A case report of severe hyponatremia secondary to Paxlovid‐induced SIADH

Key Clinical Message

Nirmatrelvir‐ritonavir (Paxlovid) is a brand‐new oral antiviral medication for treating mild to severe COVID‐19. The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for ritonavir‐nirmatrelvir on December 22, 2021, to treat COVID‐19. We describe a case of mild COVID‐19 infection who developed severe hyponatremia following the administration of Paxlovid. Clinical and laboratory evaluations suggest SIADH, likely secondary to Paxlovid. The potential side effects of this medication still require further study.

Summary of the case findings.

1. INTRODUCTION

Hyponatremia is the most common electrolyte disturbance encountered in clinical practice, and its severity depends on the blood sodium concentration and the onset of the condition. ¹ Its incidence among hospitalized patients ranges from 15% to 30%, ² while ambulatory‐based‐care presentations represent 21% of cases. ³ Patients over 60 years are at higher risk of hyponatremia, with a prevalence of 18% among nursing home residents. ⁴ Mild hyponatremia (serum [Na⁺] 130–135 mmol/L) is usually asymptomatic; however, it may cause disturbed mental status, gait instability, and increased risk of falls. ⁵ Hyponatremia is considered a common cause of fall‐related fractures in elderlies (8.7%) with no osteoporosis. ⁶ Acute hyponatremia (<48 h) usually has more devastating consequences due to cerebral edema and life‐threatening central nervous system complications like seizures. ⁷ Syndrome of inappropriate ADH secretion (SIADH) is the most common underlying cause of hyponatremia, accounting for 46% of hyponatremic cases. ⁸ SIADH represents a diagnostic challenge for physicians as only less than 50% of patients show the common lab values for the diagnosis. ⁹ Diagnosis depends on the clinical manifestation of the euvolemic patient, the lab values of low plasma osmolality and high urine concentration, and the exclusion of other causes of hyponatremia. ⁸ It has been previously linked to many diseases, including malignancies, and various classes of drugs such as (antidepressants, anticonvulsants, antipsychotic agents, cytotoxic agents, and pain medications). ¹⁰

Nirmatrelvir‐ritonavir is a novel oral antiviral drug that has been FDA‐approved for emergency use in treating mild‐to‐moderate COVID‐19 in 2021. ¹¹ It showed high efficacy in preventing progression to the severe form of the disease, with an 89% lower risk than the placebo. ¹² No serious adverse events were associated with the drug, except for mild effects such as dysgeusia, diarrhea, hypertension, and myalgia. ¹²

This report presents a case of a 74‐year‐old female diagnosed with SIADH 7 days after taking nirmatrelvir‐ritonavir for a mild–moderate case of COVID‐19.

2. CASE PRESENTATION

A 74‐year‐old female with a past medical history of hypertension, hyperlipidemia, and essential thrombocytosis presented to the emergency department on April 27, 2022, with altered mental status for 1 day. It was preceded by dizziness and gait instability on April 25, 2022, and was not associated with focal weakness, numbness, loss of consciousness, slurred speech, or head trauma. On April 24, 2022, she reported severe nausea associated with nonbloody vomiting twice, not associated with abdominal pain or change in bowel habits, and she could not tolerate any oral intake. She had been diagnosed with a COVID‐19 infection on April 17, 2022, when she had a fever, nasal congestion, sore throat, and cough without shortness of breath. She has had three doses of the Pfizer vaccine, the most recent of which was 8 months ago. She was seen by her medical provider on April 21, 2022, and her symptoms were consistent with mild to moderate COVID‐19 infection. Because of her age and comorbidities, she was prescribed nirmatrelvir‐ritonavir (Paxlovid) for 5 days (see Table 2 for the sequence of symptoms). She had no allergies and was on the medication list, as in Figure 1. There was no recent medication except Paxlovid. There was no family history of serious illnesses. On room air, she had a temperature of 37°C, a blood pressure of 120/85, a respiratory rate of 15, and an oxygen saturation of 99. She was sluggish and focused solely on her surroundings. Her mucosa was wet, and the results of her chest, heart, and abdominal examinations were all within normal limits. The cranial nerves, muscle tone, power, and sensations were normal on both sides.

TABLE 2.

Chronological order of the symptoms.

Date	Symptoms
4/17/2022	Fever, nasal congestion, sore throat and cough (COVID‐19)
4/21/2022	Evaluated by her provider and Paxlovid was prescribed
4/24/2022	Nausea and vomiting
4/25/2022	Dizziness and gait instability
4/27/2022	Confusion and presented to the ED

FIGURE 1.

Graph of the hyponatremia correction rate.

There was no intracerebral hemorrhage or infarction on the CT scan of the head. Laboratories revealed a serum sodium level was 107 mmol/, and the remainder is listed in Table 1. An X‐ray of the chest revealed bilateral basal atelectasis. The urine sodium, urine osmolality, and serum osmolality were 53, 400, and 229, respectively. Our first impression was that the patient's mental state had been disturbed due to acute hyponatremia (Table 3). A loading dose of 100 mL of 3% normal saline was administered, followed by a 20 mL/h infusion. In cases of severe hyponatremia, our hospital protocol is to administer 2 mcg of desmopressin every 8 h for 48 h, with salt levels monitored every 2 h. The patient appeared to be euvolemic during the examination, and the history did not indicate dehydration. SIADH was identified based on the volume status, recent COVID‐19 infection, recent Paxlovid prescription, and excessive urine salt and osmolality. Paxlovid was stopped, and the patient was admitted to the intensive care unit for close monitoring. The graph below shows that the sodium was gradually rectified (Figure 1). A one‐liter water limit was implemented, and once the sodium level reached 124, hypertonic saline was stopped, and sodium chloride pills of 2 g were administered thrice daily.

