Efficacy and safety of the investigational complement C5 inhibitor zilucoplan in patients hospitalized with COVID-19: an open-label randomized controlled trial.

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

A public health value-based healthcare paradigm for HIV.

BACKGROUND: HIV patients face considerable acute and chronic healthcare needs and battling the HIV epidemic remains of the utmost importance. By focusing on health outcomes in relation to the cost of care, value-based healthcare (VBHC) proposes a strategy to optimize quality of care and cost-efficiency. Its implementation may provide an answer to the increasing pressure to optimize spending in healthcare while improving patient outcomes. This paper describes a pragmatic value-based healthcare framework for HIV care. METHODS: A value-based HIV healthcare framework was developed during a series of roundtable discussions bringing together 16 clinical stakeholder representatives from the Belgian HIV reference centers and 2 VBHC specialists. Each round of discussions was focused on a central question translating a concept or idea to the next level of practical implementation: 1) how can VBHC principles be translated into value-based HIV care drivers; 2) how can these value-based HIV care divers be translated into value-based care objectives and activities; and 3) how can value-based HIV care objectives and activities be translated into value-based care indicators. Value drivers were linked to concrete objectives and activities using a logical framework approach. Finally, specific, measurable, and acceptable structure, process and outcomes indicators were defined to complement the framework. RESULTS: Our framework identifies 4 core value areas where HIV care would benefit most from improvements: Prevention, improvement of the cascade of care, providing patient-centered HIV care and sustaining a state-of-the-art HIV disease management context. These 4 core value areas were translated into 12 actionable core value objectives. For each objective, example activities were proposed. Indicators are suggested for each level of the framework (outcome indicators for value areas and objectives, process indicators for suggested activities). CONCLUSIONS: This framework approach outlines how to define a patient- and public health centered value-based HIV care paradigm. It proposes how to translate core value drivers to practical objectives and activities and suggests defining indicators that can be used to track and improve the framework's implementation in practice.

Dynamics of the Cellular and Humoral Immune Response After BNT162b2 Messenger Ribonucleic Acid Coronavirus Disease 2019 (COVID-19) Vaccination in COVID-19-Naive Nursing Home Residents.

Short-term humoral and cellular immune responses are diminished after BNT162b2 messenger ribonucleic acid coronavirus disease 2019 (COVID-19) vaccination in COVID-19-naive nursing home residents, a population particularly vulnerable to the disease. We found both responses to decline after 4 weeks and remain lower than those of healthcare workers after 24 weeks, with an estimated half-life of the antibody response of 47 days. At 4 weeks, older age was significantly associated with a decreased humoral response, and diabetes mellitus and active malignancy were associated with a decreased cellular response. Our results imply that COVID-19-naive nursing home residents are a target group for booster vaccination trials.

Clinical characteristics and outcomes of COVID-19 in people living with HIV in Belgium: A multicenter, retrospective cohort.

The aim of this study was to describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among people living with HIV (PLWH) in Belgium. We performed a retrospective multicenter cohort analysis of PLWH with either laboratory-confirmed, radiologically diagnosed, or clinically suspected COVID-19 between February 15, 2020 and May 31, 2020. The primary endpoint was outcome of COVID-19. Secondary endpoints included rate of hospitalization and length of hospital stay and rate of Intensive Care Unit (ICU) admission and mechanical ventilation. One hundred and one patients were included in this study. Patients were categorized as having either laboratory-confirmed (n = 65), radiologically-diagnosed (n = 3), or clinically suspected COVID-19 (n = 33). The median age was 51.3 years (interquartile range [IQR] 41.3-57.3) and 44% were female. Ninety-four percent of patients were virologically suppressed and 67% had a CD4+ cell count more than or equal to 500 cells/µl. Overall, 46% of patients required hospitalization and the median length of hospital stay was 6 days (IQR 3-15). Age more than or equal to 50 years, Black Sub-Saharan African patients, and being on an integrase strand transfer inhibitor-based regimen were associated with being hospitalized. ICU admission and mechanical ventilation was required for 15% and 10% of all patients respectively. Overall, 9% of patients died while 78 (77%) patients made a full recovery. HIV patients with COVID-19 experienced a high degree of hospitalization despite having elevated CD4+ cell counts and a high rate of virologic suppression. Matched case-control studies are warranted to measure the impact that HIV may have on patients with COVID-19.

