Towards a better detection of patients at-risk of linezolid toxicity in clinical practice: a prospective study in three Belgian hospital centers.

Introduction: Linezolid is a last-resort antibiotic for infections caused by multidrug-resistant microorganisms. It is widely used for off-label indications and for longer than recommended treatment durations, exposing patients at higher risk of adverse drug reactions (ADRs), notably thrombocytopenia. This study aimed to investigate ADR incidence and risk factors, identify thrombocytopenia-related trough levels based on treatment duration, and evaluate the performance of predictive scores for ADR development. Methods: Adult in- and outpatients undergoing linezolid therapy were enrolled in three hospitals and ADRs and linezolid trough levels prospectively monitored over time. A population pharmacokinetic (pop-PK model) was used to estimate trough levels for blood samples collected at varying times. Results: A multivariate analysis based on 63 treatments identified treatment duration ≥10 days and trough levels >8 mg/L as independent risk factors of developing thrombocytopenia, with high trough values correlated with impaired renal function. Five patients treated for >28 days did not develop thrombocytopenia but maintained trough values in the target range (<8 mg/L). The Buzelé predictive score, which combines an age-adjusted Charlson comorbidity index with treatment duration, demonstrated 77% specificity and 67% sensitivity to predict the risk of ADR. Conclusion: Our work supports the necessity of establishing guidelines for dose adjustment in patients with renal insufficiency and the systematic use of TDM in patients at-risk in order to keep trough values ≤8 mg/L. The Buzelé predictive score (if ≥7) may help to detect these at-risk patients, and pop-PK models can estimate trough levels based on plasma samples collected at varying times, reducing the logistical burden of TDM in clinical practice.

Mortality-related risk factors of inpatients with diabetes and COVID-19: A multicenter retrospective study in Belgium.

BACKGROUND AND AIMS: We describe mortality-related risk factors of inpatients with diabetes and coronavirus disease 2019 (COVID-19) in Belgium. METHODS: We conducted a multicenter retrospective study from March to May, 2020, in 8 Belgian centers. Data on admission of patients with diabetes and COVID-19 were collected. Survivors were compared to non-survivors to identify prognostic risk factors for in-hospital death using multivariate analysis in both the total population and in the subgroup of patients admitted in the intensive care unit (ICU). RESULTS: The study included 375 patients. The mortality rate was 26.4% (99/375) in the total population and 40% (27/67) in the ICU. Multivariate analysis identified older age (HR 1.05 [CI 1.03-1.07], P<0.0001) and male gender (HR 2.01 [1.31-3.07], P=0.0013) as main independent risk factors for in-hospital death in the total population. Metformin (HR 0.51 [0.34-0.78], P=0.0018) and renin-angiotensin-aldosterone system blockers (HR 0.56 [0.36-0.86], P=0.0088) use before admission were independent protective factors. In the ICU, chronic kidney disease (CKD) was identified as an independent risk factor for death (HR 4.96 [2.14-11.5], P<0.001). CONCLUSION: In-hospital mortality due to the first wave of COVID-19 pandemic in Belgium was high in patients with diabetes. We found that advanced age and male gender were independent risk factors for in-hospital death. We also showed that metformin use before admission was associated with a significant reduction of COVID-19-related in-hospital mortality. Finally, we showed that CKD is a COVID-19-related mortality risk factor in patients with diabetes admitted in the ICU.

Gen Z and HIV-Strategies for Optimizing the Care of the Next Generation of Adolescents Living with HIV.

The management of adolescents living with HIV represents a particular challenge in the global response to HIV. The challenges specific to this age group include difficulties engaging and maintaining them in care, challenges with transition to adult care, and limited therapeutic options for treatment-experienced patients, all of which have been jeopardized by the COVID-19 pandemic. This paper summarizes some of the challenges in managing adolescents living with HIV, as well as some of the most recent and innovative therapeutic approaches in this population.

Availability and readiness of the health facilities to provide HIV counseling and testing and prevention of mother-to-child transmission services in Burkina Faso: a trend analysis from 2012 to 2018.

