This cohort study assesses the association of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) treatment with risk of SARS-CoV-2 infection among US veterans with migraine disorder. Is there an association of calcitonin gene–related peptide (CGRP) monoclonal antibody (mAb) use with risk of SARS-CoV-2 infection and developing severe clinical outcomes?In this cohort study of 354 294 US veterans with migraine disorder , CGRP mAb treatment was not associated with a significant increase or reduction in risk of SARS-CoV-2 infection, hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death.These findings suggest that CGRP mAbs may be used as a prophylaxis for patients with migraine who are at risk of or have COVID-19. Calcitonin gene–related peptide (CGRP), a neuropeptide involved in migraine pathophysiology, is also a key neuroimmune modulator. CGRP antagonists may help mitigate the hyperinflammatory response observed in patients with COVID-19; however, findings from the literature are contradictory, and to date, no study has investigated the safety and effectiveness of CGRP antagonists against COVID-19.To evaluate the association between CGRP monoclonal antibody (mAb) treatment and risk of SARS-CoV-2 infection and sequela hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death.This retrospective cohort study analyzed the electronic health records of US veterans aged 18 to 65 years who were diagnosed with migraine disorder and were at risk of COVID-19 between January 20, 2020, and May 19, 2022.Initiation of CGRP mAbs.The main outcome was cumulative incidence of SARS-CoV-2 infection. Odds of 30-day hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death were secondary outcomes.Among 8 178 652 eligible person-trials (354 294 veterans), 9992  initiated CGRP mAbs and 8 168 660  did not initiate CGRP mAbs. Over a 28-month follow-up period, 1247 initiators (12.5%) and 780 575 noninitiators (9.6%) tested positive for SARS-CoV-2. After censoring persons who deviated from treatment, the incidence was 7.4 cases per 1000 person-months among initiators and 6.9 per 1000 person-months among noninitiators. The inverse probability–weighted observational analogs of intention-to-treat and per-protocol hazard ratios were 0.95  and 0.93 , respectively. No significant differences in the likelihood of hospitalization , requiring supplemental oxygen , use of mechanical ventilation , or death  were observed between CGRP mAb initiators and noninitiators who tested positive for SARS-CoV-2.In this cohort study, CGRP mAb treatment was not associated with positive SARS-CoV-2 test results or risk of severe COVID-19 outcomes, suggesting that CGRP mAbs may be used for migraine prevention during the COVID-19 pandemic. Given the few events of requiring supplemental oxygen, use of mechanical ventilation, and death, replication analysis in a larger sample of patients later in the course of disease is warranted. Preliminary studies on the effect of CGRP in sepsis or COVID-19 are inconsistent. A blinded randomized trial in a porcine model found that olcegepant was not beneficial in polymicrobial sepsis.12 A cross-sectional study reported that CGRP levels were decreased in 57 patients with COVID-19 and suggested that restoration of normal CGRP circulatory levels can be therapeutic.13 On the contrary, another prospective cohort study observed that higher plasma CGRP levels were associated with a higher risk of hospitalization and pulmonary intravascular coagulopathy, highlighting a role for plasma CGRP in sustaining COVID-19–related hyperinflammation.14 Furthermore, a multicenter study did not find significant differences in COVID-19 prevalence or disease course among 300 patients with migraine who received or did not receive CGRP mAbs.15 To address this knowledge gap, we used data from the Veterans Health Administration (VHA), the largest integrated health system in the US, and emulated a target trial to examine the association of CGRP mAbs with risk of SARS-CoV-2 infection and developing severe clinical outcomes among US veterans who were diagnosed with migraine disorder between January 20, 2020, and May 19, 2022.Cytokine storm is implicated in severe COVID-19, leading to acute respiratory distress syndrome and septic shock.STROBE) reporting guideline for cohort studies.We designed this retrospective cohort study to emulate a target trial of CGRP mAbs vs placebo among US veterans who were diagnosed with migraine disorder in the VHA. 16 The eligibility criteria were the same as those described for the target trial. To minimize measurement errors, we restricted the study sample to individuals in regular contact with the health care system, as prescriptions and hospitalizations outside the VHA were not captured. Individuals who had serious hypersensitivity to CGRP mAbs were rare and difficult to identify using administrative data. Therefore, we assumed that receiving CGRP mAbs indicated that there was a determination of no hypersensitivity. CGRP mAb prescriptions were identified using outpatient pharmacy records for erenumab, fremanezumab (225 mg/1.5 mL), and galcanezumab (120 mg/mL). We searched for eptinezumab but found no records of dispense. Individuals with a concurrent cluster headache and receiving galcanezumab, 100 mg/mL, were excluded from the study. Next, we classified eligible individuals according to the strategy of compatibility with their data at baseline. We assumed groups were exchangeable conditional on baseline demographics , care assessment need score,17 migraine characteristics , comorbidities , and number of COVID-19 vaccine doses  COVID-19 Shared Data Resource, which includes analytical variables provisioned by the VA Informatics and Computing Infrastructure on all VHA enrollees who had a polymerase chain reaction test positive for SARS-CoV-2 within the VHA system or those who tested positive outside the VHA but were documented in the VHA records. COVID-19–related clinical outcomes  within 30 days of an index positive SARS-CoV-2 test result, COVID-19–related symptoms within 30 days prior to the index date, and inflammatory markers within 7 days after the index date were extracted from the VA COVID-19 Shared Data Resource for secondary and exploratory analyses. We defined the date of CGRP mAb initiation to be the first date of a prescription release from the pharmacy and calculated the discontinuation date using the monthly dose and quantity of autoinjectors in each prescription. We considered treatment to be continuous if there was a gap of less than 30 days following the end of the days’ supply of the last fill. Each individual was followed up from baseline until the month of first COVID-19 infection, death, loss of follow-up (defined as the last date of a VHA encounter in October 2022), or administrative end of follow-up , whichever happened first. The emulated target trial was a series of trials starting at each of the 28 months between January 20, 2020, and May 19, 2022. Each individual may have met the eligibility criteria several times over the follow-up period and participated in multiple trials.For statistical efficiency, we estimated the association of CGRP mAb treatment with risk of SARS-CoV-2 infection by pooling data across all eligible person-trials. The intention-to-treat analysis examined the association of initiation of CGRP mAbs at baseline with risk of SARS-CoV-2 infection. To estimate the observational analog, we fitted a pooled logistic regression model including an indicator of CGRP mAb initiation and baseline confounders. We assumed that there were no unmeasured confounders. Given the covariates included in the model and a low monthly incidence of SARS-CoV-2 infection within levels of those covariates, the exponentiated coefficient for the CGRP mAb initiator approximated the intention-to-treat hazard ratio (HR). Of interest, the per-protocol analysis examined the association of adherence to the assigned treatment strategy throughout follow-up, which required additional adjustment for potential selection bias due to loss of follow-up. Estimation of the per-protocol outcome needed to be adjusted for potential selection bias due to loss of follow-up. First, we censored individuals at the month when they discontinued CGRP mAb treatment in the initiator group and censored individuals at the month when they initiated CGRP mAbs in the noninitiator group. Next, we fitted the same pooled logistic regression model as for the intention-to-treat analysis with this censored data, with stabilized inverse probability of treatment weighting (IPTW) applied to adjust for time-varying confounders . We estimated the weight by fitting 2 separate models to allow the probability to differ according to prior treatment status among (1) person-trials that included participants who were untreated in the previous month or (2) person-trials that included participants who were treated in the previous month. Because we allowed a 30-day gap, the probability of receiving treatment for the month after treatment initiation was equal to 1. Individuals stopped contributing to the weight models once they deviated from their assigned treatment strategy. We evaluated different covariate structures to select the best-fitted model that produced weights with smaller variance. A mean estimated weight far from 1 or the presence of extreme values was considered as a model misspecification or violation of the positivity assumption.2 tests. Inflammatory markers were displayed as medians and IQRs and compared using a Wilcoxon rank sum test. P values were adjusted using the Bonferroni procedure for multiple comparisons. All statistical analyses were performed using R, version 4.1.3 . A 2-tailed P value <.05 was used to indicate statistical significance.Secondary analysis of the clinical outcomes was performed among patients with a positive SARS-CoV-2 test result. Weighted logistic regression was used to estimate the odds of hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death with adjustment of baseline covariates. To address the cluster effect due to replications, robust sandwich-type variance estimation was used to correct the SEs. Preindex symptoms among unique individuals were displayed as counts and percentages, and the difference between initiators and noninitiators were compared using χThe After censoring persons who deviated from their assigned treatment, 565 initiators (5.7%) and 771 215 noninitiators (9.4%) tested positive for SARS-CoV-2. The median duration of initiators receiving CGRP mAbs was 5 months . The incidence of SARS-CoV-2 infection was 7.4 per 1000 person-months among initiators and 6.9 per 1000 person-months among noninitiators. The mean of the stabilized weight