A comprehensive literature scoping review of infection prevention and control methods for viral-mediated gene therapies.

Objective: This comprehensive literature scoping review outlines available infection prevention and control (IPC) methods for viral-mediated gene therapies and provides one IPC strategy for the healthcare setting based on a single-center recommendation. Methods: A team of experts in pharmacy, healthcare epidemiology, and biosafety with experience in viral-mediated gene therapy was assembled within a pediatric hospital to conduct a comprehensive literature scoping review. The comprehensive review included abstracts and full-text articles published since 2009 and utilized prespecified search terms of the five viral vectors of interest: adenovirus (AV), retrovirus (RV), adeno-associated virus (AAV), lentivirus (LV), and herpes simplex virus (HSV). Case reports, randomized controlled trials, and bench research studies were all included, while systematic reviews were excluded. Results: A total of 4473 case reports, randomized control trials, and benchtop research studies were identified using the defined search criteria. Chlorine compounds were found to inactivate AAV and AV, while alcohol-based disinfectants were ineffective. There was a relative paucity of studies investigating surface-based disinfection for HSV, however, alcohol-based disinfectants were effective in one study. Ultraviolent irradiation was also found to inactivate HSV in numerous studies. No studies investigated disinfection for LV and RV vectors. Conclusions: The need to define IPC methods is high due to the rapid emergence of viral-mediated gene therapies to treat rare diseases, but published clinical guidance remains scarce. In the absence of these data, our center recommends a 1:10 sodium hypochlorite solution in clinical and academic environments to ensure complete germicidal activity of viral-mediated gene therapies.

ACKR3 Proximity Labeling Identifies Novel G protein- and ß-arrestin-independent GPCR Interacting Proteins.

The canonical paradigm of GPCR signaling recognizes G proteins and ß-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and ß-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of ß-arrestin. We identified proteins involved in the endocytic machinery and evaluated a subset of proteins conserved across several GPCR-based proximity labeling experiments. We discovered that the bone morphogenic protein 2-inducible kinase (BMP2K) interacts with many different GPCRs with varying dependency on ß-arrestin. Together, our work highlights the existence of modulators that can act independently of G proteins and ß-arrestins to regulate GPCR signaling and provides important evidence for other targets that may regulate GPCR signaling.

GPCR kinases differentially modulate biased signaling downstream of CXCR3 depending on their subcellular localization.

Some G protein-coupled receptors (GPCRs) demonstrate biased signaling such that ligands of the same receptor exclusively or preferentially activate certain downstream signaling pathways over others. This phenomenon may result from ligand-specific receptor phosphorylation by GPCR kinases (GRKs). GPCR signaling can also exhibit location bias because GPCRs traffic to and signal from subcellular compartments in addition to the plasma membrane. Here, we investigated whether GRKs contributed to location bias in GPCR signaling. GRKs translocated to endosomes after stimulation of the chemokine receptor CXCR3 or other GPCRs in cultured cells. GRK2, GRK3, GRK5, and GRK6 showed distinct patterns of recruitment to the plasma membrane and to endosomes depending on the identity of the biased ligand used to activate CXCR3. Analysis of engineered forms of GRKs that localized to either the plasma membrane or endosomes demonstrated that biased CXCR3 ligands elicited different signaling profiles that depended on the subcellular location of the GRK. Each GRK exerted a distinct effect on the regulation of CXCR3 engagement of ß-arrestin, internalization, and activation of the downstream effector kinase ERK. Our work highlights a role for GRKs in location-biased GPCR signaling and demonstrates the complex interactions between ligands, GRKs, and cellular location that contribute to biased signaling.

Location bias: A "Hidden Variable" in GPCR pharmacology.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and ß-arrestins. Many agonists of GPCRs promote "biased" responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential "hidden variables" that regulate this behavior. One contributor is "location bias," which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.

Phosphorylation barcodes direct biased chemokine signaling at CXCR3.

G protein-coupled receptor (GPCR)-biased agonism, selective activation of certain signaling pathways relative to others, is thought to be directed by differential GPCR phosphorylation "barcodes." At chemokine receptors, endogenous chemokines can act as "biased agonists", which may contribute to the limited success when pharmacologically targeting these receptors. Here, mass spectrometry-based global phosphoproteomics revealed that CXCR3 chemokines generate different phosphorylation barcodes associated with differential transducer activation. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomics studies. Mutation of CXCR3 phosphosites altered ß-arrestin 2 conformation in cellular assays and was consistent with conformational changes observed in molecular dynamics simulations. T cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles. Our results demonstrate that CXCR3 chemokines are non-redundant and act as biased agonists through differential encoding of phosphorylation barcodes, leading to distinct physiological processes.