BACKGROUND: Provider-Initiated HIV Testing and Counseling (PITC) and Prevention of Mother-To-Child Transmission (PMTCT) are key services for achieving the goal of complete elimination of HIV. However, there is limited evidence on the ability of health facilities to provide these services in Burkina Faso. Therefore, we aimed to assess the trends and disparities in the availability and readiness of health facilities to provide PITC and PMTCT services in Burkina Faso between 2012 and 2018. METHODS: We performed a secondary analysis of facility-level data from the World Health Organization's Service Availability and Readiness Assessment (SARA) surveys conducted in 2012, 2014, 2016, and 2018 in Burkina Faso. The availability and readiness of health facilities were assessed using SARA's manual, and linear regressions were used to examine trends. RESULTS: Between 2012 and 2018, the mean proportion of health facilities providing PITC services increased, but not significantly, from 82.9% to 83.4% (p = 0.11), with the mean readiness index significantly decreasing from 71.5% to 65.4% (p < 0.001). This decrease concerned the staff and guidelines (73.8% to 50.5%; p < 0.001), equipment (79.0% to 77.4%; p < 0.001), and medicines and commodities (54.2% to 45.2%; p < 0.001) domains. Regarding the PMTCT services, the mean proportion of health facilities globally providing the service significantly decreased from 83.7% in 2012 to 67.7% (p = 0.030) in 2018, and the mean readiness significantly decreased from 53.2% in 2012 to 50.9% in 2018 (p = 0.004). This decreasing trend was related to the staff and training (80.3% to 57.6%; p < 0.001) and medicines and commodities (9.2% to 6.5%; p < 0.001) domains. The global significant negative trend of readiness was mainly observed at the primary level of healthcare (52.7% to 49.4%; p = 0.030). Four regions experienced a significant decrease in the readiness index of health facilities to provide PMTCT services: Cascades, Centre, Centre-Sud, and Sud-Ouest, while Haut-Bassins and Nord regions showed increasing trends. CONCLUSION: Availability and readiness of health facilities to provide PITC and PMTCT remain suboptimal in Burkina Faso. Actions to strengthen the skills of professionals and enhance the availability of medicines and commodities while focusing more on health regions with significant decreasing trends are urgently needed to improve the quality of services for HIV.

Evaluation of a commercial interferon-γ release assay for the detection of SARS-CoV-2 T-cell response after vaccination.

Objective: Evidence regarding the role of cellular immunity in protecting against COVID-19 is emerging. To better assess immune status, simple and robust assays measuring specific T-cell responses associated with humoral responses are needed. We aimed to evaluate the Quan-T-Cell SARS-CoV-2 test for measuring cellular immune responses in vaccinated healthy and immunosuppressed subjects. Methods: T-cell responses were assessed in healthy vaccinated and unvaccinated and unexposed healthcare workers to determine the sensitivity and specificity of the EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test performed on vaccinated kidney transplant recipients (KTRs). Results: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity (87.2%) and specificity (92.3%) at the calculated 147 mIU/mL cutoff, with an 88.33% accuracy. In KTRs, specific cellular immunity was lower than the antibody response; however, those with a positive IGRA result produced as much IFN-γ as healthy individuals. Conclusions: The EUROIMMUN SARS-CoV-2 Quan-T-Cell IGRA test showed good sensitivity and specificity for the detection of specific T-cell responses against the SARS-CoV-2 spike protein. These results present an additional tool for better management of COVID-19, especially in vulnerable populations.

Healthcare system's preparedness to provide cardiovascular and diabetes-specific care in the context of geopolitical crises in Burkina Faso: a trend analysis from 2012 to 2018.