was 1.000 and ranged from 0.007 to 50.429. Details of the weight estimation are described in eTables 3 and 4 and the eFigure in P = .04), such as abdominal pain  and sore throat . There were no statistically significant differences in dyspnea between initiators and noninitiators . During the first 7 days after a positive test result, the median C-reactive protein levels were 2.3 mg/dL  among initiators and 2.5 mg/dL  among noninitiators , which was not a significant difference. However, initiators had significantly lower ferritin  and procalcitonin  levels than noninitiators.In this cohort study, we emulated a target trial to evaluate the association of CGRP mAb treatment with SARS-CoV-2 infection and severe clinical outcomes among veterans in the largest integrated health care system in the US. Treatment with CGRP mAb was not associated with risk of SARS-CoV-2 infection. Among those who tested positive for SARS-CoV-2, there were no significant differences in hospitalization, oxygen supplementation, mechanical ventilation, or COVID-19–related death between CGRP mAb initiators and noninitiators.15 However, the ascertainment of cases in that study was mostly based on self-reported symptoms, which may have led to a biased conclusion. In a 24-week clinical trial of eptinezumab for migraine prevention, the incidence of COVID-19, recorded as treatment-emergent adverse events, was also similar between treatment (6.2%) and placebo (5.4%) groups.21 Our study did not find a significant difference in the incidence of COVID-19 between patients receiving or not receiving CGRP mAbs (7.4 vs 6.9 cases per 1000 person-months), suggesting that CGRP mAbs may be used among patients who are at risk of or have COVID-19.Although there is little biological reason to be concerned that CGRP antagonists may predispose patients to greater risk of contracting COVID-19, there is limited clinical evidence on the safety of prescribing CGRP mAbs for patients with migraine at risk of COVID-19. A multicenter study conducted between May and November 2020 found that the proportion of COVID-19 cases among patients treated with CGRP mAbs was 16.1%, which was not significantly different from the 11% among patients not treated with mAbs.22 Raised IL-6 levels and cytokine storm are associated with severe clinical outcomes in patients hospitalized with COVID-19, and administration of IL-6 antagonists is associated with reduced 28-day all-cause mortality.25 Yet, there is no study, to our knowledge, that directly observed the efficacy of CGRP antagonists for patients with COVID-19, and results from animal or observational studies are controversal.27 In our study, although we found that patients with migraine who were treated with CGRP mAbs had better inflammatory profiles , which could have been associated with better outcomes,28 their clinical courses were no better than controls in terms of hospitalization, requiring supplemental oxygen or mechanical ventilation, and death. However, those results should be interpreted with caution due to the small number of events in addition to the fact that CGRP induces inotropy, suppresses elevated pulmonary arterial pressure, and attenuates cardiac remodeling,30 which may be beneficial to patients with severe COVID-19 who develop acute respiratory distress and septic shock. The olcegepant trial concluded that the worse 72-hour survival rate observed in the treatment group could be explained by unstable hemodynamics.12 In addition, a recent meta-analysis found that patients hospitalized with COVID-19 had better survival if they experienced headache as a symptom.31 Considering the role of CGRP in migraine pathophysiology, the authors hypothesized that an increase in the CGRP level, which triggered headache as 1 of the COVID-19 symptoms, is a host compensatory response against COVID-19.The discussion about repurposing CGRP antagonists to treat COVID-19 was based on findings that CGRP can enhance IL-6 production in vitro.32 One possible explanation is that receipt of a CGRP mAb is associated with a more positive health belief; 3 failures of conventional preventatives may not change patients’ perceptions so that they are more likely to react to cues when they experience COVID-19 symptoms. Patients treated with mAbs and their prescribers should be aware that milder symptoms of COVID-19 may present differently compared with symptoms in patients not treated with mAbs.Of note, we found patients with COVID-19 who were treated with CGRP mAbs were more likely to report mild symptoms , but there were no significant differences in moderate symptoms such as dyspnea.34 In addition, even though the study sample started with 354 294 eligible veterans, after conditioning on the probability of receiving CGRP mAbs and testing positive for SARS-CoV-2, the number of patients who required supplemental oxygen or mechanical ventilation or who died was small. Furthermore, the veterans in this sample were relatively young and healthy. The potential protective effects of CGRP antagonist may only occur among patients who are at high risk of developing severe COVID-19. However, considering the lower risk of progressing to severe COVID-19 with a less virulent variant, further investigation and collaborations are needed to fully understand the role of CGRP and its antagonist in the context of infection and the inflammatory process.This study has several limitations. First, the median duration of CGRP mAb treatment was 5 months, which limited the ability to examine longer-term outcomes. Second, the conditional exchangeability assumption is untestable. However, we used expert knowledge to identify confounders associated with CGRP mAb initiation, explored various confounders and functional forms , and checked weight distribution for misspecifications to enhance the assumption’s plausibility. Third, the administrative data only captured patients with COVID-19 who tested positive for SARS-CoV-2 within or outside the VHA who had the case documented in the records. Prescriptions and hospitalizations outside the VHA were not captured. However, conducting this study within a national integrated health care system and up-to-standard VHA data minimized the misclassification bias. Additionally, CGRP mAb initiators tend to have higher levels of health care–seeking behaviors, reflected in more SARS-CoV-2 tests (1.2 vs 0.7), leading to overrepresentation and potentially a false-negative conclusion. Future studies should consider sensitivity analysis to explore residual confounding and mismeasurement.In this cohort study on CGRP mAb treatment and COVID-19 outcomes in veterans with migraine, there was no significant difference in the incidence of COVID-19 or sequela hospitalization between CGRP mAb recipients and nonrecipients, suggesting that CGRP mAbs may be used for migraine prevention among patients who are at risk of or have COVID-19. However, there were few events of requiring supplemental oxygen, use of mechanical ventilation, and death among CGRP mAb initiators, indicating that replication analysis in a larger sample of patients later in the course of disease may be warranted.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in hundreds of millions of coronavirus cases, as well as millions of deaths worldwide. Coronavirus Disease 2019 (COVID-19), the disease resulting from exposure to this pathogen, is characterized, among other features, by a pulmonary pathology, which can progress to “cytokine storm”, acute respiratory distress syndrome (ARDS), respiratory failure and death. Vaccines are the unsurpassed strategy for prevention and protection against the SARS-CoV-2 infection. However, there is still an extremely high number of severely ill people from at-risk populations. This may be attributed to waning immune response, variant-induced breakthrough infections, unvaccinated population, etc. It is therefore of high importance to utilize pharmacological-based treatments, despite the progression of the global vaccination campaign. Until the approval of Paxlovid, an efficient and highly selective anti-SARS-CoV-2 drug, and the broad-spectrum antiviral agent Lagevrio, many pharmacological-based countermeasures were, and still are, being evaluated in clinical trials. Some of these are host-directed therapies (HDTs), which modulate the endogenic response against the virus, and therefore may confer efficient protection against a wide array of pathogens. These could potentially include Biological Warfare Agents (BWAs), exposure to which may lead to mass casualties due to disease severity and a possible lack of efficient treatment. In this review, we assessed the recent literature on drugs under advanced clinical evaluation for COVID-19 with broad spectrum activity, including antiviral agents and HDTs, which may be relevant for future coping with BWAs, as well as with other agents, in particular respiratory infections. This is most likely an underestimate, and according to the WHO , the numbers might be much higher. In the first two years of the pandemic (2020–2021), WHO estimates the excess mortality  to be 14.83 million people, 2.74 times the actual reported cases for this period (5.42 million) [The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent that led to the outbreak of the COVID-19 (Coronavirus Disease 2019) pandemic, which resulted in approximately 660 million infected and approximately 6.7 million deaths worldwide as of the end of December 2022 . Although the development of the inflammatory response is a critical mechanism of the innate immune system for coping with viruses and other pathogens, the aforementioned excessive activation of those mechanisms might in many cases lead to pathological results, mainly severe tissue injury and even death .Although the vaccines developed against SARS-CoV-2, particularly the mRNA-based vaccines that underwent swift emergency approval process, are the ultimate tool in the prevention of disease development and reduction of its severity, a significant part of the world’s population has yet to be vaccinated or exposed to the virus. In addition, in a small but non-negligible part of the population, the vaccine is not effective (such as immunocompromised patients). Furthermore, the immune response fades over time, necessitating repeated vaccinations, and vaccine-resistant variants, such as the Omicron and its derivatives, have also emerged . All of The COVID-19 pandemic has catalyzed significant advancements in medical research, including the development of diagnostic tools, rapid identification methods of new variants, and widespread administration of mRNA vaccines. Additionally, numerous studies have been conducted to investigate the potential of