Mycoplasma genitalium acquisition and macrolide resistance after initiation of HIV pre-exposure prophylaxis in men who have sex with men.

OBJECTIVES: Recent evidence shows that patients using HIV pre-exposure prophylaxis (PrEP) have an increased rate of bacterial STIs, including syphilis, chlamydia and gonorrhoea. Our study aimed to describe the acquisition and the susceptibility for macrolides of Mycoplasma genitalium in men who have sex with men (MSM) on PrEP. METHODS: We studied all MSM who started PrEP in the AZ Sint-Jan Hospital Bruges from 1 June 2017 to 31 March 2019 with at least one follow-up visit. Patients were screened for M. genitalium and other STIs with pooled rectal swabs, pharyngeal swabs and first-voided urine, and blood samples at baseline and quarterly intervals after initiating PrEP. TaqMan Array Card technology was used to detect M. genitalium and determine macrolide-resistance mediating mutations in region V of the 23S rRNA gene (A2058G, A2059G, A2058C and others). Patients with an STI were treated based on a national guideline. RESULTS: 131 MSM (median age 40 years, range 20-79) were included in the study. The median follow-up time was 12 months (IQR 6.1-17). Baseline prevalence of M. genitalium was 6.9% and incidence rate after PrEP initiation was 28.8 per 100 person-years (95% CI 21.7 to 37.2), without significant differences in proportions between the first four quarterly intervals. All but one acquisitions were asymptomatic. Younger age and positivity for M. genitalium at baseline were significantly associated with incident M. genitalium acquisition. The observed proportion of macrolide resistance increased not significantly from 44% at baseline to 57%-86% after PrEP initiation. None of the 27 macrolide-resistant M. genitalium acquisitions could be linked to azithromycin exposure in the three preceding months. CONCLUSIONS: After initiation of PrEP, we found a stable incidence of almost exclusively asymptomatic M. genitalium. However, a non-significant trend of an increased percentage of macrolide-resistant strains was observed.

A case of a surgical-site infection with Staphylococcus condimenti.

INTRODUCTION: Coagulase-negative staphylococci (CNS) are considered to have a medium or low pathogenic capacity when compared to S. aureus. Among the more harmless, CNS are those that are used in the food industry, represented by S. carnosus, whose genome has extensively been studied. Its genome was found to contain several genomic sequences that have a virulent function in the pathogenic S. aureus. Even though these genes are probably not virulent in S. carnosus, their presence might indicate a more virulent potential. We report the third clinical case associated with a surgical-site infection with S. condimenti, which belongs to these food industry related CNS. It corresponds to a blood stream infection, secondary to a surgical-site infection. RESULTS: Antibiotic susceptibility testing indicated a resistance to erythromycin and rifampicin, which was partly confirmed by the presence of a macrolide resistance gene by PCR screening for S. aureus virulence factors. Although no other putative virulence factors were detected, this organism managed to cause a severe post-operative wound infection. CONCLUSION: This case shows that CNS that are currently used in the food industry may play a role in human infection. With technologies such as MALDI-TOF, pathogens that are regarded non-pathogenic could be identified more often. Therefore, the risk of different Staphylococcus strains used in the food industry must be better assessed.

Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations.