Phosphorylation barcodes direct biased chemokine signaling at CXCR3.

G protein-coupled receptor (GPCR) biased agonism, the activation of some signaling pathways over others, is thought to largely be due to differential receptor phosphorylation, or "phosphorylation barcodes." At chemokine receptors, ligands act as "biased agonists" with complex signaling profiles, which contributes to the limited success in pharmacologically targeting these receptors. Here, mass spectrometry-based global phosphoproteomics revealed that CXCR3 chemokines generate different phosphorylation barcodes associated with differential transducer activation. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered ß-arrestin conformation in cellular assays and was confirmed by molecular dynamics simulations. T cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles. Our results demonstrate that CXCR3 chemokines are non-redundant and act as biased agonists through differential encoding of phosphorylation barcodes and lead to distinct physiological processes.

The evaluation of electrolyzed water, sodium dichloroisocyanurate, and peracetic acid with hydrogen peroxide for the disinfection of patient room surfaces.

BACKGROUND: Sporicidal disinfectants are necessary to control Clostridioides difficile and Candida auris. Novel application methods such as electrostatic sprayers may increase disinfection effectiveness. We employed a standardized protocol to assess 3 sporicidal disinfectants: electrolyzed water (EW), sodium dichloroisocyanurate (NaDCC) and peracetic acid/hydrogen peroxide (PAA/H2O2). METHODS: The study was conducted at 2 New York City hospitals (1,082 total beds) over an 18-month period. The 3 chemicals were applied by housekeeping personnel following the hospital protocol; the use of electrostatic sprayers was incorporated into EW and NaDCC. In randomly selected rooms, 5 surfaces were sampled for microbial colony counts after cleaning. Data analyses were performed using negative binomial logistic regression. RESULTS: We collected 774 samples. NaDCC-disinfected surfaces had a lower mean colony count (14 colony forming units [CFU]) compared to PAA/H2O2 (18 CFU, P = .36) and EW (37 CFU, P < .001). PAA/H2O2 and EW had more samples with any growth (both P < .05) compared to NaDCC. NaDCC applied with wipes and an electrostatic sprayer had the lowest number of samples with no growth and <2.5 CFU/cm2 (difference not significant). CONCLUSIONS: The use of NaDCC for surface disinfection resulted in the lowest bacterial colony counts on patient room high touch surfaces in our study.

Rethinking Surge Preparedness After COVID-19: Effective Patient Load Balancing Within Health Systems and Beyond.

Within weeks of New York State's first confirmed case of COVID-19, New York City became the epicenter of the nation's COVID-19 pandemic. With more than 80,000 COVID-19 hospitalizations during the first wave alone, hospitals in downstate New York were forced to adapt existing procedures to manage the surge and care for patients facing a novel disease. Given the unprecedented surge, effective patient load balancing-moving patients from a hospital with diminishing capacity to another hospital within the same health system with relatively greater capacity-became chief among the capabilities required of New York health systems. The Greater New York Hospital Association invited members of downstate New York's 6 largest health systems to talk about how each of their systems evolved their patient load balancing procedures throughout the pandemic. Informed by their insights, experiences, lessons learned, and collaboration, we collectively present a set of consensus recommendations and best practices for patient load balancing at the facility and health system level, which may inform regional approaches to patient load balancing.

Location bias contributes to functionally selective responses of biased CXCR3 agonists.

Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, ß-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, ß-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.

A Qualitative Exploration of Pregnancy Experience With a Nutrient-Dense, Plant-Rich Dietary Pattern: A Pilot Study.

INTRODUCTION: A nutrient-dense, plant-rich diet may be promising as a nutrition intervention for pregnant women for a number of factors. Factors include the possibility of a decreased risk for gestational diabetes, excess weight gain, and preeclampsia. Little is known about the experience of following this type of dietary pattern while pregnant and what barriers are present that should be addressed in a large-scale intervention. METHODS: Qualitative interviews were used to understand the personal experience of women who aimed to eat a nutrient-dense plant-rich diet while pregnant. Semi-structured interviews were conducted from June to August 2020. RESULTS: Three main themes regarding a nutrient-dense plant-rich diet emerged. First, family and social influence played an important role. Second, women who had a previous pregnancy felt they had fewer pregnancy symptoms on this diet. Last, the participants may have experienced a reduced milk supply on this dietary plan. CONCLUSION: Future research should consider family context as a factor in adherence to a nutrient-dense plant-rich dietary pattern, investigate the possible associations between nutrient-dense plant-rich dietary patterns and reduced nausea and vomiting in early pregnancy, and determine whether nutrient-dense, plant-rich dietary patterns contribute to a reduction in milk production for women who experience over-engorgement.