existing and novel drugs to treat patients, both for individuals with severe illness and those in the community.https://emergency.cdc.gov/agent/agentlist-category.asp, accessed on 18 January 2023), there is no approved or efficient treatment to date [This review focuses on the available treatments for COVID-19, with a particular emphasis on antiviral drugs and host-directed therapies (HDTs). Antiviral drugs act directly against the virus and disrupt its ability to survive and/or replicate in the human body, while HDTs modulate the endogenous response (both excessive and deficient) to the virus, potentially leading to improved clinical outcomes. Owing to their broad mechanism of action, HDTs may also be effective against biological threat agents. Biological warfare agents may harm or incapacitate a very large number of human beings due to efficient infectivity and severity of disease . In some to date . In addiThis review aims to leverage the vast knowledge that has been amassed regarding COVID-19 to identify effective treatment options that are relevant as countermeasures to biological threat agents owing to their mechanism of action. We discuss the drugs that have been clinically approved for COVID-19 treatment, as well as those that have demonstrated potential effectiveness in advanced clinical trials. By doing so, we hope to contribute to the ongoing efforts to combat this disease and other potential biological threats, in particular biological threat agents sharing SARS-CoV-2 pathophysiological processes .In the later stages of infectious diseases such as COVID-19, antimicrobial treatments may not be effective due to the fact that primarily damage at this stage is caused by the pathological disease responses rather than the pathogens. This is evidenced by the fact that there are often low titers of pathogen in the host during late-stage, critical disease. This is where host-directed therapies (HDTs) come into play, as they activate under-activated or suppress over-activated endogenous pathways to cope with a wide range of pathogens. HDTs have a lower risk of resistance developing by the pathogen compared to direct antiviral drugs, although they may have an increased risk of toxicity . ThroughIn patients with severe COVID-19, pro-inflammatory cells such as macrophages and neutrophils secrete high levels of inflammatory cytokines, leading to excess inflammation and potentially resulting in multi-organ failure and systemic collapse . Hereinafter, we elaborate on HDTs aimed at reducing the overstimulation of the inflammatory response (“cytokine storm”) without compromising the proper immune system activity in combating the virus.Several drug treatments have shown clinical benefits in COVID-19 patients by targeting the excessive immune response, including steroids, anti-cytokines, kinase inhibitors and selective serotonin reuptake inhibitors (SSRIs), as well as drugs that have undergone advanced clinical examination such as Sabizabulin, Vilobelimab, and Metformin.Steroids have shown promise as potent anti-inflammatory agents in treating the “cytokine storm”, which, as has been mentioned above, is a hallmark of severe COVID-19. Dexamethasone, a steroid recommended for use in COVID-19 patients, has been shown to reduce mortality rates by approximately 33% in mechanically ventilated patients and about 20% in patients requiring noninvasive oxygen treatment. Recent studies have estimated that treatment with Dexamethasone saved the lives of about one million COVID-19 patients worldwide as of March 2021 . A phase 2 clinical trial of early treatment with the inhaled steroid Budesonide in mild–moderate COVID-19 patients demonstrated effectiveness in reducing rates of emergency room visits and hospitalizations, shortening recovery time, and improving clinical symptoms [These findings underscore the potential of steroid treatment at all stages of COVID-19 and other respiratory diseases caused by pathogens.Progressive elevation of various inflammatory cytokines, including Interleukin-6 (IL-6), IL-1β and granulocyte–macrophage colony-stimulating factor (GM-CSF), is directly associated with disease severity. Significantly higher serum levels of pro-inflammatory cytokines are observed in critically ill patients, prompting specific anti-cytokine treatment for prevention of tissue damage ,11,12,13Monoclonal antibodies against cytokine IL-6 have shown promise in mitigating the pathology and “cytokine storm” associated with severe COVID-19 . https://www.fda.gov/media/150319/download, accessed on 9 May 2023). This emergency use authorization was based, in addition to the aforementioned studies, on smaller clinical studies conducted on hundreds of patients . On 21 December 2022, the drug (in combination with systemic steroids) was granted formal FDA approval .Tocilizumab is a monoclonal antibody that targets the IL-6 receptor. This drug has demonstrated efficacy when administered to severely ill patients within two days of admission to an intensive care unit (a multicenter cohort study of 4485 patients conducted from March to May 2020). A significant reduction in mortality within 30 days was observed (27.5% in the treated group compared to 37.1% in the control group) . A subseSarilumab, another monoclonal antibody targeting the IL-6 receptor, has been found to be effective in reducing mortality rates in COVID-19 cases. In meta-analyses comparing Sarilumab to Tocilizumab, Sarilumab showed potential effectiveness, although Tocilizumab appeared to be more effective overall ,18. HoweAnakinra, a recombinant Interleukin-1 (IL-1) receptor antagonist, is a drug that inhibits the activity of cytokine IL-1. Several studies have shown that IL-1 plays a key role in the development of the “cytokine storm” in patients infected with SARS-CoV-2, and that the levels of the pro-inflammatory cytokine IL-1β increase significantly following infection . In a phObservational and retrospective studies, as well as smaller clinical trials, have also demonstrated the efficacy of Anakinra in improving survival rates, preventing deterioration to pulmonary failure, and improving inflammation indicators in COVID-19 patients ,24,25,26On 2 November 2020, Anakinra received emergency use authorization (EUA) from the FDA for the treatment of severe COVID-19 patients who are hospitalized with pneumonia, are in need of oxygen support, and are also characterized by elevated levels of soluble urokinase plasminogen activator receptor (suPAR) in plasma. The clinical efficacy of the drug treatment was demonstrated in a subgroup analysis and was maintained up to 90 days after treatment onset .Infliximab is a monoclonal antibody against TNFα. When administered alone in a phase 3 clinical trial, a 41% relative reduction in measured mortality rates up to day 28 of treatment was observed . Chances for clinical status improvement were also higher (43.8% increase) up to day 14 from treatment start. The drug was administered in combination with steroids or Remdesivir [Monoclonal antibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF) are being developed as anti-inflammatory therapies. GM-CSF is a cytokine that activates the development of immune system cells (granulocytes and macrophages) from precursor cells, and it has been implicated in the inflammatory processes. Antibodies against GM-CSF and its receptor have been developed for the treatment of chronic inflammatory diseases such as arthritis and asthma . High lep < 0.04), though mild (84% versus 78%) increase in survival rates in non-invasively mechanically ventilated patients up to day 28 of treatment compared to patients who did not receive Lenzilumab. However, according to a statement by Humanigen, the company which develops this drug, a separate clinical trial examining the effect of the drug in combination with Remdesivir  showed no benefit compared to treatment with Remdesivir alone .Lenzilumab is a monoclonal antibody that targets GM-CSF. Results from a phase 3 clinical trial in approximately 500 critically ill patients  show that treatment with the drug led to a statistically significant  in COVID-19 patients with systemic inflammation, Otilimab did not demonstrate efficacy in patients aged 18 and older, but there was a partial positive trend observed in the subgroup of patients aged 70 and older in terms of survival rates and decrease in inflammatory markers  . While tThe JAK inhibitors Baricitinib and Tofacitinib are drugs used to treat joint inflammatory diseases by inhibiting the JAK1/2 and JAK1/JAK3 enzymes, respectively . ImatiniA meta-analysis of four controlled clinical trials  showed that treatment with Baricitinib in hospitalized COVID-19 patients led to a significant decrease in a 28-day mortality, as well as a positive trend  in the reduction in invasive mechanical ventilation (IMV) or ECMO support ,33. The Similarly, treatment with Tofacitinib led to a significant decrease in mortality or in the development of respiratory failure (18.1% vs. 29% in the placebo group) within 28 days. Death from any cause through day 28 occurred in 2.8% vs. 5.5% of those in the Tofacitinib or placebo group, respectively .Imatinib has revolutionized the treatment of Chronic Myeloid Leukemia (CML) by dramatically improving patient outcomes. It works by binding to the active site of the Bcr-Abl kinase and blocking its activity, which in turn inhibits the proliferation and survival of leukemic cells. In the past, it was demonstrated that the drug leads to hemodynamic improvements in patients diagnosed with pulmonary arterial hypertension through protective effects on healthy blood vessels  by, amonFluoxetine/Fluvoxamine, used to treat depression, are medications that belong to the SSRIs family. These medications have an anti-inflammatory effect that is mediated through agonism to sigma-1 receptors (S1Rs), which leads to a decrease in cytokine production . In a laSabizabulin is a chemotherapeutic drug currently undergoing clinical trials for the treatment of prostate cancer. It works through microtubule disruption, which is a key component of the cytoskeleton. Sabizabulin is bound to the active site of Colchicine .https://www.biospace.com/article/veru-s-lead-compound-shows-promise-as-antiviral-anti-inflammatory-therapeutic-for-covid-19, accessed on 18 May 2023). In a phase 3 clinical trial involving 204 participants (134 of whom were treated with Sabizabulin), a significant decrease in mortality rates (24.9% absolute reduction), a 43% relative reduction in ICU days (p = 0.0013), a 49% relative reduction in days on mechanical ventilation (p = 0.0013), and a 26% relative reduction in days in the hospital (p = 0.0277) were demonstrated in moderately to severely ill patients (with a high risk of ARDS and death) compared to the placebo group [Compared to Colchicine, Sabizabulin binds with high affinity to the “Colchicine binding” pocket in the β-tubulin subunit, and has a superior pharmacokinetic profile, resulting in longer circulatory presence ,61. The bo group . DespiteOn the one hand, the complement system plays an important role in pathogen clearance. On the other, unregulated complement activation plays a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9 and severe acute respiratory syndrome coronavirus (SARS-CoV-1). In particular, the C5a component of the complement system and its receptor, C5aR1, play an important role in inflammatory processes, particularly in tissue and blood vessel damage by recruiting neutrophils and monocytes to the site of inflammation. Blockade of C5a signaling has been implicated in the treatment of ALI induced by highly pathogenic viruses . https://www.fda.gov/media/166823/download, accessed on 18 May 2023).Vilobelimab is a monoclonal antibody (mAb) that targets C5a. During the COVID-19 pandemic, it has been shown that levels of C5a in COVID-19 patients are positively correlated with disease severity, and that C5aR1 antagonists prevent the development of acute lung injury in mice exposed to SARS-CoV-2 . ResultsMetformin is a drug used to treat type II diabetes mellitus (T2DM) with anti-inflammatory activity, including suppression of cytokine release (IL-6 and IL-1β), inhibition of inflammasome activity , actAbatacept is an analogue of CTLA-4 that prevents the generation of a co-stimulatory signal in antigen-presenting cells, thereby preventing overactivation of the immune system. Treatment with the drug as a single dose led to a decrease in mortality rates documented up to day 28 after treatment: 11% in the treatment group (509 patients with moderate or severe conditions) as opposed to 15.1% in the control group  . At the The immune response of the host is a critical factor in determining the pathogenicity of viruses and their ability to cause disease. COVID-19 patients experience severe illness due to the suppression of immune activity at the onset of the disease and excessive activity in its later stages. The SARS-CoV-2 virus is known to evade the host’s defense mechanisms through various mechanisms such as promoting programmed cell death of natural killer cells (NK cells) and delaying the production of interferon-α and-β ,83. In tThe interferon response is the first line of defense against viruses. Detection of viruses by the innate immune system leads to the production of type I  and III (IFNλ) interferon responses . AccordiThe suppression of the interferon response in COVID-19 patients, alongside the potential therapeutic value of IFNs, has led to pre-clinical and clinical studies to evaluate the effectiveness of this treatment. Some of the clinical trial results are indeed very encouraging, particularly in terms of therapeutic intervention in the early stages of the disease, and in particular regarding IFNλ.The administration of Pegylated IFNλ-1a has previously been examined for the treatment of Hepatitis B/C/D. A single subcutaneous injection within 7 days of symptom onset led to a 50% reduction (2.7% compared to 5.6% in the control group) in hospitalizations and emergency room (ER) admissions by day 28 of treatment, as well as a 60% decrease in mortality. This was demonstrated in a phase 3 clinical trial in non-hospitalized patients (approximately 900 patients received Pegylated IFNλ-1a out of the 1900 patients enrolled), the majority of whom (84%) were vaccinated against COVID-19. The treatment was effective for infection with various SARS-CoV-2 variants, including Omicron .SNG001, IFN β-1a, which is administered by nebulization to hospitalized patients for 14 days, demonstrated therapeutic potential  alongside a positive safety profile in a phase 2 clinical trial of about 100 participants  . AlthougNitazoxanide, an anti-parasitic drug from the thiazolide family, activates the innate immune system by upregulating the expression of type I IFN pathway genes TLR7 and TLR8. These are involved in antiviral activity against various viruses ,94. AddiUpon entering a host, the virus initiates its replication process by binding to cells with appropriate receptors, such as pneumocytes and enterocytes. SARS-CoV-2 enters the infected cell through endocytosis, mediated by the spike protein of the virus that binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the hosts’ cells. Following endocytosis, the virus releases its genome into the host cell cytoplasm, initiating the translation process for viral protein synthesis. These proteins assist in the replication of the viral genome and the creation of viral envelopes. Ultimately, all viral components assemble into complete virions that are released from the host cell through the process of exocytosis. The life cycle of the virus can be divided into three main stages: entry, genome replication, and release from the host cell ,102. In ClinicalTrials.gov, NCT04784559). In terms of the drug’s potential as a broad-spectrum antiviral treatment, it has been shown in the past that eEF1A plays an important role in the replication of RNA viruses [Plitidepsin is a chemotherapeutic drug used to treat plasma cell disorders (multiple myeloma). Plitidepsin inhibits the eukaryotic translation-elongation-factor-1A (eEF1A), an endogenous protein involved in the translation process of viral and cellular proteins. The drug was shown to inhibit viral replication, including in mice infected with SARS-CoV-2. It should be noted that the antiviral activity of the drug against SARS-CoV-2 is 27.5 times more potent than that of Remdesivir ,104, and viruses ,107, inc viruses  and resp viruses . Additio viruses . This inFor some of the drugs mentioned above , an additional mechanism of direct antiviral activity is involved by interfering with cellular mechanisms involved in the viral life cycle and survival.In addition to its anti-inflammatory activity discussed earlier, Baricitinib acts directly by potentially inhibiting numb-associated kinases  that influence AP-2, a scaffolding protein vital for the entry and proliferation of the virus into cells . It has Direct antiviral activity is attributed to microtubule (MT) inhibition as MTs play an important role in intracellular transport of virus particles and regulation of other processes . The impIn addition to the immunomodulatory activity mentioned above, Imatinib has shown antiviral activity (inhibition of virus replication) against MERS and SARS-CoV-1 in the early stages of infection, after internalization and endosomal trafficking, by inhibiting viral fusion to the endosome membrane . SpecifiIn addition to its suppressing the over-activated immune response (discussed earlier), a direct antiviral effect was demonstrated for Metformin via 5′-AMP-activated protein kinase (AMPK) activation . An antiAs the pandemic progressed, several antiviral drugs have been developed that have demonstrated effectiveness in treating COVID-19 patients. One of the most effective drugs is Paxlovid (Nirmatrelvir/Ritonavir) , which iUnlike Paxlovid, several broad-spectrum antiviral drugs that have demonstrated clinical efficacy against SARS-CoV-2 may serve as a therapeutic arsenal against viruses on the bio-threat list. Remdesivir is a broad-spectrum antiviral drug. This drug was the first to be approved as a treatment for COVID-19. Remdesivir is a prodrug of the adenosine analog that inhibits the viral RNA-dependent RNA polymerase (RdRp) enzyme . The druMolnupiravir is an oral antiviral drug that has been clinically approved for the treatment of COVID-19. Like Remdesivir, it works by inhibiting the RdRp enzyme. The drug has lower efficacy compared to Paxlovid for treating COVID-19  , but unlNitric Oxide (NO) is a gaseous signaling molecule involved in many physiological and pathological processes. In particular, NO has antimicrobial effects in vitro and in vivo ,132. It Treatments with immunomodulatory drugs that affect the activity of the immune system should be applied with great caution due to the critical role of the immune system in coping with pathogens and the increased risk of adversely impacting the course of infections ,140. HowIt is important to emphasize that the antimicrobial activity of the drugs mentioned in this section is addressed as a platform for discussion purposes only. In case of need, each drug should be examined for its potential effectiveness against different biological threat agents, including conducting clinical trials, dose adjustments and a formal and specific use approval by the proper authorities.Combining antibodies directed against Y. pestis with methylprednisolone in mice exposed subcutaneously to Y. pestis improved survival and inflammatory markers tested . In a pnSome of the drugs discussed in this review have direct or indirect antimicrobial activities, such as Metformin, which has been shown to have antiviral ,146 and The drug Nitazoxanide has been shown to have antibacterial effects in combination with antibiotics  as well Concerning biological threat viral agents, kinase inhibitors, including Imatinib, Baricitinib, and Tofacitinib, are at different stages of clinical and preclinical research to evaluate their effectiveness as broad-spectrum antiviral treatments .In this review, we expanded on therapeutic treatments that have been tested clinically in COVID-19 patients and demonstrated efficacy. We expanded on HDTs, as well as on broad-spectrum antiviral drugs.It is important to emphasize that the effectiveness of the treatments mentioned above is context dependent. Efficacy varies, depending on the stage and severity of the disease. Some drugs were suggested only for late stages of the disease in severe patients (such as Dexamethasone), while others were only helpful when administered in early stages . Anakinra, for example, has four parameters influencing therapeutic efficacy: duration of treatments , dose (≥100 mg), administration route (intravenous) and early initiation of therapy .Some drugs showed efficacy only when administered in combination with another drug . Baricitinib was initially approved as part of a combination treatment, and only later approved as a stand-alone treatment.A class effect could not be implemented automatically, as there was often a difference in efficacy between drugs belonging to the same family. For example, in some JAK inhibitors, no efficacy or only partial efficacy was observed. This could be due to differences in their activity against different JAK isomers, differences in safety and pharmacokinetic data, or the presence of direct antiviral elements that exist