Infectious diseases continue to pose a significant global health burden, causing substantial morbidity and mortality worldwide. While considerable efforts have been invested to improve treatment strategies and reduce the adverse outcomes associated with infections, identifying additional prognostic markers that can help predict patient outcomes remains a vital area of research. One such potential marker of interest is serum phosphate level, which has been implicated in various physiological processes and disease states.

Phosphate, an indispensable mineral vital for cellular energy metabolism, bone mineralization and a myriad of enzymatic reactions, plays a fundamental role in maintaining homeostasis throughout the human body (1). Perturbations in phosphate levels have been linked to a wide range of pathological conditions, encompassing renal dysfunction, cardiovascular disease and metabolic disorders. Furthermore, within the cellular landscape, phosphate assumes a central role as a valuable “currency.” The paramount energy carrier, adenosine triphosphate (ATP), relies on phosphate bonds to liberate and transfer energy during cellular metabolic processes (2). Additionally, phosphate actively engages in cellular signalling pathways, mediating crucial phosphorylation events that govern enzyme activity and gene expression, thereby influencing diverse cellular functions such as growth, proliferation and differentiation (3).

In an interesting study published in 2022, Yang et al. examined the association between phosphate levels and mortality in critically-ill patients admitted to the intensive care unit (ICU) for various reasons (4). Among 24,289 patients, elevated phosphate levels were independently associated with an increased risk of ICU mortality, hazard ratio 1.06 (95% confidence interval (CI): 1.02–1.09, p < 0.001). Two other studies (5, 6), both published in 2023, indicated similar results, but focused specifically on patients with sepsis. Among 1,855 patients with sepsis, Black et al. (5) reported higher mortality among those with phosphate levels in the highest quartile (>4.0 mg/dL) than in the three lower quartiles. Among 9,691 patients with sepsis, Xu et al. (6), observed higher 28-day mortality among those with hyperphosphatemia within 2 days of ICU admission. Importantly, the above studies included only patients with sepsis who were hospitalized in critical care units.

Though most patients with infectious diseases are hospitalized in medical and surgical wards, rather than the ICU, only scarce research has investigated the relation between phosphate levels on admission and mortality rates. Consequently, the objective of this nationwide study was to examine a possible association between serum phosphate levels and mortality rates in patients with infectious diseases hospitalized outside the ICU.

In this large study of patients with infections disease hospitalized outside of the ICU, hyperphosphatemia on admission was associated with short- and long-term mortality, target organ damage and longer hospital stay. To a lesser extent, hypophosphatemia was associated with short- and long-term mortality and target organ damage. A multivariate analysis showed a J-shaped association between phosphate levels and mortality.

The findings of the current study, which comprised hospitalized patients with infectious diseases, are in line with the findings of a large study that investigated the association between phosphate levels and mortality (11). That study included 42,336 patients admitted to Mayo Clinic in Rochester over a four-year period, for a wide variety of diseases. Their results, like ours, revealed a J-shaped curve, indicating associations of both low (<3.1 mg/dL) and high (>4.2 mg/dL) serum phosphate levels with higher in-hospital mortality. Even after adjusting for potential confounding factors, both low and high serum phosphate levels remained significantly associated with in-hospital mortality. However, as highlighted earlier, while that study conducted several subgroup analyses, it did not specifically analyze patients with infectious diseases.

The main clinical question that arises from our research is the mechanism linking phosphate levels with the infectious process and prognosis. Stemming from this is the question as to whether phosphate levels are only a prognostic marker or whether correcting them may affect prognosis. Three important elements constitute possible links between hypophosphatemia and infection. First, hypophosphatemia results from acute respiratory alkalosis, a clear sign of the onset of sepsis. In healthy persons, hyperventilation (to partial pressure of carbon dioxide <20 mmHg) can lower serum phosphate concentrations to below 1 mg/dL (0.32 mmol/L) (12). This is probably the most common cause of marked hypophosphatemia in hospitalized patients (13). Second, patients with acute infection tend to develop hyperglycemia and increased insulin secretion. The underlying reasons are elevated cortisol levels and increased secretion of catecholamines and glucagon, as well as increased gluconeogenesis and glycogenolysis (14). Insulin secretion in itself is directly related to hypophosphatemia (15). Lastly, severe infectious disease may lead to decreased intestinal absorption (16), thus resulting in hypophosphatemia. Similarly, it is worth highlighting the two main factors associated with an infectious process and causing hyperphosphatemia. The first is the decreased renal clearance seen in acute kidney injury, which often accompanies acute infections in hospitalized patients (17). The second is the cellular shift causing hyperphosphatemia, which results from acute lactic acidosis (18). This classic phenomenon accompanies severe infectious diseases, especially those that include a decrease in cell perfusion. We suspect that the non-symmetrical J-shaped curve of the association between phosphate levels and mortality can be explained by the more clinically significant causes of hyperphosphatemia that relate to poor prognosis, rather than the more benign causes of hypophosphatemia.

Regarding the well-known association between hyperphosphatemia and renal failure mentioned above, we emphasize that we analysed specifically the association between hyperphosphatemia and mortality, while statistically neutralizing the accompanying renal failure. Indeed, this study identified phosphate as a significant prognostic marker regardless of renal failure. This supports the possibility that hyperphosphatemia is more likely related to target organ damage and tissue degradation than to renal failure itself.

Our study has a number of limitations. First, the phosphate levels were measured over a period of up to 1 week from hospital admission, and not at the same point in time for all the patients included in the study. Second, an unknown proportion of patients with infection actually qualified for the diagnostic criteria of sepsis, and it is not always feasible to discern these from those who did not qualify. Another shortcoming of the study is the inability to distinguish patients with acute and chronic renal failure. Finally, the study relies on administrative data, which is usually not intended for clinical research. However, the methodology is well-established, both in our previous studies of the same cohort (19, 20) and in a leading international study in this field, conducted by Martin et al. (8) and published in 2003.

A key strength of the present study is the size of the population and its scope. Our cohort contained data collected over about 20 years, from eight hospitals. For both before and after hospital admission, the study utilized the extensive uniform database of CHS, with its rich demographic and clinical data. These included confounders such as underlying comorbidities and chronic medications, thus enabling robust multivariate analysis.

To conclude, the present study found a J-shaped relation between phosphate levels and prognosis in patients hospitalized with infectious diseases, regardless of their renal function. Future clinical studies regarding the pathophysiology and therapeutic implications of these findings should explore the utility of correcting phosphate levels and clarify whether phosphate abnormalities are more than just a marker of target organ damage.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Soroka medical center ethics committee. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

AF: Supervision, Writing – original draft. AS: Data curation, Methodology, Software, Writing – original draft. VV: Validation, Writing – review & editing. MB: Formal analysis, Project administration, Writing – review & editing. YB: Formal analysis, Writing – review & editing. JD: Supervision, Methodology, Writing – original draft.