Bone marrow fibrosis impact on response to azacitidine in myelodysplastic syndromes.

Bone marrow fibrosis in myelodysplastic syndromes (MDS) has been associated with poor outcome. However, these studies were conducted prior to the widespread use of azacitidine in the management of MDS. Our study aimed to assess whether treatment with azacitidine ameliorates the inferior outcome in MDS with fibrosis. A retrospective study of all patients diagnosed with MDS and treated with azacitidine over 3 years in two institutions was performed. A total of 21 patients were included in this study. Approximately half of these had moderate to severe bone marrow fibrosis at the start of treatment with azacitidine. The median overall survival was 34 months in patients with non-fibrotic bone marrow compared to 14 months in patients with fibrotic marrow (p=0.0007). Median event-free survival was 26 months versus 12 months (p=0.0027) in patients with non-fibrotic and fibrotic marrow, respectively. In multivariate analysis, bone marrow fibrosis was an independent factor in overall survival. Transfusion requirement was not different between the two groups. Despite the small sample size, we observed a worse outcome in azacitidine treated patients with MDS and fibrotic marrow. We suggest a prospective larger study to confirm the above finding.

The impact of a provider motivational interviewing-based training on chronic pain management in a federally-qualified health center.

BACKGROUND: While the issue of opioid misuse is very complex, pharmacists have a unique opportunity to participate in interprofessional, team-based care. Motivational interviewing (MI) has been shown to be effective in chronic disease management and could improve patient engagement and chronic pain outcomes. OBJECTIVES: To determine the impact of an MI-based provider training on changes in chronic pain management prescribing and on provider and patient perceptions. METHODS: Providers participated in a pharmacist-led, 4-session educational intervention covering the CDC opioid prescribing guidelines, pain management, clinical pearls, and MI. Providers were then asked to implement the training in patient appointments for chronic pain management and refer appropriate patients for follow-up on goals. In the follow-up, student pharmacists called patients twice monthly for three months using MI. To address the primary outcome, the number of opioid prescriptions, morphine daily equivalents, and naloxone prescriptions were recorded and compared from the electronic medical record for the year preceding and following the intervention. Patients and providers completed surveys to assess the impact of these interventions. RESULTS: Providers (n = 11) reported increased confidence in MI from baseline to 12 months following the intervention but no change in satisfaction. Patients (n = 19) were able to set and accomplish 20 goals throughout the phone call intervention. Meanwhile, the number of opioid prescriptions significantly decreased from 569 to 368 prescriptions per year before and after the intervention, respectively. Morphine daily equivalents per prescription decreased from 26.8 to 26.4 for the year before versus the year following the intervention. CONCLUSIONS: MI interventions for providers and patients may positively impact goal setting and opioid prescribing. However, MI alone may not successfully address provider satisfaction and patient physical functioning. Pain management is an area that may benefit from a multi-faceted, interprofessional approach.

Food as medicine? Exploring the impact of providing healthy foods on adherence and clinical and economic outcomes.

Background: Chronic disease prevalence is increasing. Adherence to dietary guidelines is low (<50%) despite positive impacts in disease progression, clinical outcomes, and medical costs. It is important to summarize the impact of providing medically-tailored meals to patients on adherence rates, clinical outcomes, and potential economic outcomes. Methods: A systematic review was conducted to identify, extract, and appraise food-provision studies from January 1, 2013-May 1, 2018 for heart disease, diabetes (DM), and chronic kidney disease (CKD). The key findings related to adherence and clinical outcomes were compiled. Published literature was utilized to determine the economic impact of key clinical outcomes. Results: Across diseases, 100 articles (N = 43,175 patients) were included. Dietary adherence was considered "compliant" or ≥ 90% consistently. Significant (p < 0.05) clinical outcomes included 5-10% LDL reduction, 4-11 mmHg SBP reduction, 30% reduction in metabolic syndrome prevalence, 3-5% weight reduction, 56% lower CKD mortality rates, and increased dialysis-free time (2 years:50%, 5 years:25%, calculated cost savings of 80.6-94.3%). Literature review showed these outcomes would result in decreased: cardiovascular (CV) event risk (20-30% reduction: $5-11 billion annually), hospitalization costs ($1-8 billion), and dialysis rates (25-50% reduction: $14-29 billion annually). For heart failure patients, results include: 16% fewer readmissions (saving $234,096 per 100 patients) and a 38-day shorter length of stay (saving $79,425 per hospitalization). Conclusion: Providing medically-tailored meals significantly increases dietary adherence above 90% and allows patients to realize significantly better chronic disease control. Through this, patients could experience fewer complications (CV events, hospital readmissions and dialysis), resulting in significant annual US healthcare cost reduction of $27-48 billion.