in parallel to the anti-inflammatory activity only in certain drugs. Another example is SSRIs, whose effectiveness in COVID-19 patients was mainly demonstrated in sigma-1 receptor agonists.A broad coverage range: viruses, bacteria, toxins and more due to the endogenous nature of the effect.Reduced risk of developing microbial resistance .HDTs have prominent advantages over drugs with direct antimicrobial activity, allowing their use for dealing with a variety of pathogens:Obviously, this does not contradict the possibility of combining HDT with drugs with direct antimicrobial activity (as well as combining different HDTs operating via different mechanisms).Mesenchymal stromal cells (MSCs), which have demonstrated potential efficacy in both preclinical models and clinical settings against infectious diseases  via direct antimicrobial mechanisms or host-directed therapy (HDT). However, MSCs also face several challenges such as safety and regulatory issues . ClinicaDrug delivery systems and novel formulations are expected to streamline and optimize therapeutic treatments. Among other objectives, these systems aim to enable more convenient treatments , reduce drug side effects  and/or improve bioavailability. For example, a phase 1 clinical trial has been conducted to test an inhalable or intranasal formulation of the drug Niclosamide. Niclosamide is a drug possessing 40 times the potency of Remdesivir in Vero cells against SARS-CoV-2. However, it is not adequately absorbed when administered to COVID-19 patients .Due to the exceptional efficacy of both mRNA vaccines for COVID-19 and the approved antiviral drugs for treating COVID-19 disease, motivation for relevant clinical trials has significantly declined. Nonetheless, we believe it is still essential to monitor ongoing research in the following areas of emerging modalities of medicine and advanced therapeutic approaches:All of the above is relevant for coping with biological threat agents. The drugs reviewed here may be repurposed to serve as a therapeutic arsenal for dealing with these agents, which are extremely deadly pathogens with the potential to cause mass casualties. Some of these pathogens are devoid of approved treatment, while for others standard treatment options leave room for improvement.The current pandemic has led to significant investment in resources and budgets to develop diverse medical treatments, technologies and devices, resulting in an unprecedented pace and volume of clinical trials. This was fueled by both the medical urgency and government participation in funding and fast-forwarding the research. Like many challenging emergencies of the past, the pandemic has catalyzed substantial progress in developing, testing and approving therapeutics that, under normal circumstances, would have taken much longer to achieve. The enormous amount of data derived from so many clinical trials is a once-in-a-lifetime opportunity to establish broad-spectrum antimicrobial treatments that would be suitable for diverse infectious diseases, in particular diseases derived from exposure to biological threat agents. Every possible clinical data point should be utilized for preparing and dealing with future outbreaks.Such events would require treatment protocol adjustments, tailored pharmaceutical dosing and relevant drug–drug interaction studies. Obviously, none of the above negates the need for developing in-depth understanding of the pathogen and disease, allowing the dissection of which clinical state is most relevant for treatment and which of the numerous avenues described above (as well as possible future additions) are suitable for the specific outbreak.


Despite the global decline, neonatal mortality rates (NMR) remain high in India. Family members are often responsible for the postpartum care of neonates and mothers. Yet, low health literacy and varied beliefs can lead to poor health outcomes. Postpartum education for family caregivers, may improve the adoption of evidence-based neonatal care and health outcomes. The Care Companion Program (CCP) is a hospital-based, pre-discharge health training session where nurses teach key healthy behaviors to mothers and family members, including skills and an opportunity to practice them in the hospital. We conducted a quasi-experimental study to assess the effect of the CCP sessions on mortality outcomes among families seeking care in 28 public tertiary facilities across 4 Indian states. Neonatal mortality outcomes were reported post-discharge, collected via phone surveys at four weeks postpartum, between October 2018 to February 2020. Risk ratios (RR), adjusting for hospital-level clustering, were calculated by comparing mortality rates before and after CCP implementation. A total of 46,428 families participated in the pre-intervention group and 87,305 in the post-intervention group; 76% of families completed the phone survey. Among the 33,599 newborns born before the CCP implementation, there were 1386 deaths (NMR: 41.3 deaths per 1000 live births). After the intervention began, there were 2021 deaths out of 60,078 newborns born . There may be a substantial benefit to family-centered education in the early postnatal period to reduce neonatal mortality. Neonatal mortality disproportionately affects families in low-to-middle income countries (LMICs) , 2. WithMost deaths can be prevented by providing Continuum of Care (CoC) in a structured way from pregnancy to the post-delivery period . InterveAlthough certain healthcare interventions can only be provided by skilled healthcare personnel, there are many practices that caregivers can and should do on an ongoing basis, but the caregivers need to be first equipped through training to do so . Postnathttps://www.zotero.org/google-docs/?SXBXbC. Through two to three days of training of trainers, nurses and health educators receive training on health behavior change and skills to effectively communicate health information by engaging their audiences. They are provided teaching aids that include videos played on television monitors in the postnatal wards, flipcharts, demonstration tools (e.g. dolls) used for role-playing, and hand-outs. Using these varied materials, nurses and health educators conduct group classes for families in postnatal wards for approximately 30 minutes per session. CCP sessions are conducted 3–5 times per week at each postpartum ward, depending on a hospital’s preference. Additionally, families receive post-discharge follow-up through a dedicated WhatsApp-based platform, which reiterates key behavior change messages. Further, this approach allows for two-way communication, providing families the opportunity to ask questions and receive guidance from Noora Health’s affiliate support staff (both doctors and nurses). Initial findings from two hospitals showed promising results for increased family behavior change and reduction in preventable complications and facility readmissions [The Care Companion Program (CCP) trains families on essential maternal and neonatal care during their hospital stay. Noora Health, a non-profit organization, supports the design of CCP, which is being implemented with local partners across district hospitals in seven states of India . The CCPmissions . ThroughA large evaluation study assessing the impact of the CCP intervention on knowledge, practice, and outcomes among families seeking childbirth care in 28 facilities across 4 Indian states has been underway since 2019. The data collection for the main study was temporarily paused due to the COVID-19 pandemic from March, 2020 to June, 2022. Here, we are reporting the findings from the mid-point analysis assessing the early impact of the CCP on neonatal mortality, prior to the COVID-19 pandemic.A quasi-experimental study design was used to assess the impact of CCP on maternal and neonatal health outcomes. Data collected from October 2018 to February 2020 were analyzed for mortality outcomes in this interim analysis. Among the 28 study hospitals, 24 district-level hospitals (DHs) were selected randomly from 91 high and low delivery-load hospitals in three Indian states, Karnataka (KA), Punjab (PB), and Madhya Pradesh (MP), in which CCP would be implemented. In Maharashtra (MH), four government medical college hospitals were also included.Trained investigators collected contact details of the mothers in the hospital, after delivering the baby, and just before discharge. Among eligible participants, consent for the study was asked for in the hospital, and reconfirmed at the time of the survey call. In the event of a maternal or neonatal death prior to discharge; maternal age less than 18 years; or no consent provided; mothers/families were excluded from the study. At the end of the neonatal period (i.e. 4 weeks post discharge), the study staff called the consenting and eligible mothers to learn about vital status and neonatal care behaviors. Those who were not reached or those who refused the interview were marked as incomplete. At the beginning of the follow-up phone call, vital status of the mother and newborn was collected. Maternal deaths during pregnancy, during hospital delivery before discharge, abortions, home deliveries, or those who died after 28 days and before 42 days are not included. In cases of a maternal or neonatal death, information around neonatal care behaviors or sociodemographic data were not collected due to ethical concerns of continuing the interview. As a result, it is not possible to adjust our statistical analysis by sociodemographic characteristics.Data from the pre-intervention period prior to the CCP launch date at each facility were compared to post-intervention data, which was collected in a continuous fashion after the CCP launch date at that facility. We assessed the effect of the program with an intention-to-treat approach, irrespective of whether individuals in the intervention facilities were trained or not. No time elapsed between when the program started and data collection began. We compared the post-discharge mortality for mothers and neonates in the pre-intervention period to the post-intervention period.In the original evaluation design, we focused on behavior change around neonatal care. Assuming an 80% power and an alpha level of 0.05, it was hypothesized that the rate of unsafe cord care would drop by 21%. Assuming a classic pre-post single setting sample calculation, it was concluded that 330 per facility would suffice to detect statistically significant differences . In a post hoc sample size calculation, we estimated the power of this analysis to detect differences in neonatal mortality rates (NMR) and maternal mortality rates (MMR) using R version 4.1. With the current