 mmol/L. After receiving 500 mL saline, plasma Na was raised to 121 mmol/L. As symptoms persisted, the patient received 200 mL 3% NaCl.
The following day, the patient was symptom free and her plasma sodium level raised to 132 mmol/L. The infusion was then changed to 0.3% NaCl and terminated after 24 h of administration. The sodium level was confirmed to be normalized and the patient was discharged.

Discussion
Various adverse events have been reported after receiving SARS-CoV-2 mRNA vaccination. Reports ranged from common symptoms such as fever, headache, and fatigue to severe diseases such as thrombosis with thrombocytopenia syndrome (1). To date, several cases of SIADH associated with coronavirus disease 2019 have been reported, and the mechanism is being elucidated (2). On the other hand, reports of SIADH associated with vaccination are very few (3,4,5,6,7). We experienced the case of severe hyponatremia after receiving SARS-CoV-2 mRNA vaccination. Upon admission, while there were no overt signs of dehydration such as tachycardia or hypotension, the possibility of mild dehydration due to vomiting and poor oral intake could not be excluded and extracellular fluid was administered. Despite this, the hyponatremia and its associated symptoms did not improve with initial intravenous infusion. As the results of the laboratory examination were consistent with SIADH, we concluded that SIADH was the most likely diagnosis based on the clinical course and laboratory findings. There were no signs of inflammation, pulmonary lesions, or other factors causing SIADH, and the time course suggested that SIADH could be related to vaccination. In previous case reports similar to the present case, it has been postulated that the increase in inflammatory cytokines such as C-reactive protein (CRP) and interleukin (IL)-6 induced by vaccination stimulates antidiuretic hormone secretion (7). Furthermore, another study in mice showed that SARS-CoV-2 mRNA vaccination induces escalation of plasma IL-6 levels (8). Although IL-6 levels were not measured in this case, a slight elevation of CRP was observed. It is possible that the increase in inflammatory cytokines due to vaccination may be associated.
Another possible diagnosis in this case is mineralocorticoid-responsive hyponatremia of the elderly (MRHE), a syndrome first described by Ishikawa et al. in 1987 as a differential diagnosis of SIADH, particularly among elderly patients (9). This syndrome is characterized by age-related decreased sodium reabsorption and hyporesponsiveness of the reninangiotensin-aldosterone system. As the patient in this case was elderly and taking an angiotensin receptor blocker, she was considered to be at high risk for MRHE. However, despite the fact that MRHE typically requires discontinuation of angiotensin receptor blockers and supplementation with mineralocorticoids to improve plasma sodium levels (10), improvement was achieved in this case without such management, leading us to conclude that SIADH was the more likely diagnosis.
In this case, the patient presented with severe hyponatremia and impaired consciousness, a potentially life-threatening condition, that improved with prompt administration of 3% saline solution. Hyponatremia should be considered in the differential diagnosis of patients presenting with unexplained nausea, headache, or disorientation after vaccination, as severe hyponatremia can occur and should not be overlooked. It is possible that cases of hyponatremia following vaccination may be more common than reported, as some patients with mild symptoms may not seek medical evaluation. Clinicians should be aware of the potential for hyponatremia, particularly SIADH, associated with SARS-CoV-2 mRNA vaccination.
The primary limitation of this case report is that the cause of SIADH has only been presumptively linked to the SARS-CoV-2 mRNA vaccination and has not been definitively proven. Additionally, the exclusion of MRHE as a diagnosis is uncertain as renin and aldosterone levels were not measured. Further research is needed to clarify the pathophysiology of SIADH potentially caused by SARS-CoV-2 mRNA vaccination.