Refractory Hyponatremia due to Systemic Infection: A Systematic Review

Introduction: Hyponatremia is a condition in which the sodium serum level is below the normal range. This condition is most common in hospitalized patients receiving systemic infection therapy and can lead to worse outcomes, potentially life-threatening. Objective: This study aimed to summarize the incidence of refractory hyponatremia due to systemic infection therapy. Methods: This was a systematic literature search conducted in October 2023 on the online database PubMed regarding refractory hyponatremia due to systemic. The analysis excluded narrative reviews, non-English studies


INTRODUCTION
Electrolytes play a role in the normal conduction function of body cells.Electrolytes contain ions such as sodium, potassium, calcium, phosphorus, and magnesium, all of which play a key role in maintaining body homeostasis. 1 Sodium ions, as extracellular fluid cations, are an electrolyte that helps to maintain the normal distribution of water and osmotic pressure in body fluids.Hyponatremia is an electrolyte balance disorder that frequently occurs in hospitalized patients, with a prevalence of 15-40%. 2 Hyponatremia is defined as having a serum sodium level of ≤135 mEq/l. 3Aside from being the most common electrolyte balance disorder, hyponatremia can lead to life-threatening complications. 4 Acute hypotonic hyponatremia, occurring in less than 48 hours, can cause cerebral edema, which manifests as decreased volume status in cases of gastrointestinal losses, adrenal insufficiency, or cerebral salt wasting syndrome (CSWS), volume status expansion in cases of heart failure and liver cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH) in normal volume status. 5 Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of hyponatremia.SIADH happens when the body releases the antidiuretic hormone (ADH) without being properly stimulated.This leads to hypotonic and euvolemic hyponatremia, as well as high osmolality in the urine. 3In addition, infections are known to contribute to the incidence of hyponatremia, and conversely, hyponatremia is associated with prolonged hospitalization, poor outcomes, and higher mortality rates in patients with infections.Hyponatremia may also play a diagnostic role in distinguishing the pathogen causing a particular infection. 6Several studies have discussed hyponatremia in patients with infectious disease. 6,7As far as the author knows, there has been no systematic analysis of the relationship between systemic infections and refractory hyponatremia, which is associated with high mortality and difficult treatment.Therefore, in this article, the author would like to summarize refractory hyponatremia due to systemic infection.

OBJECTIVE
This study aimed to conduct a systematic review of case reports on refractory hyponatremia due to systemic infection.

METHODS
This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Supplement 1) and is registered in the PROSPERO online database (PROSPERO Identifier: CRD42021256746).A systematic literature search regarding refractory hyponatremia due to systemic infections was carried out on the online database PubMed in October 2023.The search used a combination of keywords: "refractory hyponatremia" or "relapsed hyponatremia" or "recurrent hyponatremia" or "resistant hyponatremia" or "intractable hyponatremia" or "persistent hyponatremia" or "permanent hyponatremia" or "syndrome of inappropriate antidiuretic hormone" or "systemic infection" or "viremia" or "bacteremia" or "parasitemia" or "sepsis."The analysis excluded narrative reviews, non-English studies, and studies that only discussed transient hyponatremia or local infections.
Screening and data extraction were performed independently by the authors.All studies discovered through the literature search were screened against the title and abstract to determine the study's relevance.Studies deemed relevant through the screening were then subjected to full-text review.After a full-text review, studies that were deemed relevant were included in the final analysis.Figure 1 shows the PRISMA 2020 reference search and collection flowchart.All studies (n = 10) were case reports of 11 patients suspected of having refractory hyponatremia due to a systemic infection.

RESULTS
Table The initial search yielded 330 studies.A total of nine duplicate studies, as well as 110 narrative reviews or non-English studies, were excluded.A total of 211 studies were screened for relevance of title and abstract.Only 27 studies passed the title and abstract screening, and full text reviews were conducted.Based on the full text review, only 10 studies were included in the final analysis, 5 studies were excluded due to lack of access to the full text, and 12 studies were excluded for not listing systemic infection as a cause.The case studies are summarized in Table 1, and the baseline patient characteristics are listed in Table 2.