GPCR systems pharmacology: a different perspective on the development of biased therapeutics.

G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors and are the target of approximately one-third of all Food and Drug Administration (FDA)-approved pharmaceutical drugs. GPCRs interact with many transducers, such as heterotrimeric G proteins, GPCR kinases (GRKs), and ß-arrestins. Recent experiments have demonstrated that some ligands can activate distinct effector proteins over others, a phenomenon termed "biased agonism." These discoveries have raised the potential of developing drugs which preferentially activate therapeutic signaling pathways over those that lead to deleterious side effects. However, to date, only one biased GPCR therapeutic has received FDA approval and many others have either failed to meet their specified primary end points and or demonstrate superiority over currently available treatments. In addition, there is a lack of understanding regarding how biased agonism measured at a GPCR leads to specific downstream physiological responses. Here, we briefly summarize the history and current status of biased agonism at GPCRs and suggest adoption of a "systems pharmacology" approach upon which to develop GPCR-targeted drugs that demonstrate heightened therapeutic efficacy with improved side effect profiles.

Motivational interviewing and vaccine acceptance in children: The MOTIVE study.

BACKGROUND AND OBJECTIVE: Vaccine coverage have been less than desired in young children in part due to parental vaccine hesitancy. Addressing health beliefs through patient-centered communication approaches such as motivational interviewing (MI) may improve vaccine confidence. Thus, the objective of this study was to determine the difference in paediatric vaccination coverage rates based on the Advisory Committee on Immunization Practices (ACIP) and Centers for Disease Control and Prevention (CDC) recommended schedule in children 0-6 years of age after an educational intervention for providers and integration of an MI-based communication tool, MOTIVE (MOtivational Interviewing Tool to Improve Vaccine AcceptancE). METHODS: Paediatric and family practice providers in a federally qualified health center in the United States completed an educational intervention regarding vaccine hesitancy and use of the MOTIVE tool. Providers then implemented the MOTIVE tool to address common health beliefs using strong, presumptive vaccine recommendations and an MI framework during encounters with patients 0-6 years of age. Data were collected from 1-year pre-educational intervention (July 2018-June 2019, N = 2504) and post-intervention (July 2019-March 2020, N = 1954) to examine differences in vaccination coverage rates and documented vaccine refusals. RESULTS: Use of the MOTIVE tool was associated with a statistically significant increase in IIV vaccination coverage rate in children 6 months to 6 years of age (32.4% versus 43.9%, p < 0.01). A significantly increased Hib vaccination coverage rate was observed in children 0-18 months of age. Patients with commercial insurance also had significantly higher vaccination coverage rates for the DTaP, IPV, and VAR vaccines during the intervention period. Use of the MOTIVE tool was associated with a decrease in documented vaccine refusals per 100 patients in children 0-6 years of age (31.5 versus 17.6, p < 0.01). CONCLUSION: Use of an MI-based communication tool may decrease vaccine refusals and improve childhood vaccination coverage rates, particularly for IIV. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03934008, https://clinicaltrials.gov/ct2/show/NCT03934008, deidentified individual participant data will not be made available.

Safety and Efficacy of Prophylactic Levofloxacin in Pediatric and Adult Hematopoietic Stem Cell Transplantation Patients.