OBJECTIVE: This study aimed to evaluate the trends of the availability and readiness of the healthcare system to provide cardiometabolic (cardiovascular diseases (CVD) and diabetes) services in Burkina Faso in multiple political and insecurity crises context. DESIGN: We performed a secondary analysis of repeated nationwide cross-sectional studies in Burkina Faso. DATA SOURCE: Four national health facility survey data (using WHO Service Availability and Readiness Assessment (SARA) tool) conducted between 2012 and 2018 were used. PARTICIPANTS: In 2012, 686 health facilities were surveyed, 766 in 2014, 677 in 2016 and 794 in 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcomes were the availability and readiness services indicators defined according to the SARA manual. RESULTS: Between 2012 and 2018, the availability of CVD and diabetes services significantly increased (67.3% to 92.7% for CVD and 42.5% to 54.0% for diabetes). However, the mean readiness index of the healthcare system to manage CVD decreased from 26.8% to 24.1% (p for trend <0.001). This trend was observed mainly at the primary healthcare level (from 26.0% to 21.6%, p<0.001). For diabetes, the readiness index increased (from 35.4% to 41.1%, p for trend=0.07) during 2012-2018. However, during the crisis period (2014-2018), both CVD (27.9% to 24.1%, p<0.001) and diabetes (45.8% to 41.1%, p<0.001) service readiness decreased. At the subnational level, the readiness index for CVD significantly decreased in all regions but predominantly in the Sahel region, which is the main insecure region (from 32.2% to 22.6%, p<0.001). CONCLUSION: In this first monitoring study, we found a low level and decreased trend of readiness of the healthcare system for delivering cardiometabolic care, particularly during the crisis period and in conflicted regions. Policymakers should pay more attention to the impact of crises on the healthcare system to mitigate the rising burden of cardiometabolic diseases.

Efficacy, durability, and tolerability of bictegravir/emtricitabine/tenofovir alafenamide for the treatment of HIV in a real-world setting in Belgium.

OBJECTIVES: Our objective was to evaluate the efficacy, durability, and tolerability of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in a real-world setting in Belgium. METHODS: This was a retrospective, multicentre cohort study involving adult treatment-naïve (TN) and treatment-experienced (TE) people living with HIV receiving BIC/FTC/TAF between 1 January 2019 and 30 September 2020. The primary outcome was rate of virological suppression (plasma HIV-1 viral load <50 copies/mL; on-treatment analysis) at weeks 24 and 48. The main secondary outcomes included loss of virological suppression (LVS; two consecutive viral loads of >200 copies/mL after being virologically suppressed) by week 48 and analysis of resistance-associated mutations at time of LVS; tolerability of BIC/FTC/TAF over the 48-week study period; and change in weight and proportion of participants reporting a >10% weight gain at week 48. RESULTS: Overall, 2001 participants were included. Through 48 weeks, overall rate of virological suppression was 93.5%, with similar results observed in the following subgroups: age ≥50 years (92.7%), women (92.8%), Black sub-Saharan African (91%), TN (94%), TE (93.2%), and non-suppressed at baseline (86.6%). LVS was observed in 0.7% (n = 14) of participants, with one participant developing resistance-associated mutations to nucleoside reverse transcriptase inhibitors (184 V) and integrase strand transfer inhibitors (263KR). Of the 131 (6.5%) treatment discontinuations, the most common reason was an adverse event (2.4%), with the most frequent being central nervous system/psychiatric (0.4%) and gastrointestinal (0.4%) toxicity. Median weight gain at week 48 was 2 kg (interquartile range -1 to 5), and a >10% weight increase was observed in 11.6% of participants. CONCLUSION: In this large real-world cohort, BIC/FTC/TAF showed excellent virological efficacy in a diverse population of patients with HIV. Rare occurrence of emergent drug resistance was observed, and treatment was well tolerated.

Antiretroviral therapy and weight gain in antiretroviral treatment-experienced HIV patients: A review.