sample size, the study has 98% power to detect the estimated difference in NMR of 8.7 deaths per 1000 live births between the pre- and post-CCP session groups. Additionally, the current sample size has 70% power to detect the estimated difference in MMR of 6.9 deaths per 100,000 delivered mothers.We used logistic regression models to assess the impact of the intervention (pre versus post) on neonatal and maternal mortality. Our dataset was limited to those who reported outcomes during a follow-up call. The regression models reporting risk ratios and risk differences were adjusted for hospital-level clustering; however, we were unable to adjust for sociodemographic data as this information was not collected from families who experienced a death. All analyses were completed with STATA 16 .Additionally, we compared the rate of change between pre and post CCP against the general NMR trend within India. General NMR trends for India from 2012–2019 is sourced from the World Bank .We received IRB approval for primary data collection from ACE Ethics Committee and SPECT based in Bangalore, India and Delhi, India respectively. The primary data with identifiable information were collected and maintained in India; deidentified data were shared with collaborators for analysis. For this secondary analysis (DCGI Reg. No. ECR/141/Indt/KA/2013), Harvard University Institutional Review Board (Protocol # IRB19-1140) deemed the study exempt. All participants underwent an oral consent process at the hospital and again during the follow-up phone call, which was audio recorded.We collected phone numbers from a total of 133,733 families in the hospital, with 46,428 from the pre-intervention period and 87,305 from the post-intervention period . We succAmong families that did not experience neonatal or maternal death, socio-demographic details are shown in Among the 33,599 newborns before the Program, there were 1386 deaths (NMR: 41.3 deaths per 1000 live births). After the intervention began, there were 2021 deaths out of 60,078 newborns born (NMR: 33.6 deaths per 1000 live births). The unadjusted Risk Ratio (RR) for neonatal mortality in the pre-intervention compared to post-intervention group was 0.82 . After adjusting hospital clustering, the risk ratio was similar RR = 0.82, 95% CI: 0.71, 0.93 .Reduction in maternal mortality was not significant. In the pre-intervention period, 23 maternal deaths of 33,599 births occurred after facility discharge and post-intervention 37 maternal deaths out of 60,078 births occurred . The unaIn In this large cohort, the family-centered Care Companion Program was associated with a reduced NMR compared to the pre-implementation period. In our previous studies, an increase in important neonatal behaviors has been associated with reduced mortality; improved adherence to key behaviors included uptake of dry cord care by 4%, skin-to-skin care practice by 78%, and 56% decrease in neonatal readmissions . Here, tDue to a shortage of staff and a lack of parental knowledge about correct neonatal care practices, Family-Centered Care (FCC) is becoming a key opportunity to improve postnatal care . TraininThe NMR per 1000 births observed in our study  is much higher than the national average in the same time frame (24.9) . This diComparing the rate of change of NMR decrease from CCP compared to the larger general trends, the secular trend explains only a part of the difference we have seen. We did not see any new Maternal and Child Health initiatives occur in all intervention facilities in the 1.5 years between the pre- and post-data collection. However, programs like LaQshya  and non-The strengths of our study are the large sample size and representative data from multiple government facilities across 4 states. We adjusted for the cluster effect of the site using a logistic regression model to get a range around the point estimate. The pre-post study design allowed for a comparison group from the same hospitals, with similar populations seeking care, and similar settings reducing the variability.There are five key limitations of our data. First, we could not measure the outcomes in the non-responders. We have compensated for this by calculating the NMR by including a denominator where we know the outcomes. Second, state-level estimates were not found to be significant, whereas the pooled estimates were. The tables for these analyses can be found in Postnatal training for caregiver skills could supplement health-systems’ existing efforts to reduce neonatal mortality. The estimated trend toward reduction in neonatal mortality over this short time span during CCP implementation is encouraging. Further studies should collect additional demographic details around deaths to understand at-risk populations. Further death reviews ascertaining the cause and timing of death as well as further exploring any causal pathways such as knowledge and practice of caregiving behaviors can help elucidate potential mechanisms involved in reducing mortality. Family-centered approaches to healthcare can help ensure proper patient care extends beyond hospitals into homes and lead to improved health outcomes. Noora Health plans to expand CCP’s footprint and evaluate the impact of caregiver education across condition areas and geographies.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.


Pharmacy benefit can be purchased as part of an integrated medical and pharmacy health package—a carve-in model—or purchased separately and administered by an external pharmacy benefit manager—a carve-out model. Limited peer-reviewed information is available assessing differences in use and medical costs among carve-in versus carve-out populations.To compare total medical costs per member per year (PMPY) and utilization between commercially self-insured members receiving carve-in to those receiving carve-out pharmacy benefits overall and by 7 chronic condition subgroups.This study used deidentified data of members continuously enrolled in Cambia Health Solutions self-insured Blue plans without benefit changes from 2017 through 2018. Cambia covers 1.6 million members in Oregon, Washington, Idaho, and Utah. The medical cost PMPY comparison was performed using multivariable general linear regression with gamma distribution adjusting for age, gender, state, insured group size, case or disease management enrollment, 7 chronic diseases, risk score (illness severity proxy), and plan paid to total paid ratio (benefit richness proxy). Medical event objectives were assessed using multivariable logistic regression comparing odds of hospitalization and emergency department (ED) visit adjusting for the same covariates. Sensitivity analyses repeated the medical cost PMPY comparison excluding high-cost members, greater than $250,000 annually. Chronic condition subgroup analyses were performed using the same methods separately for members having asthma, coronary artery disease, chronic obstructive pulmonary disease, heart failure, diabetes mellitus, depression, and rheumatoid arthritis.P < 0.001), translating into an average $148 lower medical cost PMPY . After adjustment, the carve-in group had an estimated 15% (P < 0.001) lower hospitalization odds and 7% (P < 0.001) lower ED visit odds. Of 7 chronic conditions, significantly lower costs (12%-17% lower), odds of hospitalization (22%-36% lower), and odds of ED visit (16%-20% lower) were found among members with carve-in benefits for 5 conditions .There were 205,835 carve-in and 125,555 carve-out members meeting study criteria. Average age (SD) was 34.2 years (18.6) and risk score (SD) 1.1 (2.3) for carve-in versus 35.2 years (19.3) and 1.1 (2.4), respectively, for carve-out. Members with carve-in benefits had lower medical costs after adjustment (4%, These findings suggest that integrated, carve-in pharmacy and medical benefits are associated with lower medical costs, fewer hospitalizations, and fewer ED visits. This study focused on associations, and defining causation was not in scope. Possible reasons for these findings include plan access to both medical and pharmacy data and data-informed care management and coordination. Future research should include investigation of integrated data use and its effect across the spectrum of integrated health plan offerings, provider partnerships, and analytic strategies, as well as inclusion of analyzing pharmacy costs to encompass total cost of care. What is already known about this subjectGrey literature publications have found significantly lower associated medical costs, hospitalization rates, and emergency department (ED) rates among individuals receiving integrated medical and carve-in pharmacy benefits compared with those receiving carve-out pharmacy benefits.According to grey literature reports, medical costs were consistently in the single digit percentage point lower, ranging from $77 to $240 lower medical costs per member per year (PMPY) among the carve-in pharmacy benefit population.Some reports included chronic condition subanalyses with findings directionally similar to the lower overall medical cost and lower health care utilization for carve-in benefits.What this study addsStudy findings add to what has been reported in the grey literature regarding medical costs, odds of a hospitalization event, and odds of an ED event among members receiving carve-in pharmacy benefits concurrently compared with those with carve-out pharmacy benefits.P < 0.001) and financially important 4% lower medical cost at $148 PMPY, 15% lower odds of a hospitalization event, and 7% lower odds of an ED visit over 2 years, among the pharmacy benefit carve-in members compared with temporally concurrent pharmacy benefit carve-out population within the same medical insurer.This study found a small but statistically significant —a carve-out model. Both models promote savings through pharmacy network channel discounts; mail order pharmacy services; formulary management; pharmaceutical manufacturer rebates; and clinical offerings, such as specialty pharmacy services, utilization management, clinical programs, medication therapy management, drug utilization review, and care or disease management.6 However, rigorous statistical comparisons of carve-in and carve-out savings for pharmacy costs in the peer-review and grey literature are difficult to find, likely because carve-in and carve-out PBMs have access to pharmacy costs only for their members with no comparator data.There may be differences in how carve-in PBMs and carve-out PBMs might achieve these aims. In theory, carve-out PBMs may benefit from singular focus, flexibility to allow employers to design drug benefit coverage specific to their employee population, and volume to