Objectives: To develop a population model describing temocillin pharmacokinetics (PK) in patients undergoing haemodialysis and investigate how pharmacokinetic/pharmacodynamic (PD) targets can be met with different dosage regimens. Patients and methods: Sixteen patients received the currently licenced dosing of 1, 2 or 3 g of temocillin (total of 61 doses) corresponding to an inter-dialytic period of 20, 44 or 68 h, respectively, and a dialysis period of 4 h. A non-linear mixed-effects model was developed jointly for total and unbound temocillin serum concentrations. The performance of clinically feasible dosing regimens was evaluated using a 5000-subject Monte Carlo (MC) simulation for determining the highest MIC for which the PK/PD target of 40%ƒT>MIC would be reached in 90% of patients [probability of target attainment (PTA)]. This PK study was registered at ClinicalTrials.gov (NCT02285075). Results: Temocillin unbound and total serum concentrations (429 samples) were used to fit an open two-compartment model with non-linear albumin binding and first-order elimination. In addition to total body clearance, dialysis clearance was modelled using the Michaels function. The currently licenced dosing achieved a 90% PTA for an MIC up to 8 mg/L. A new temocillin dosage regimen was designed that would achieve a 90% PTA for an MIC of 16 mg/L (MIC90 of target organisms) adjusted to patient weight and inter-dialytic period. Conclusions: Currently licensed dosage regimen is suboptimal for MICs >8 mg/L (frequently found in clinical isolates). Model-based simulations allowed suggestion of a new dosage regimen with improved probability of microbiological success, applicability in routine clinical practice and more appropriate for empirical therapy.

Bone scan findings in erythromelalgia.

The use of hyaluronic acid nanoshells has been proposed to encapsulate prodrugs and exploit the mechanisms of interactions between living cells, like endocytes or cancer cells and hyaluronic acid, which is a natural component of the extracellular matrix. In this review we describe the potential and the limits of this promising research trend and discuss the theoretical advantages of such an engineering approach. Is it a possible scalability to increase the efficacy and biodegradability of molecules like contrast media and radiotracers especially for neuroradiology and nuclear medicine studies.

Dose-finding study of rivaroxaban in hemodialysis patients.

BACKGROUND: Use of vitamin K antagonists for the prevention of stroke and systemic embolism in dialysis patients with nonvalvular atrial fibrillation is controversial. However, no good alternatives presently are available. The anti-factor Xa antagonist rivaroxaban is contraindicated for lack of pharmacokinetic, pharmacodynamic, and clinical data. This study aims to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban in maintenance hemodialysis patients. STUDY DESIGN: Pharmacokinetic and pharmacodynamic study. SETTING & PARTICIPANTS: 18 maintenance hemodialysis patients without residual kidney function at 2 centers. DRUG ADMINISTRATION, OUTCOMES, & MEASUREMENTS: (1) A single dose of 10mg of rivaroxaban was administered at the end of each of 3 consecutive dialysis sessions and area under the curve (AUC) and the effect on coagulation parameters were measured for 44 hours thereafter. (2) A single dose of 10mg of rivaroxaban was given 6 to 8 hours before a dialysis session and the effect of dialysis on rivaroxaban concentrations was evaluated. (3) To assess potential accumulation, 10mg of rivaroxaban was given once daily and AUC was measured during 24 hours on days 1 and 7. RESULTS: Mean AUC0-44 of rivaroxaban plasma concentrations after a single dose of 10mg was 2,072µg/L/h, mean maximum concentration was 172.6µg/L, and mean terminal elimination half-life was 8.6 hours. Dialysis had no appreciable effect on rivaroxaban plasma concentrations. Mean trough concentration after multiple daily doses of 10mg was 20.2µg/L. LIMITATIONS: Higher rivaroxaban doses and patients with substantial residual kidney function were not studied. CONCLUSIONS: A 10-mg dose of rivaroxaban in hemodialysis patients without residual kidney function results in drug exposure similar as published for 20mg in healthy volunteers. Rivaroxaban is not eliminated by dialysis. There is no accumulation after multiple daily dosing. The efficacy and safety of rivaroxaban in hemodialysis patients should be the subject of a large randomized trial.

A patient-centered vision of care for ESRD: dialysis as a bridging treatment or as a final destination?