The risk of developing non-AIDS events (NAEs) remains higher in persons living with HIV-1 (PLWH) compared to the general population despite progress made in the treatment by antiretroviral (ARV). Particular attention is therefore given to the management of risk factors associated with NAEs during the follow-up of PLWH, including overweight. Factors associated with weight gain in PLWH are multifactorial and include demographics, HIV disease-related, lifestyle, cultural, and antiretroviral therapy (ART)-associated factors. All these confounding factors make it difficult to interpret the potential link between ARVs and weight gain. In antiretroviral treatment- experienced PLWH, confounding factors such as the return to normal health or the advanced stage of disease can be ruled out compared to naïve patients which somewhat facilitates the interpretation of weight gain. Weight gain after ART switch is modest, not generally a big concern in clinical practice in this population and correlated more strongly with baseline regimen, especially after the stop of TDF or EFV, than with sex-, race-, or HIV-related factors. It remains uncertain whether this is due to the loss of a weight suppressive effect of prior regimens with older agent such as TDF or EFV or a weight gain effect of the newer regimens especially TAF and/or INSTI, or both. The mechanisms linked to weight gain attributed to the new ARVs as well as its possible reversibility are not yet elucidated. Clinicians who switched ARV regimen of experienced PLWH should be aware of this side effect and of this potentially consequences on the global health.

Perceptions, attitudes, and practices of a Belgian teaching hospital's physicians, pharmacists, and nurses regarding antibiotic use and resistance: survey towards targeted actions for Antimicrobial Stewardship.

OBJECTIVES: This study aimed to identify barriers to the proper use of antibiotics by healthcare professionals and to help the hospital Antimicrobial Stewardship develop suitable actions for the staff. METHODS: In a Belgian teaching hospital, a survey was conducted among physicians, pharmacists, and nurses involved in antibiotherapy. Questions from the 2019 European Center for Disease Prevention and Control (ECDC) survey were analyzed based on components of the COM-B model (capabilities, opportunities, and motivations). First, collected data were reviewed with the Ethnos software to analyze the different COM-B model components. For statistical analyses, responses were grouped into three clear-cut answers in a Fisher's exact test. RESULTS: Overall, 400 staff members were included. We found that our professions, combined, have a good perception of antibiotic resistance (97.8%). For capabilities, however, only 77.2% state that they have sufficient knowledge, with 91.3%, 71.5%, and 63.0% for physicians, nurses, and pharmacists, respectively. For opportunities (access to resources, information, and training), it is observed that 72.2% report having easy access to the guidelines they need to manage infections. In comparison, for 64.2% of the respondents, this information changed their opinion on the useless or inappropriate prescription, administration, and delivery of antibiotics. For 55.0%, this information has enabled them to change their practices. Finally, for motivations, 92.8% of respondents state that they know about the link between their practices and the emergence and spread of antibiotic resistance. However, only 65.0% of participants say they have a role in managing antibiotic resistance. We found that 5 out of 8 questions are significantly dependent on the profession: 2 inquiries related to capability, 1 to opportunity, and 2 to motivation. CONCLUSION: We found that responses to the ECDC questionnaire are related to the profession. While some topics are universal/cross-functional, others must be explicitly tailored to each professional category. Information is useless if not accessible. Communication and provision of documents are thus paramount.

Efficacy, durability, and tolerability of dolutegravir/lamivudine and dolutegravir/rilpivirine for the treatment of HIV in a real-world setting in Belgium.