Patient Characteristics
A total of 11 patients were analyzed.The mean age of the patients was 46.63 years, with most of them being male (63.64%).Strongyloides stercoralis hyperinfection was the most common systemic infection in patients (54%).It was followed by disseminated varicella-zoster virus (VRZ) infection (28%), tuberculosis (9%), and cytemic nocardiosis (9%).The conditions that triggered patients' immune systems to weaken were mostly immunosuppressant treatment recipients (73%), such as those who had a kidney transplant, a stem cell transplant (SCT), leprosy, immune thrombocytopenic purpura (ITP), or non-Hodgkin lymphoma (NHL).Miliary tuberculosis was the second most common predisposing factor at 18%, followed by Human Immunodeficiency Virus (HIV) and Human T-Lymphotropic Virus (HTLV) infections at 9% each.The pathophysiology of hyponatremia was predominantly SIADH (91%), with one case involving the CSWS mechanism (9%).

Hyponatremia in disseminated Varicella Zoster Infection
Most patients with disseminated VZV infection are immunocompromised due to HIV infection, chronic illness, or chemotherapy.SIADH is found in about two thirds of these cases of disseminated infection.It is thought to be caused by VZV-induced direct encephalitis of the posterior pituitary or chest wall. 9isseminated infection inducing encephalitis could potentially explain two phenomena simultaneously, namely disseminated cutaneous involvement and SIADH in the first patient.However, many instances of disseminated encephalitis are challenging to diagnose clinically since viral culture in cerebrospinal fluid is not always possible.Instead, this patient's symptoms of encephalitis and hyponatremia may overlap.On the other hand, it is known that some regularly used drugs for HIV-infected patients (Pentamidine and Vidarabine) can trigger SIADH.
However, a drug-induced cause of SIADH in this patient could be ruled out, as none of these drugs were given to the patient. 8The second patient's central nervous system involvement in disseminated VZV infection was confirmed by cerebrospinal fluid (CSS) analysis, but there was no imaging or cellular evidence of inflammation in the brain or pituitary gland.Therefore, the local mechanism causing the release of anti-diuretic hormone remains uncertain.The third patient had some similarities with the second patient, but due to limited examination results, the cause of hyponatremia and its association with disseminated VZV infection are still unclear. 9In the fiftth patient, disseminated VZV infection was caused by low CD4 levels, in addition to a history of chemotherapy and radiation in NHL.Hyponatremia due to SIADH was proposed as a frequent manifestation after conventional chemotherapy for NHL patients, but the influence of disseminated infection on SIADH was not further elucidated. 11

Hyponatremia in Tuberculous Meningitis with Sepsis
The fourth patient presented with hyponatremia that was refractory to fluid correction and was later found to have a background of cerebral salt wasting syndrome (CSWS).Hyponatremia due to CSWS, unlike the other cases, is a differential diagnosis of SIADH. 10 CSWS is a condition characterized by hyponatremia with elevated urinary sodium levels and hypovolemia that has a very different treatment compared to SIADH.Patients with SIADH are subjected to fluid restriction, while those with CSWS require fluid administration and sodium supplementation. 18he mechanism of CSWS, as well as hyponatremia in this condition, is still a matter of debate.The first mechanism is related to the release of natriuretic peptides in the form of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). 10NP is released due to increased atrial strain and increased ventricular load from a surge in sympathetic outflow. 19BNP is thought to be released by brain tissue in response to brain injury and enters the systemic circulation through a compromised bloodbrain barrier. 18ANP and BNP may also be released by the hypothalamus as a protective mechanism against increased intracranial pressure.These two natriuretic peptides are hypothesized to inhibit sympathetic outflow, the renin-aldosterone system, and vasoconstrictor peptide production, ultimately resulting in decreased aldosterone efficacy and a reduction in the kidney's ability to reabsorb sodium. 19NP, more specifically, acts on the renal ductus collectivus to inhibit sodium reabsorption and decrease renin release. 18The second mechanism, the injured sympathetic nervous system, is thought to no longer be able to promote sodium reabsorption and is therefore unable to re-stimulate renin release due to hypothalamic injury. 18Furthermore, CSWS may be a direct injury to the renal sympathetic innervation.This is shown by the fact that the disruption of sympathetic nerve input to the juxtaglomerular apparatus can make it harder for kidneys to reabsorb sodium, urate, and water in the renal proximal tubules, as well as decrease the release of renin and aldosterone. 20