The ESRD population is heterogeneous, including patients without severe comorbidity for whom dialysis is a bridge to transplantation or a long-term maintenance treatment, as well as patients with a limited life expectancy as a result of advanced age or severe comorbidity for whom dialysis will be the final treatment destination. The complex medical and social context of this latter group fits poorly in the homogeneous, disease-centered, and process-driven approach of many clinical practice guidelines for dialysis. In this commentary, we argue that the standards of treatment allocated to each individual patient should be defined not merely by his or her disease state, but also by his or her preferences and prognosis. In this more patient-centered approach, three attainable treatment goals with a corresponding therapeutic approach could be defined: (1) dialysis as bridging or long-term maintenance treatment, (2) dialysis as final treatment destination, and (3) active medical management without dialysis. For patients with a better overall prognosis, this approach will emphasize complication prevention and long-term survival. For patients with a limited overall prognosis, strictly disease-centered interventions often impose a treatment burden that does not translate into a proportional improvement in quantity or quality of life. For these patients, a patient-centered approach will place more emphasis on palliative management strategies that are less disease specific.

Hemodialysis catheter design and catheter performance: a randomized controlled trial.

BACKGROUND: A complication of long-term use of tunneled cuffed catheters for hemodialysis is the high rate of infection and thrombus-related dysfunction. Specific mechanical features of tunneled cuffed catheters may improve hemodynamic performance and decrease thrombosis and infection rates. However, there currently is no proven advantage of one design over another. STUDY DESIGN: Single-center randomized clinical trial. SETTING & PARTICIPANTS: 302 hemodialysis patients who required a tunneled cuffed catheter as temporary or definite vascular access. INTERVENTION: Palindrome Symmetric Tip Dialysis Catheter or HemoStar Long-Term Hemodialysis Catheter. OUTCOMES & MEASUREMENTS: The primary end point was primary assisted patency. Secondary end points were incidence of catheter-related bloodstream infections (CRBSIs), thrombosis, and 2 indicators of rheologic function: mean effective blood flow rate and urokinase use. RESULTS: Mean primary assisted patency was 135.9 days for Palindrome and 136.5 days for HemoStar (P=0.8). Definite CRBSI occurred in 0.24 and 0.10/1,000 catheter-days for Palindrome and HemoStar, respectively (P=0.3). Removal rates for thrombosis that could not be resolved with thrombolysis were 0.53 and 0.43/1,000 catheter-days for Palindrome and HemoStar, respectively (P=0.7). Urokinase use was lower for Palindrome than for HemoStar, as evidenced by a lower number of urokinase infusions/1,000 catheter-days (17 and 35; P<0.001) and higher number of catheters that never required thrombolysis (58% and 45%; P=0.03). Mean effective blood flow rate was higher for Palindrome than for HemoStar (333 and 304mL/min; P<0.001). LIMITATIONS: Single-center nonblinded trial. CONCLUSIONS: Primary assisted patency and incidence of infection and thrombosis were similar for both catheter types. The Palindrome catheter required less thrombolysis and achieved higher blood flow rates than the HemoStar catheter. These findings suggest that mechanical catheter design may improve catheter rheology, but does not affect risks for thrombosis and infection and hence catheter survival.

Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study.

BACKGROUND: Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP. METHODS: To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 µg of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire. RESULTS: At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets. CONCLUSIONS: Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.

Longitudinal patterns of inflammatory mediators after acute HIV infection correlate to intact and total reservoir.

Background: Despite the beneficial effects of antiretroviral therapy (ART) initiation during acute HIV infection (AHI), residual immune activation remains a hallmark of treated HIV infection. Methods: Plasma concentrations of 40 mediators were measured longitudinally in 39 early treated participants of a Belgian AHI cohort (HIV+) and in 21 HIV-negative controls (HIV-). We investigated the association of the inflammatory profile with clinical presentation, plasma viral load, immunological parameters, and in-depth characterization of the HIV reservoir. Results: While levels of most soluble mediators normalized with suppressive ART, we demonstrated the persistence of a pro-inflammatory signature in early treated HIV+ participants in comparison to HIV- controls. Examination of these mediators demonstrated a correlation with their levels during AHI, which seemed to be viremia-driven, and suggested involvement of an activated myeloid compartment, IFN-γ-signaling, and inflammasome-related pathways. Interestingly, some of these pro-inflammatory mediators correlated with a larger reservoir size and slower reservoir decay. In contrast, we also identified soluble mediators which were associated with favorable effects on immunovirological outcomes and reservoir, both during and after AHI. Conclusion: These data highlight how the persistent pro-inflammatory profile observed in early ART treated individuals is shaped during AHI and is intertwined with viral dynamics.