negotiate drug costs and rebates with manufacturers. Some carve-out PBMs claim to be able to save employers large amounts in drug costs over time.7 Holistic management of the patient and their medications may also lead to avoidance of unnecessary health care–related events. For example, a recent study showed that utilization management leveraging integrated claims for people with a substance use disorder can lower opioid prescription volume and emergency department (ED) visits.8The perceived added value of integrated medical and pharmacy benefits via carve-in is that integrated data inform clinical offerings more efficiently and quickly. When leveraged effectively, integrated data can inform utilization management; authorization decisions; chronic condition care management including medication adherence, behavioral health conditions related to prescription drug abuse, and those conditions served by specialty drugs; and population health management.16 From 2010 to 2012, 3 Blue Cross/Blue Shield (BCBS) nonpeer-reviewed studies were reported with a trend toward lower total medical cost savings per member per year (PMPY) in the carve-in populations ranging $116 to $217, or 6% to 7%; however, the associated lower medical cost was only statistically significant in the largest study.13 The national BCBS Association (2013) abstract and poster and BCBS Rhode Island (2018) self-report found significantly lower medical costs in the carve-in group .12 Further, lower PEPM medical costs were found for members with cancer (3%), hypertension , diabetes mellitus , and substance use disorder (19%).12 In addition to Blue plan reports, self-reports by other insurers have been released with similar findings with chronic conditions HTN, DM, rheumatoid arthritis (RA), and coronary artery disease (CAD) subanalyses.16Although unable to compare drug claim data for carve-out members, integrated benefit plans have the advantage of access to medical claims data for both carve-in and carve-out members. Several health plans have performed pharmacy benefit carve-in versus carve-out assessments on medical costs and use, with results pointing to lower medical costs among members with integrated pharmacy benefits, as follows.17 Given that a large population of Blue plan members within Cambia Health Solutions have carve-in and carve-out pharmacy benefits, Cambia had the opportunity to investigate medical costs and health care utilization rates comparing members with carve-in to those with carve-out pharmacy benefits in the northwest United States, replicating the methods used in the BCBS Association study and added a priori subanalyses of 7 chronic conditions.A large portion of self-insured employers choose a carve-out pharmacy benefit design. This may be due to rapidly rising drug costs, consultant influence and business relationships, and marketing efforts that offer rebates or other discounts that are considered without comparative information, given the lack of peer-reviewed publication of utilization and cost analysis comparing carve-in versus carve-out benefits.11 The same study member attribution methods, study population characteristics, statistical testing, and statistical modeling were performed, by the same personnel, as for the BCBS Association study. A change from the BCBS Association study was to exchange CAD for hyperlipidemia and to add the rheumatoid arthritis chronic condition, a priori. All 7 chronic conditions were defined a priori, and no other chronic conditions were added or removed from the analyses. The BCBS Association study used the diagnostic cost grouper (DCG) risk score, and this study used the Cotiviti DxCG Intelligence risk score. An additional covariate in this study was member enrollment in health plan care management or disease management.This study used 2 years of data and replicated methods used in the BCBS Association study.Cambia Health Solutions covers 1.6 million members in Oregon, Washington, Idaho, and Utah with approximately 65% of members with self-insured commercial coverage having carve-in and 35% having carve-out pharmacy benefits. Analyses included deidentified claims data from 2017 and 2018 calendar years with no protected health information. Thus, it does not constitute human subjects research and is not subject to Internal Review Board review. This 2-year period included the most recent complete calendar years when data collection began.This retrospective concurrent comparison cohort study included data from claims files for Cambia members with continuous commercial coverage of a self-insured health plan and indication of pharmacy benefits as integrated (carve-in) versus separate (carve-out). Members were excluded if there was a major change in benefit design over the 2017-2018 study period. Major changes include a change to or from a consumer directed health plan, change in insured product type , change in pharmacy coverage, or any payment amount from a government program . Some members had missing characteristics—specifically unknown gender or employer group size—and were excluded from analysis.The primary outcome was total medical costs PMPY, annual average, over the 2-year study period. Secondary outcomes included 2 binary indicators: presence of at least 1 hospitalization and presence of at least 1 ED visit during the 2-year study period.Member characteristics include age in years, gender, state of residence, enrollment in health plan care or disease management (CM/DM), plan paid to total paid ratio, group size, member predicted risk score, and 7 chronic conditions.18Enrollment in health plan CM/DM includes members who are referred by providers, self-enrolled by calling for assistance, or engage with outreach by CM/DM clinicians after identification through proprietary algorithms based on patterns of risk identified in claims data . The plan paid to total paid ratio is used as a proxy for the group benefit generosity, also known as the “actuarial value.” Under the Affordable Care Act, a health insurance plan’s actuarial value indicates the average share of medical spending that is paid by the plan, as opposed to being paid out of pocket by the member. The plan paid to total paid ratio considers a plan’s various cost-sharing features, such as deductibles, coinsurance, copayments, and out-of-pocket limits.19 The DxCG Intelligence risk score is a proxy for illness severity with the primary purpose to predict future health care expenditure based on the individual’s age, gender, and diagnoses generated from patient encounters with the medical system, excluding pharmacy. The DxCG Intelligence risk is normalized to 1 and expressed on linear scale. A member with a risk score of 1 is expected to have the average future medical cost; a member with risk score of 2 is expected to have 2 times the future medical cost of the average member.19Group size refers to the size of the self-insured organization  through which the member receives insurance. The predicted risk score and chronic condition identification came from industry standard software. DxCG Intelligence risk scores from Cotiviti were generated for each member.11 A priori, CAD was exchanged for hyperlipidemia due to provision for a more severe condition, and RA was added to assess a specialty drug condition. The conditions were identified by Optum Impact Pro software and include asthma, CAD, COPD, congestive heart failure (CHF), depression, DM, and RA.20The 7 chronic conditions in this analysis were identified as chronic conditions of interest a priori. Five of the 7 were identical to those used in a previous study the authors conducted and from which this study was intended to replicate as closely as possible.Descriptive statistics, distribution of covariates, and unadjusted outcomes were calculated with differences between the carve-in and carve-out groups tested using analysis of variance (ANOVA) for continuous and chi-square test for categorical variables. Unadjusted relative cost (RC) was calculated between the carve-in and carve-out groups. An RC of 1 indicates no difference in PMPY medical costs. An RC less than 1 indicates that the carve-in group had lower medical costs by a multiplier of the RC value. An RC of greater than 1 indicates the carve-in group had higher medical costs than the carve-out group.21 Based on their findings, the gamma log link model was the best fitting model because it had the smallest root mean square error and mean absolute error. To further assess the use of the gamma log link before fitting models, a modified Park test was performed to assess heteroscedasticity and distribution of total medical costs in this study.The distribution of medical costs tends to skew to higher costs, with a small proportion of individuals having extremely high costs. Dodd et al. (2006) compared several multivariable regression analysis methods of costs displaying this skew: normal and bootstrapped multiple linear regression, median regression, gamma model with the log link, and normal linear regression of log costs.A generalized linear model with gamma distribution log link was fit with each covariate separately to assess independent effect on RC. To assess the primary outcome of total medical cost PMPY, a generalized linear model with gamma distribution log link was fit including all covariates to adjust for baseline differences between the carve-in and carve-out groups. A sensitivity analysis was performed excluding any member with $250,000 or more in annual medical cost in 2017 or 2018 to remove the impact from extremely expensive members at a customary reinsurance threshold.P < 0.05 were considered statistically significant. It is important to note that with large samples, as found in this study, a P value of < 0.001 may be more appropriate for the primary comparisons, which were considered in interpreting findings for primary outcomes in this study.22 For the subanalyses by chronic conditions, with 15,000 members or fewer in each group, then P < 0.05 is a reasonable threshold. For both primary and secondary outcomes, 95% confidence intervals (CI) are provided to inform variability in the comparisons.Multivariable logistic regression models estimated the odds of hospitalization and the odds of ED visit adjusting for the same covariates as the primary analysis to adjust for baseline differences. Seven subgroup analyses were performed separately for members with each of the chronic conditions using the same analytic methods described for the primary and secondary outcomes. Two-sided There were 858,458 distinct Cambia members with some self-insured commercial medical coverage in 2017 or 2018. After excluding members with noncontinuous coverage , there were 368,740 members