OBJECTIVES: A paradigm shift from three-drug regimens to two-drug regimens (2DRs) is currently taking place in real-world clinical practice. This study aimed to describe the efficacy, durability, and tolerability of dolutegravir (DTG)/lamivudine (3TC) and DTG/rilpivirine (RPV) in a real-world setting. METHODS: This was a retrospective, observational, multicentre (ten centres in Belgium) study involving adult treatment-naïve and treatment-experienced people living with HIV on DTG/3TC or DTG/RPV between 1 January 2019 and 30 September 2020. The primary endpoint was rate of virological suppression (VS; plasma HIV-1 viral load [VL] <50 copies/ml) using an on-treatment analysis. Main secondary endpoints included the proportion of people that experienced loss of VS (LVS; defined as two consecutive HIV-1 VLs of >200 copies/ml after initially achieving VS) and a resistance analysis at the time of LVS; rate, incidence, and reasons for discontinuation of treatment (stopping treatment or changing any component of the 2DR); and change in weight, along with the proportion of people reporting a >10% weight gain. Ordinal logistic regression analysis examined associations between baseline variables and >10% on-treatment weight gain. RESULTS: Overall, 948 people were included, of whom 734 (77%) were on DTG/3TC and 214 (23%) were on DTG/RPV. Baseline characteristics included 54% aged ≥50 years, 31% female, 31% Black sub-Saharan African, 95% treatment-experienced, and 8% with HIV-1 VL ≥50 copies/ml. Through 48 weeks, the rate of VS for the overall cohort was 98.3% (99.1% with 3TC; 96.2% with RPV). LVS was observed in 0.5% (n = 5) of the overall population (n = 1 [3TC group], n = 4 [RPV group]). There were 40 treatment discontinuations (4.2%, n = 27 [3TC group]; n = 13 [RPV group]), corresponding to an incidence of 4.7 per 100 patient-years. The most common reason for discontinuation was an adverse event (1.4%), with neurotoxicity the most frequent (0.5%). Median on-treatment weight gain at week 48 was 1 kg (interquartile range [IQR] -1-3) overall, 1 kg (IQR -1-3) in the 3TC group, and 2 kg (IQR 0-4) in the RPV group. A >10% weight increase was observed in 6.3% of people. Regression analysis showed that being on a tenofovir disoproxil fumarate-based regimen prior to 2DR initiation was the only variable associated with a >10% increase in weight from baseline (odds ratio 3.48; 95% confidence interval 1.13-10.68; p = 0.038). CONCLUSION: In this real-world analysis, the 2DRs analysed were effective, durable, and safe for those who were treatment-naive and treatment-experienced. A slight increase in weight was associated with these regimens.

COVID-19 vaccination in people living with HIV: current data and perspectives.

There is no correlation between HIV per se and other risk factors for severe COVID-19 disease. Pivotal studies have shown that vaccination is one of the effective ways to prevent severe COVID-19 illness in the general population. Studies on people living with HIV (PLWH) are scarce. The majority of these studies with mRNA (BNT126b2 and mRNA-1273) and adenovirus vector (Ad26.COV2.2 and ChAdOx1) vaccines with a low number of patients included shows that PLWH on antiretroviral treatment and with CD4 count > 200/mm³ has a robust immune response. These vaccines are thus effective in preventing severe infection caused by severe acute respiratory syndrome coronavirus 2 in PLWH. However, PLWH with a CD4 count of < 200/mm³ and uncontrolled viral load (VL) seems to have a lower immune response. COVID-19 vaccines are safe in PLWH; adverse effects are mild or moderate, and their incidence is similar to non-HIV people (NHP). The CD4 count decreased significantly and transiently, and the VL rebounded insignificantly in a few patients. A complete vaccination including a third dose is, therefore, recommended. A booster dose with an mRNA vaccine is recommended in PLWH with an advanced stage of their disease.

Antiretroviral therapy and weight gain in naive HIV-1 infected patient: a narrative review.

The prevalence of obesity has increased dramatically in recent decades worldwide. An increase in the prevalence of obesity has also been observed among people living with HIV (PLHIV) in high and low incomes countries. Antiretroviral therapy (ART), by controlling the viral load (VL) and restoring cellular immunity, has improved the health status and life expectancy in PLHIV. However, the risk of developing non-AIDS events (NAEs) remains higher than the general population. Therefore, specific attention is given to managing risk factors associated with NAEs during the follow-up of PLHIV, including obesity. Factors related to weight gain in PLHIV include demographic factors, HIV disease-related factors, and ART-associated factors. In naive PLHIV, weight gain after the initiation of ART is expected. The weight gains observed are generally not severe even if there appear to be risk factors such as the advanced stage of disease (low CD4 cells count and high VL), female sex, black race, and taking integrase strand transfer inhibitors (INSTI) associated or not with tenofovir alafenamide fumarate (TAF). The role of each antiretroviral drug per-se remains to clarify. As INSTI ± TAF has been associated with significant weight gain, further research is needed to identify the individual-level factors predictive of weight gain, the mechanisms of ART-associated weight gain and the clinical relevance of this weight gain. As PLHIV survive longer on effective ART, the prevention and management of NAEs will remain a challenge for healthcare providers.

Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Study in a Belgian Teaching Hospital.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, which can be primary (due to genetic mutation) or secondary to malignancy, infection and rheumatologic diseases. Data concerning Belgian patients with adult HLH are lacking. Methods: This retrospective study was performed in a teaching hospital in Belgium. All cases of adult HLH, from December 2010 to April 2022, were reviewed. Patients with more than five HLH-2004 criteria and/or HScore >80% were included in the study. The objective of our study was to describe clinical and biological characteristics of patients with HLH and attempt to look for variables associated with mortality. Results: Fifty-two patients were included in the final analysis. Mean age (SD) of patients was 48 (18) years old, and 29 patients were of male gender (56%). The underlying diseases associated with HLH were malignancy (M-HLH) in 22 patients, infection related HLH in 20 patients, rheumatologic disease related HLH in 7 patients, idiopathic in 2 patients and secondary to pregnancy in 1 patient. Overall mortality, mortality at 30 days and 90 days were 24/52 (46%), 13/52 (25%) and 4/52 (10%), respectively. In univariate analysis, malignancy, male sex, age and disseminated intravascular coagulation (DIC) were associated with mortality (p < 0.05). In multivariate analysis, only age was significantly associated with mortality (odds ratio, 1.053; 95% confidence interval, 1.016-1.092; p 0.005). Conclusion: In our study, the most frequent triggers were malignancy and infectious agent followed by rheumatologic disease. Risk factors for mortality were age, male sex, malignancy and DIC, but only age remained significant in multivariate analysis. Treatment guidelines are mainly based on pediatric patients, and it is important for physician to describe adult patients' outcome to better understand this disease and adapt treatment.

Safety, Efficacy, and Relapse of Nirmatrelvir-Ritonavir in Kidney Transplant Recipients Infected With SARS-CoV-2.

Introduction: The efficacy of nirmatrelvir-ritonavir (NR; Paxlovid, Pfizer, New York, NY) to decrease the risk of progression to severe COVID-19 in high-risk patients has been demonstrated. However, evidence in infected kidney transplant recipients (KTRs) is lacking. Moreover, NR has significant and potentially harmful interactions with calcineurin inhibitors (CNIs). Methods: In this single-center retrospective study, we included all KTRs treated with NR from April 28 to June 3, 2022. A standard management strategy of CNI dose adaptation (discontinuation of tacrolimus 12 hours before the start of NR and administration of 20% of the cyclosporine dose) and laboratory follow-up was applied. Results: A total of 14 patients were included. Compared with day-0 (day before NR initiation), day-7 plasma creatinine concentrations and SARS-CoV-2 viral loads were similar (P = 0.866) and decreased (P = 0.002), respectively. CNI trough concentrations at the end of the treatment were satisfactory, nonetheless, with high individual variability. After a median follow-up time of 34 days, no death or viral pneumonia were observed. Nevertheless, 2 patients experienced early SARS-CoV-2 infection relapses (at day-10 and day-21) associated with an increase in SARS-CoV-2 viral loads. Conclusion: NR can be used in KTRs but requires a strict protocol of drug adaptation. We observed 2 cases of early relapse after NR treatment that need further investigations.

A comparative analysis of the outcomes of patients with influenza or COVID-19 in a tertiary hospital in Belgium.

