key: cord-0964679-3lt7vua2 authors: Torres, Berta; Alcubilla, Pau; González-Cordón, Ana; Inciarte, Alexy; Chumbita, Mariana; Cardozo, Celia; Meira, Fernanda; Giménez, Marga; de Hollanda, Ana; Soriano, Alex; Albiach, Laia; Agüero, Daiana; Ambrosioni, Juan; Bodro, Marta; Blanco, Jose Luis; Mora, Lorena De la; García-Alcaide, Felipe; García-Pouton, Nicole; Garcia-Vidal, Carolina; Hernández-Meneses, Marta; Laguno, Montserrat; Leal, Lorna; Linares, Laura; Macaya, Irene; Mallolas, Josep; Martínez, Esteban; Martínez-Rebollar, María; María Miró, José; Mensa, José; Moreno, Asunción; Moreno, Antonio; Moreno-García, Estela; Morata, Laura; Antonio Martínez, José; Puerta-Alcalde, Pedro; Rico, Verónica; Rojas, John; Solá, Montserrat; Torres, Manuel title: Impact of low serum calcium at hospital admission on SARS-CoV-2 infection outcome date: 2020-12-02 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.11.207 sha: 719ef31b0a31686384fc7a30f091b646d6122ecb doc_id: 964679 cord_uid: 3lt7vua2 Background Calcium is an essential ion for pathogen survival and virulence and is involved in the regulation of the inflammatory response. Hypocalcemia is a common laboratory finding in critically ill patients. Data regarding levels of calcium in SARS-CoV-2 infection is scarce. Patients with SARS-CoV-2 infection who present with hypocalcemia could have a worse outcome. Methods We performed a retrospective analysis of hospitalized patients with SARS-CoV-2 infection and included all patients who had any serum calcium measurement in the first 72 hours since hospital admission. Main objective was to investigate the relation of low serum calcium with adverse outcome, measured by the requirement of high oxygen support – defined as high flow nasal cannula oxygen, non-invasive mechanical ventilation and/or invasive ventilation-, intensive care unit admission or death. Results A total of 316 patients were included in the study. Median age was 65 years (IQR 55-74), 65% were men. Hypocalcemia within 72 hours since hospital admission was present in 63% of patients. A higher number of patients in the hypocalcemia group required high oxygen support during hospitalization (49% vs 32%; p = 0,01) and were admitted to the ICU (42% vs 26%; p = 0,005). No differences in mortality were observed between groups. Conclusions Hypocalcemia is frequent in hospitalized patients with SARS-CoV-2 infection and can identify patients with worse outcome. More studies are needed to understand the role of calcium metabolism in SARS-CoV-2 infection and to address the clinical implications and therapeutic interventions it might have. -Almost two thirds of patients with SARS-CoV-2 infection present with hypocalcemia at hospital admission -Hypocalcemia at admission is related to high oxygen support requirement any time during hospitalization. -Patients with hypocalcemia at admission had two times more probability to be admitted to the Intensive Care Unit during hospitalization than patients with normal calcium at admission. Calcium is an essential ion for pathogen survival and virulence and is involved in the regulation of the inflammatory response. Hypocalcemia is a common laboratory finding in critically ill patients. Data regarding levels of calcium in SARS-CoV-2 infection is scarce. Patients with SARS-CoV-2 infection who present with hypocalcemia could have a worse outcome. We performed a retrospective analysis of hospitalized patients with SARS-CoV-2 infection and included all patients who had any serum calcium measurement in the first 72 hours since hospital admission. Main objective was to investigate the relation of low serum calcium with adverse outcome, measured by the requirement of high oxygen Clinical characteristics of SARS-CoV-2 infected patients have already been reported and several laboratory parameters have been identified as prognostic markers (2) (3) (4) . Calcium is an important ion involved in different cellular processes and it has been recognized as critical for pathogen survival and virulence. Moreover, calcium metabolism is known to regulate the inflammatory response in critically ill patients (5) . Patients with SARS-CoV-2 infection who present with hypocalcemia could present a more severe clinical syndrome. Clinical and laboratory information of hospitalized patients with a SARS-CoV-2 infection is retrospectively being collected and managed using REDCap electronic data capture tools hosted at Hospital Clínic(6). We performed a retrospective analysis of the database and included all patients who had at least one calcium determination in the first 72 hours since hospital admission. Calcium was measured in milligrams per deciliter and corrected for proteins measured in the same blood test (Corrected serum calcium = serum calcium / 0.6 + (total proteins / 18.5). Study was approved by the local ethics committee. Epidemiological and clinical data, laboratory findings, chest X ray results and patient outcomes were reviewed. The main objective of the study was to investigate the relation of low serum calcium levels