Levofloxacin has been widely used for bacteremia prophylaxis in the pre-engraftment setting for patients undergoing hematopoietic stem cell transplantation (HSCT), but data supporting this practice are inconsistent. In addition to concern for lack of benefit, there are also concerns that this practice could increase the rates of Clostridioides difficile (C diff) infections, the incidence of multidrug-resistant organisms (MDRO) or lead to increased incidence of acute graft-versus-host disease (aGVHD) by disrupting the gut microbiome. This study aimed to assess the safety and efficacy of levofloxacin as bacterial prophylaxis in pediatric and young adult patients undergoing allogeneic or autologous HSCT at a single pediatric center. We conducted a retrospective chart review evaluating patients age ≥6 months who underwent HSCT at our center between January 1, 2016, and July 31, 2020. Patients who underwent transplantation before March 2018 did not receive levofloxacin prophylaxis, whereas those who underwent transplantation after April 2018 did receive levofloxacin prophylaxis. Each transplantation was included as a separate episode if the patient underwent more than 1 transplantation during the inclusion time. The primary outcome of this study was the proportion of patients who experienced at least 1 bacterial bloodstream infection (BSI) in the first 100 days post-transplantation. Secondary outcomes included the number of non-levofloxacin antibiotic days post-transplantation, the incidence of aGVHD, the occurrence of C diff infections, and development of MDRO. A total of 370 HSCT recipients with a median age of 6.7 years (range, 0.5 to 39 years) were included in this study. Seventy-two patients had undergone more than 1 transplantation, and thus we had 443 transplantations to observe. Of these, 216 did not include levofloxacin prophylaxis and 227 included levofloxacin prophylaxis. There were no differences in baseline characteristics between the 2 groups except for age; patients in the non-levofloxacin prophylaxis group were younger (8.1 years vs 9.6 years; P = .05). There were no between-group differences in rates of death at 100 days, antibiotic use, fungal infections, or MDRO infections. Patients in the non-prophylaxis group developed more bacterial BSI in the first 100 days post-HSCT (27% versus 17%; P = .004) and more C diff infections (20% versus 9%; P = .003) than patients who received levofloxacin prophylaxis. In addition, more aGVHD was seen in the patients without levofloxacin prophylaxis (P = .014). Levofloxacin prophylaxis given from day -2 of HSCT through engraftment was significantly associated with decreased bacterial BSI in the first 100 days post-transplantation and was not associated with increased risks of C diff, aGVHD, or MDRO. Our study supports the use of levofloxacin prophylaxis in the peritransplantation period. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Protocol and Preliminary Results of the Nutritarian Women's Health Study: A Longitudinal Effectiveness-Implementation Hybrid Study Assessing Dietary Intake and Health Outcomes.

Whole-food plant-rich dietary patterns have been shown to be associated with significant health benefits and disease-risk reduction. One such program, which has been gaining popularity, is the micronutrient-dense plant-rich (mNDPR) "Nutritarian" diet. The goal of this study is to determine the feasibility of implementing an online mNDPR "Nutritarian" intervention program and to determine the effectiveness of this program in reducing risk of chronic disease in women. The Nutritarian Women's Health Study is a long-term online longitudinal hybrid effectiveness-implementation study. Participants are recruited through social media, medical professionals/offices, and nutrition-related events and conferences. Participants receive online nutrition education and complete regular self-reported questionnaires regarding lifestyle, nutrition practices, and health. The online intervention program appears to be feasible and effective. Some decline in dietary adherence, particularly for certain food types, was observed during the study. For groups at risk, based on body mass index or waist-to-height ratio, there were initial decreases in body mass index and waist-to-height that leveled off over time, in some cases returning to baseline measures. The study suggests the implementation of the Nutritarian dietary pattern, through an online intervention component, may be effective in reducing the risk of chronic disease, with implications for clinical and public health practice.

Implementation of a motivational interviewing-based decision tool to improve childhood vaccination rates: Pilot study protocol.

BACKGROUND: Parental concerns regarding the safety and efficacy of vaccines have been on the rise over the past decade, resulting in a decline in comprehensive vaccine coverage in children. Healthcare practitioners face many challenges when recommending childhood vaccinations, with many parents refusing vaccination due to these and other concerns. Effective communication strategies and tools can equip providers to communicate with vaccine hesitant parents, but validated tools are currently lacking. OBJECTIVES: This study aims to develop a validated parental communication tool utilizing motivational interviewing to increase vaccination adherence in children ages 6 years and younger. METHODS: The MOTIVE (Motivational Interviewing Tool to Improve Vaccination Adherence) tool will first be developed based on the most recent literature regarding vaccine hesitancy and related health beliefs. Following tool development, the tool will be reviewed via an external review process to ensure practicality of the tool for use in clinical practice. In implementing the MOTIVE tool, providers and clinic staff will be trained regarding vaccine hesitancy and motivational interviewing. The tool will then be implemented in routine well-child appointments. The primary outcome of this study is the percentage of children 0-6 years of age completing all recommended doses of the core vaccine series after implementation of the MOTIVE tool as compared to prior vaccination years. Secondary outcomes will also include parental attitudes towards vaccines and provider knowledge regarding motivational interviewing components and vaccine hesitancy. PROJECT IMPACT: Following completion of this study, the MOTIVE tool will be made available for other providers for use in their own clinical practice. The availability of effective communication tools will allow healthcare providers to engage in productive conversations regarding vaccination, aiming to increase vaccine uptake.

Biased agonism at chemokine receptors.

In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.