Should we screen for coronary artery disease in asymptomatic chronic dialysis patients?

The hemodialysis population is characterized by a high prevalence of 'asymptomatic' coronary artery disease (CAD), which should be interpreted differently from asymptomatic disease in the general population. A hemodynamically significant stenosis may not become clinically apparent owing to impaired exercise tolerance and autonomic neuropathy. The continuous presence of silent ischemia may cause heart failure, arrhythmias, and sudden death. Whether revascularization of an asymptomatic dialysis patient improves outcome remains a moot point, although several observational studies and one small RCT suggest a benefit. It can therefore be defended to screen asymptomatic dialysis patients for CAD. A number of noninvasive screening tests are available, but none has proved equally practical and reliable in the dialysis population as in the general population. Myocardial perfusion scintigraphy (MPS) before and after a pharmacological stress such as dipyridamole can reveal both ischemia and myocardial scarring. When compared with coronary angiography, low sensitivities were reported and attributed to impaired vasodilation to dipyridamole in dialysis patients. A more likely explanation is that not every anatomical stenosis will lead to impaired coronary blood flow on MPS. Numerous studies have shown an incremental prognostic value of dipyridamole-MPS over clinical data for prediction of adverse cardiac events, in some studies even over coronary angiography. Pending the availability of high-quality evidence, in our opinion asymptomatic dialysis patients could undergo dipyridamole-MPS, followed by coronary angiography in case of an abnormal scan. This combined physiological and anatomical evaluation of the coronary circulation allows us to determine which coronary stenosis is clinically relevant and therefore should be revascularized.

Chronic Schistosomiasis Presenting with Migrating Pulmonary Manifestation after Recent COVID-19 Infection: HRCT Findings.

Teaching Point: Chronic pulmonary schistosomiasis should be suspected in symptomatic patients with an endemic background presenting with migrating pulmonary lesions on high resolution computed tomography scan.

Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment.

GM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22).

Implementation of a dose calculator for vancomycin to achieve target trough levels of 15-20 microg/mL in persons undergoing hemodialysis.

UNLABELLED: (See the article by Brown et al, on pages 164-166.) BACKGROUND: Vancomycin is a key antibiotic for the treatment of Gram-positive bacterial infections in patients undergoing dialysis. Vancomycin has a narrow therapeutic range. Overdosing imposes a risk of nephro- and ototoxicity, wherease underdosing predisposes to treatment failure and the emergence of drug resistance. Trough levels of 15-20 µg/mL have been identified as the optimal target trough levels. METHODS: A multivariate model called the vancomycin dose calculator (VDC) was prospectively developed and validated to permit accurate vancomycin dosing in persons undergoing hemodialysis. RESULTS: The model identified 3 simple parameters that were responsible for 94.6% of the variance observed: predialysis vancomycin trough level, dry body weight, and period to the next dialysis session. Maintenance dosing was accurate in 77.9% of patients, whereas major over- and underdosing were avoided in the remaining patients. The mean measured trough level of 16.5 µg/mL was 5.6% lower than the mean predicted trough level of 17.5 µg/mL. With regard to loading doses, a fixed loading dose of 20 mg/kg led to subtherapeutic trough levels in one-half of patients. CONCLUSIONS: The VDC permits accurate vancomycin maintenance dosing based on predialysis trough level, dry body weight, and period to the next dialysis session in the majority of patients undergoing hemodialysis. Higher loading doses that accounted for the period to the next dialysis may be more appropriate than fixed loading doses used in this study.