in the first 72 hours since hospital admission with adverse outcome, defined by the need of high oxygen support, ICU admission or death during hospitalization. We also performed a multivariate logistic analysis in order to assess if low serum calcium at admission was an independent risk factor for ICU admission or death. All continuous variables are expressed in medians and interquartile ranges. Categorical variables are expressed as an absolute value and relative frequencies. Means of continuous variables were compared with t-student test, and binary variables were compared with the Chi-Squared test, between low (hypocalcemia) and normal calcium level patients. Univariate logistic regression was performed to assess association of At the time of database export 552 registries were introduced in the online database. Of them, 316 patients had at least one measurement of calcium in the first 72 hours since hospital admission and were included in the study. Of the 316 patients included, 206 (65%) were men and median age was 65 years (IQR, 55-74). Baseline characteristics are described in Table 1 However, in all these cases, a probable SARS-CoV-2 infection was diagnosed by compatible analytical, radiological and laboratory findings. The most frequent laboratory test findings at admission were elevation in lactate dehydrogenase (85%), ferritin (74%), D-dimer (63%) and low count of lymphocytes (62%). Electrolyte imbalances were also observed: hyponatremia, hypokalemia and hypomagnesemia appeared in 17, 18 and 19% respectively ( Table 2 ). The most frequently altered electrolyte was calcium. The percentage of patients with calcium lower than 8,5 mg/dl was 63%. Forty-four percent of all patients required high oxygen support any time during hospitalization. One hundred and fourteen patients (36%) were admitted to the intensive Table 3) . Patients with hypocalcemia had any underlying condition, as a global, more frequently than patients with normal calcium (87% vs 78%; p= 0.02). There were not any other significant differences in baseline characteristics or symptoms at presentation, with exception of cough (73% vs 64%; p= 0.04) ( (defined in the study as ionized calcium < 1.18 mmol/L; normal range 1.16 to 1.31 mmol/L) was observed in 82% of COVID-19 patients and was reported to be a risk factor for ICU admission and death in the univariate but not in the multivariate analysis(17). Serum calcium lower than 8.5 mg/dl in our study was also a risk factor for need of high oxygen support and ICU admission but not for death. Low levels of calcium seem to be associated with other laboratory features (higher LDH, lower J o u r n a l P r e -p r o o f lymphocytes count) that have been repeatedly reported to be independent risk factors for SARS-CoV-2 progression in hospitalized patients (4) . Calcium is essential for virus life cycle and virulence. The calcium pump SCAP1 has been identified as a protein used by many viruses. It regulates the intracellular calcium concentration required by proteases involved in virus maturation (18) . In addition to this, the SARS-CoV-2 envelope E-protein is a viroporin that forms calcium permeable channels and alters calcium homeostasis within cells boosting the activation of the NLRP3 inflammasome, which leads to the overproduction of IL-1β(19). Due to the fact that calcium homeostasis is tightly regulated by hormonal processes, the above-mentioned mechanisms would not totally explain the magnitude of the low serum calcium levels observed in SARS-CoV-2 infection and in other viruses. A possible relation of hypocalcemia and inflammation may therefore exist. According to some studies in animal models, cytokines, concretely IL-1β, can upregulate the expression of the calcium sensing receptor (CaSR), a membrane protein that can sense changes in calcium concentration (20) . CaSR upregulation reduces the set point for circulating calcium suppression of PTH secretion. Thus, a lower circulating calcium concentration, even concentrations in the hypocalcemic range, would be sufficient to reduce PTH secretion and, as a consequence, to decrease serum calcium (21) . Taking into account that calcium is an inflammation mediator, some authors have supported the theory that hypocalcemia can act as a regulator of inflammation (22) . This mechanism would explain the observed relationship between low levels of calcium and more severe SARS-CoV-2 infection with worse prognosis, and it could then be possible that patients with higher levels of inflammatory cytokines would present with lower serum calcium concentration. Unfortunately, we did not measure interleukin J o u r n a l P r e -p r o o f levels in our study, thus, we could not demonstrate the relationship between low levels of calcium with a higher degree of inflammation. Irrespective of the mechanism responsible for hypocalcemia, it appears that low levels A Novel Coronavirus from Patients with Pneumonia in China Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. 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