Hyponatremia in S. stercoralis hyperinfection
Strongyloides stercoralis hyperinfection occurs when filariform larvae spread to various organs, causing end-organ damage. 17Most patients with hyperinfection have a history of living in or visiting areas endemic for S. stercoralis, and there are conditions that lead to an immunosuppressed status in patients.In immunocompromised patients, the host defense system is dysregulated, resulting in the loss of normal innate and adaptive defenses against helminth infection.In addition, hematogenous spread of worms also allows enteric bacteria to enter the bloodstream through damaged mucosa.As a result, mortality is very high (up to 87%) due to secondary bacteremia/sepsis or meningitis from these enteric pathogens. 16he sixth patient had a history of migration from Colombia, South America, a region endemic for S. stercoralis infection, as well as travel to Venezuela.The patient was also on oral corticosteroid therapy for ITP, which predisposes to disseminated infection with this species.However, the patient did not have any central nervous system manifestations or pulmonary infiltration; therefore, the mechanism by which this hyperinfection induced SIADH remains unclear. 12nother patient, 37, had a history of migration from Mexico, an endemic area for S. stercoralis, with no subsequent travel history.This raised the likelihood of chronic infection while living in the United States.This patient also had disseminated tuberculosis infection, which increases the predisposition to Strongyloides hyperinfection.On the other hand, Strongyloides hyperinfection can trigger the reactivation of latent tuberculosis.A decreased lymphocyte count also increases the risk.The patient's SIADH caused hyponatremia that was resistant to fluid restriction; miliary pulmonary tuberculosis was suspected of causing SIADH in this patient. 17owever, persistent hyponatremia can occur due to prolonged vomiting symptoms, or vice versa, due to sodium dilution in cases of fluid retention.One possible mechanism is SIADH, which occurs when plasma osmolality is low, potassium levels are normal, and there is no significant pulmonary and central nervous system pathology. 13,14In cases of persistent hyponatremia and terminal hypoglycemia, the presence of SIADH indicates adrenal insufficiency in sepsis or disseminated abdominal malignancy.
In the seventh pasient, there was an adrenal crisis after adrenal hemorrhage, the trigger of which was unknown and was most likely caused by sepsis or strongyloides hyperinfection.Protein-losing enteropathy caused by seere-manutrition can cause mmunodeficiency, but in this patient, the corticosteroids that were given for ITP (at least 20 mg/day) were the most important factor. 13The tenth patient's immunodeficiency condition was a result of a history of alcohol abuse and HTLV-1 infection. 16

Hyponatremia in Nocardiosis Systemic
The ninth patient was at risk of nocardia infection due to long-term therapy for graft rejection and thir advanced age.Systemic nocardiosis causes inappropriate release of antidiuretic hormone (ADH), which leads to hypotonic hyponatremia and impaired water excretion.SIADH frequently occurs in hospitalized patients, and its causes can be classified as malignancy, pulmonary, or central nervous system disorders, including medication.In this patient, SIADH is likely due to eutopic ADH production related to the patient's pulmonary nocardiosis, as central nervous system involvement can be ruled out through head CT scans.This syndrome can also be associated with the use of tacrolimus, but in this patient, the treatment was unlikely to affect SIADH, as the patient improved with anti-microbials and fluid restriction, even though tacrolimus was routinely administered. 15

CONCLUSION
Hyponatremia refractory can be seen in patients with systemic infection who have undergone therapy, which may be mediated by SIADH, CSWS, or other mechanisms.
Most systemic infections are underpinned by one or more conditions that weaken the immune system.Several therapies for systemic infections lead to hyponatremia refractory.Treatment for the condition can vary depending on the therapy mechanism; for example, fluid restriction can improve SIADH, while replacement fluid is necessary for CSWS.In addition, addressing the primary issue of systemic infection should remain the top priority in treating the patient, irrespective of any potential side effects.On the other hand, treatment of systemic infection is still prioritized due to its contribution to the patient's hyponatremia state.

Figure 1 .
Figure 1.Flowchart of PRISMA 2020 referance search and collection 1. Case report

Table 2 .
Characteristics of refractory hyponatremia patients with systemic infection