with continuous self-funded commercial insurance of which 18,866 (5.1%) had only partial pharmacy benefit coverage and 12,749 (3.5%) had some other major benefit change. Of the remaining members, 207,423 were identified to have continuous carve-in benefits and 129,702 to have continuous carve-out benefits. After removing 840 (0.4%) and 3,614 (2.9%) members with a government insurance payment, respectively, there were 206,583 members in the carve-in group and 126,088 members in the carve-out group. Of these, there were 748 (0.3%) carve-in and 533 (0.4%) carve-out members who were missing values for either gender or group size and were thus excluded from analysis. The final analytic cohorts consisted of 205,835 carve-in and 125,555 carve-out members, as seen in Univariable comparisons of member characteristics for the carve-in and carve-out group are displayed in d = 0.02), but the carve-out group had marginally higher risk scores in the top 2 quartile risk score groups resulting in a significant risk score difference. Baseline differences highlight the importance of reducing bias through multivariable adjustment in regression analyses.The difference in mean risk score between the groups was of small effect size  compared with the carve-out group $4,575 , yielding an unadjusted RC estimate of 0.91, P < 0.001, compared with the carve-out group. Transformed to dollar amounts, this equates to an associated $148 lower medical cost PMPY for the carve-in group. This finding of associated lower medical cost for the carve-in group remained when high-cost members were excluded with 3% lower medical cost on average after adjustment equating to $127 PMPY, P < 0.001. Medical costs were also significantly lower for the carve-in group on average for subgroups of members with 5 of the 7 chronic conditions, including asthma , CAD , COPD , DM , and depression . There was no significant difference in total medical cost PMPY for the subgroups of members with CHF (P = 0.078) and RA (P = 0.519).As shown in P< 0.001, and ED visit rates 19.3% versus 21.1%, P < 0.001. As shown in P < 0.001, and 7% lower for ED visits, P < 0.001, among the carve-in members. Odds were lower for subgroups of the carve-in group for the same 5 of 7 chronic conditions found to have significantly lower medical costs as follows: asthma , CAD , COPD , DM , and depression . There was no significant difference in odds of hospitalization or odds of ED visit for the subgroups of members with CHF  or RA .The carve-in group had lower unadjusted hospitalization rates 4.4% versus carve-out 5.2%, 13To our knowledge, this is the first peer-reviewed publication of a study assessing medical costs and health care utilization comparing individuals receiving carve-in pharmacy benefits to those receiving carve-out pharmacy benefits from self-insured employers. This large regional study found that carve-in pharmacy benefits were associated with a small, but statistically significant and financially important 4% lower PMPY medical costs at $148 PMPY, 15% lower odds of a hospitalization event, and 7% lower odds of an ED visit from 2017 to 2018. These findings did not substantially change when high-cost members were removed from analyses. In addition, these findings are supported by the subanalyses finding lower associated medical costs, odds of hospitalization and odds of ED visit for 5 of 7 chronic conditions. Specifically, lower associated medical cost PMPY ranged from $926 for carve-in members with asthma up to $4,351 for those with CAD. Lower odds of hospitalization ranged from 22% for COPD up to 36% lower for CAD members with carve-in benefits, whereas odds of ED visit ranged from 16% for CAD and DM members to 20% lower for COPD members. The associated lower medical costs within the carve-in group are consistent with grey literature reported findings from other Blue plan studies.16 Among the chronic condition findings, the Cambia results are very similar with the exception of RA in 1 non-Blue study, which was found to be 9% lower while Cambia RA carve-in was not significantly lower.14 It is possible that the sample size of Cambia RA members was too low to detect a difference in medical cost between the carve-in and carve-out groups.When compared with medical cost savings to those self-reported by non-Blue plans, whereas the amount varied across plan and location, these studies also reported similar lower medical costs PMPY.8 For example, with integrated data, Cambia care managers target members who could benefit from clinical programs and high-touch services to improve their care, manage cost and their condition, prevent additional avoidable high-cost services, and enhance their experience. It also allows them to have important conversations regarding side effects, drug interactions, medication compliance, and any barriers to filling prescriptions such as cost or transportation when engaging members in CM/DM for any serious medical event or discussing conditions discovered through medical claim diagnoses. Interestingly, the rate of enrollment in CM/DM was lower for carve-in compared with carve-out members in this study. It is possible that this lower rate was due to lower rates of serious medical events for those with long standing carve-in benefits, lower rates or severity of chronic conditions in the carve-in group, or improved ability to target outreach to only those who would most benefit when integrated data is used in identification algorithms. However, investigating these factors was beyond the scope of this study and should be studied further.Lower medical costs may be due to the availability and use of integrated data and benefits for improved care management, chronic condition management, specialty and controlled medication management, improved artificial intelligence and machine learning algorithms to match members to targeted intervention, and improved collaboration in provider partnerships to deliver care.23 Additional programs include the use of integrated data to inform general messaging and outreach to inform members and providers of next steps in treatment for specific episodes of care based on previous medical and pharmacy history and the use of integrated data in machine learning algorithms to target treatment options to a member’s predicted preferences and needs.From a personalized health management perspective, the integration of pharmacy data can enhance plan partnership with providers in value-based arrangements by providing more complete reporting on utilization and care gaps in medication adherence identified for members with specific medical diagnoses and absence of medication dispense. One such value-based arrangement program at Cambia, Common Care, includes a collaborative care management program between Cambia and providers that relies on a shared platform and proprietary technology solutions built with integrated data in order to provide a single, uniform picture of member health with insights to target intervention.11 we only included analysis of 7 a priori identified chronic conditions and did not include adjustment for other conditions.Limitations affect the interpretation of all studies using health insurance claims data. First, we were unable to compare pharmacy drug costs across the carve-in and the carve-out group, as we did not have access to drug costs for the carve-out group. We were limited to using medical claims data in this analysis, and there may be unmeasured confounders  that have an effect on interpretation of these results. Another limitation is that claims data are subject to coding errors that could affect utilization and diagnoses, although it is assumed these errors would be equally distributed across medical claims and, thus, independent of carve-in or carve-out benefit design. Due to replication methods of previous work and sample size constraints,24 Further, despite baseline differences between groups, the study is strengthened by nearly identical mean risk scores for the carve-in and carve-out groups, the large sample size, and indication that no independent covariate was associated with higher relative medical costs in the carve-in group.These findings indicate associations with carve-in pharmacy benefits and do not establish causation. Even though multivariable modeling was used to adjust for baseline cohort differences, some selection bias may exist due to characteristics unavailable in claims data, and the bias in measured covariates is reduced by an unknown degree. For example, given that the carve-in group was younger on average by 1 year and had lower rates of chronic conditions, it is possible that the effect of carve-in benefits on costs and rates of hospitalization and ED visits would be different for older and less healthy populations. However, for member characteristics included, a study has shown that multivariable covariate adjustment in regression performs well, especially with large sample sizes, compared with other statistical methods.These findings are limited to self-insured commercial groups, and findings may vary for members of government programs or members with other types of insurance. Finally, time with specified benefit design was not captured, so it is unknown when the lower cost and utilization associated with the carve-in models were first realized.These findings suggest that integrated, carve-in pharmacy and medical benefits are associated with lower medical costs, fewer hospitalizations, and fewer ED visits. Although this study focused on associations and defining causation was not in scope, possible reasons for these findings include health plan access to both medical and pharmacy data and data-informed care management and coordination. For example, it is possible that care managers have a better picture of a member’s health and are able to provide more personalized outreaches or coordinate with providers to improve outcomes. Additional benefits of integrated medical and pharmacy data may include cost stewardship efforts that can focus on both medical and drug costs; drug formulary benefits, utilization management, site of care optimization, and care gap management that can be based on member diagnoses and utilization in addition to medication use; and evaluation of medical and pharmacy services that can assess a more complete picture of cost and patient outcomes.Future research should include evaluation of this type of integrated data use and its effect across the spectrum of integrated health plan offerings, care management, provider partnerships, and analytic strategies; investigation of time insured by specified benefits and differences in plan types; and inclusion of analysis of pharmacy costs to encompass total cost of care.