INTRODUCTION: The COVID-19 pandemic has emerged as a global health problem, associated with high morbidity and mortality rates. The aim of this study was to compare the outcomes of hospitalized patients with COVID-19 or with seasonal influenza in a teaching hospital in Belgium. METHODS: In this retrospective, single-center cohort study, 1384 patients with COVID-19 and 226 patients with influenza were matched using a propensity score with a ratio of 3:1. Primary outcomes included admission to intensive care unit (ICU), intubation rates, hospital length of stay, readmissions within 30 days and in-hospital mortality. Secondary outcomes included pulmonary bacterial superinfection, cardiovascular complications and ECMO. RESULTS: Based on the analysis of the matched sample, patients with influenza had an increased risk of readmission within 30 days (Risk Difference (RD): 0.07, 95% CI: 0.03 to 0.11) and admission to intensive care unit (RD: 0.09, 95% CI: 0.03 to 0.15) compared with those with COVID-19. Patients with influenza had also more pulmonary bacterial superinfections (46.2% vs 7.4%) and more cardiovascular complications (32% vs 3.9%) than patients with COVID-19.However, a two-fold increased risk of mortality (RD: -0.10, 95% CI: 0.15 to -0.05) was observed in COVID-19 compared to influenza. ECMO was also more required among the COVID-19 patients who died than among influenza patients (5% vs 0%). CONCLUSIONS: COVID-19 is associated with a higher in-hospital mortality compared to influenza infection, despite a high rate of ICU admission in the influenza group. These findings highlighted that the severity of hospitalized patients with influenza should not be underestimated.

HYGIEIA: HYpothesizing the Genesis of Infectious Diseases and Epidemics through an Integrated Systems Biology Approach.

More than two years on, the COVID-19 pandemic continues to wreak havoc around the world and has battle-tested the pandemic-situation responses of all major global governments. Two key areas of investigation that are still unclear are: the molecular mechanisms that lead to heterogenic patient outcomes, and the causes of Post COVID condition (AKA Long-COVID). In this paper, we introduce the HYGIEIA project, designed to respond to the enormous challenges of the COVID-19 pandemic through a multi-omic approach supported by network medicine. It is hoped that in addition to investigating COVID-19, the logistics deployed within this project will be applicable to other infectious agents, pandemic-type situations, and also other complex, non-infectious diseases. Here, we first look at previous research into COVID-19 in the context of the proteome, metabolome, transcriptome, microbiome, host genome, and viral genome. We then discuss a proposed methodology for a large-scale multi-omic longitudinal study to investigate the aforementioned biological strata through high-throughput sequencing (HTS) and mass-spectrometry (MS) technologies. Lastly, we discuss how a network medicine approach can be used to analyze the data and make meaningful discoveries, with the final aim being the translation of these discoveries into the clinics to improve patient care.

Urine metabolomics links dysregulation of the tryptophan-kynurenine pathway to inflammation and severity of COVID-19.

SARS-CoV-2 causes major disturbances in serum metabolite levels, associated with severity of the immune response. Despite the numerous advantages of urine for biomarker discovery, the potential association between urine metabolites and disease severity has not been investigated in coronavirus disease 2019 (COVID-19). In a proof-of-concept study, we performed quantitative urine metabolomics in patients hospitalized with COVID-19 and controls using LC-MS/MS. We assessed whether metabolites alterations were associated with COVID-19, disease severity, and inflammation. The study included 56 patients hospitalized with COVID-19 (26 non-critical and 30 critical disease); 16 healthy controls; and 3 controls with proximal tubule dysfunction unrelated to SARS-CoV-2. Metabolomic profiling revealed a major urinary increase of tryptophan metabolites kynurenine (P < 0.001), 3-hydroxykynurenine (P < 0.001) and 3-hydroxyanthranilate (P < 0.001) in SARS-CoV-2 infected patients. Urine levels of kynurenines were associated with disease severity and systemic inflammation (kynurenine, r 0.43, P = 0.001; 3-hydroxykynurenine, r 0.44, P < 0.001). Increased urinary levels of neutral amino acids and imino acid proline were also common in COVID-19, suggesting specific transport defects. Urine metabolomics identified major alterations in the tryptophan-kynurenine pathway, consistent with changes in host metabolism during SARS-CoV-2 infection. The association between increased urinary levels of kynurenines, inflammation and COVID-19 severity supports further evaluation of these easily available biomarkers.