TABLE 1.

Showing the medication list.

Medication	Dose
Amlodipine	10 mg daily
Aspirin	81 mg daily
Calcium carbonate	500 mg three times daily
Vitamin D3	1000 units daily
Esomeprazole	40 mg daily
Simvastatin	10 mg daily
Hydroxyurea	2000 mg daily
Losartan	100 mg daily

TABLE 3.

Revealed the admission blood test results.

WBC	7.2
HGB	9.9
MCV	104
Platelet count	571
Sodium	107
Potassium	3.8
Chloride	73
CO2	25
Anion gap	9
BUN	12
Creatinine	0.52
Glucose	135
Calcium	8.1
Total protein	6.1
Albumin	4.0
Bili, total	0.8
AST	47
ALT	22
TSH	1.5
Cortisol	19.7 μg/dL

3. DISCUSSION

In our report, we describe the case of a 74‐year‐old woman who, 7 days after receiving nirmatrelvir‐ritonavir (Paxlovid) for COVID‐19 infection, experienced symptoms of hyponatremia, including altered mental status, vertigo, and gait instability. She had two mild episodes of vomiting before hospital admission, which were not associated with significant fluid or electrolyte loss. We concluded that the patient had euvolemic hyponatremia because the clinical examination showed no symptoms of fluid excess or dehydration. Euvolemic hyponatremia has a variety of differential diagnoses, including SIADH, hypoadrenalism, and hypothyroidism. ⁸ We ruled out hypoadrenalism and hypothyroidism because serum readings indicated that cortisol and TSH levels were normal. Lab values were also consistent with SIADH diagnosis criteria, including high urine osmolality, high sodium in the urine, and low plasma osmolality. ¹³ We linked SIADH to nirmatrelvir‐ritonavir, as symptoms started 3 days after initiating the drug. SIADH has been linked to several medications, such as antidepressants, anticonvulsants, antipsychotic agents, cytotoxic agents, and pain medications ¹⁰ ; however, the patient was not taking any drug of these classes. Although there is documented evidence that esomeprazole may cause hyponatremia due to SIADH, it is unlikely to be the cause in our patients because it is most likely to occur after initiating the drug while our patient has been taking it for almost a year. ¹⁴ COVID‐19 infection was associated with hyponatremia due to SIADH in a recent case series by Yousaf et al. ¹⁵ the possible mechanism for this association is increased secretion of ADH in response to cytokine storm and decreased intravascular osmolality. Hyponatremia is a prognostic factor in COVID‐19 infection, as it increases mortality risk and sepsis risk in hospitalized patients with COVID‐19. ¹⁶ However, we linked hyponatremia in our patient to nirmatrelvir‐ritonavir, not COVID‐19 infection, as the hyponatremia improved after stopping the drug. No previous studies reported any association between nirmatrelvir‐ritonavir and hyponatremia due to SIADH. However, a case series recently published on the possibility of critical use of the HIV drug (lopinavir/ritonavir) reported severe hyponatremia in one of the included patients. ¹⁷ The ritonavir added to both drugs may be incriminated, and this association needs further investigation. There is a scarcity of data on nirmatrelvir‐ritonavir, as it is a novel drug. It is associated with multiple drug–drug interactions as ritonavir is a potent cytochrome P450 (CYP) 3A4 inhibitor, which implies a proper review of patients' drug history, especially in the older population using multiple drugs. ¹¹ The possible effect of this drug on electrolyte disturbance is not well understood and needs further investigation.

4. CONCLUSION

Nirmatrelvir‐ritonavir has the potential to cause severe hyponatremia and SIADH. Medication should be discontinued immediately in case of hyponatremia. Further research on this adverse occurrence is required in future studies, particularly in the elderly population.

AUTHOR CONTRIBUTIONS

Sarah Mohamed: Conceptualization. Mostafa Reda Mostafa: Conceptualization; writing – original draft; writing – review and editing. Mohamed Magdi Eid: Writing – original draft; writing – review and editing. Yossef Hassan AbdelQadir: Writing – original draft; writing – review and editing. Yomna Ali Abdelghafar: Writing – original draft; writing – review and editing. Sarya Swed: Writing – original draft; writing – review and editing. Bishara Jahshan: Supervision; validation; visualization. Waddah Abd El‐Radi: Writing – original draft; writing – review and editing.

FUNDING INFORMATION

None.

CONFLICT OF INTEREST STATEMENT

None.

CONSENT

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Mohamed S, Reda Mostafa M, Magdi Eid M, et al. A case report of severe hyponatremia secondary to Paxlovid‐induced SIADH. Clin Case Rep. 2023;11:e7860. doi: 10.1002/ccr3.7860

DATA AVAILABILITY STATEMENT

All data generated or analyzed are included in this article.