The novel coronavirus disease (COVID-19), the reason for worldwide pandemic, has already masked around 220 countries globally. This disease is induced by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Arising environmental stress, increase in the oxidative stress level, weak immunity and lack of nutrition deteriorates the clinical status of the infected patients. Though several researches are at its peak for understanding and bringing forward effective therapeutics, yet there is no promising solution treating this disease directly. Medicinal plants and their active metabolites have always been promising in treating many clinical complications since time immemorial. Mother nature provides vivid chemical structures, which act multi-dimensionally all alone or synergistically in mitigating several diseases. Their unique antioxidant and anti-inflammatory activity with least side effects have made them more effective candidate for pharmacological studies. These medicinal plants inhibit attachment, encapsulation and replication of COVID-19 viruses by targeting various signaling molecules such as angiotensin converting enzyme-2, transmembrane serine protease 2, spike glycoprotein, main protease etc. This property is re-examined and its potency is now used to improve the existing global health crisis. This review is an attempt to focus various antiviral activities of various noteworthy medicinal plants. Moreover, its implications as prophylactic or preventive in various secondary complications including neurological, cardiovascular, acute kidney disease, liver disease are also pinpointed in the present review. This knowledge will help emphasis on the therapeutic developments for this novel coronavirus where it can be used as alone or in combination with the repositioned drugs to combat COVID-19. Coronavirus disease-19  has just become the hot cake internationally. This disease turned out as a pandemic in 2019 and has affected nearly 60 million people worldwide by 2021. This medical health emergency though initially starts with a mild symptomatic condition but in later stages creates an oxygen deficient environment into the human system, inducing a severe respiratory distress . Acute kUpon studying various parameters, it was interestingly seen that oxidative stress plays a critical role in majority of patients. Oxidative stress is generally associated with all physiological anomalies in human. Several lines of evidence suggest that COVID-19 infection deteriorates in many patients with malnutrition, physiological stress and co-infections, all of which adversely alter the endogenous antioxidant machinery . This coMoreover, an inappropriate immune response characterized by excessive production of proinflammatory activators have been found, which results in common symptoms in severe COVID-19 patients. Increasing immunosuppression is another important source of endogenous oxidative stress resulting in imbalance in the oxidant-antioxidant ratio in the human body . This siCurcuma longa, Nigella sativa, Oroxylum indicum, Echinacea purpurea, Cinchona sp., Glycyrrhiza glabra, Camellia sinensis and various other medicinal plants have always proved to be potential candidates for major microbial infections [Many known antiviral and antimalarial drugs like remdesivir and hydroxychloroquine are broadly studied for drug repositioning against COVID-19 infection. However, traditional medicinal plants also exhibit many prophylactic or preventive effects towards this disease. Needless to pinpoint the boon of these medicinal plants and their therapeutic effects. Since the time of Charaka Samhita in 1st millennium BC and inception of Ayurveda, the use of medicinal plants has been continuing for mitigation for various ailments with minimum side effects. Many ethnomedicinal use of the plants continue to be a choice of interest across the world ,15. The fections ,17,18. Afections . PresentThe inception of the novel coronavirus disease pandemic has engulfed more than 3,972,783 lives worldwide thus far . There aThe viral architecture is a simple positive double stranded RNA makeup. The virus finds its entrance through the host angiotensin converting enzyme-2 (ACE-2). This transmembrane protein is abundant in the alveolar walls, lungs, epithelial cells and gastrointestinal tract. It makes complimentary binding site for the interaction with the viral spike protein ,23. ThisThere is a high surge of IgM in the initial weeks of viral infection followed by increased IgG level in the latter phase during immunological response . It multCurcumin longa, Oroxylum indicum, Echinacea purpurea, Cinchona sp., Glycyrrhiza glabra, Ocimum sanctum, Withania somnifera and many others have reported immensely in treating COVID-19 disease. The bioactive compounds of medicinal plants can also alleviate the cytokines storm and inhibit the induced ROS, which subsequently can neutralize the inflammatory response. The role of medicinal plants and their potent molecules in different stages of COVID-19 pathogenesis intervention are summarized in Plant based natural products have always been a boon to cure many ailments since time immemorial. Their use as antiviral compounds is studied worldwide. Natural products in the form of nutraceuticals, medicinal foods, immune booster, antioxidants, and formulations showed antiviral activities. They have shown various modes of action including targeting viral attachment, its entry and multiplication, and suppressing inflammation . TangereGlycyrrhiza glabra is one such important medicinal plant found effective against SARS-CoV-2. Its active components like glycyrrhizin, and Glyasperin A are reported to have antiviral activity particularly against spike and non-structural protein-15 (nsp15). Molecular docking and simulation study showed higher binding efficacy of G. glabra extract that can inhibit the viral entry. Glyasperin A showed higher affinity towards spike glycoprotein [Ferula asafetida have intensive binding affinities for ACE2 receptor [All viruses of coronavirus group generally have similar pattern of spike protein and its route of entrance into the host. SARS-CoV-2 being a class of coronavirus family follows similar trend of entrance into the host cells. Earlier many reports of active compounds and its role in blocking the entrance have been narrated critically. This is either done by lowering the expression of the ACE-II receptors in the cells or by blocking the receptors by the natural compounds. oprotein . Glycyrrreceptor . Epigallreceptor .In order to complete viral lifecycle, they involve the attachment to the active region of the host ACE-II receptor using the various virion surface glycoproteins. The entry mechanism of SARS CoV-2 depends primarily on TMPRSS2 and furin moieties, along with ACE-II receptor . TherefoReynoutria japonica and Reynoutria sachalinensis was found effective against the main protease (Mpro) [Panax ginseng, Zingiber officinale, Ocimum basilicum are potential inhibitors of the main protease required for viral replication process of coronaviruses [Punica granatum peel extracts are reported to inhibit TMPRSS2, and ACE-II significantly [Andrographis paniculata is reported to inhibit three potential key targets, papain-like receptors (PLpro), spike glycoprotein and the RdRp, which mediate the viral replication process. Neoandrographolide and 14-deoxy andrographolide, other active compounds of A. paniculata have shown to decrease 3CLpro and PLpro significantly [Additionally, the ability of the theaflavin, a component of black tea, in inhibiting the RNA dependent RNA polymerase (RdRP) active site is well documented in many recent works on COVID-19 research . Bioactie (Mpro) . Nimbin,aviruses . Punicalficantly . Androgrficantly .. Nigella sativa is another pharmacologically important plant, which contains a well-known bioactive principle thymoquinone. Being smaller in structure, this hydrophobic molecule aptly fits into the lipophilic envelope of SARS-CoV-2 inhibiting its entry and thereby replication [Quercetin, the active flavanol common in many of the medicinal plants contains five hydroxyl moieties in its pharmacophoric region, which interferes and creates a hindrance in the early stages of the viral infections. It is usually achieved by blocking the angiotensin-converting enzyme quite significantly. The combinatorial activity of quercetin with zinc has also been reported where zinc has a role in the suppression of RdRp . Some ofTable 1lication .COVID patients have surge of inflammation that is caused by increased macrophages, inflammasome and monocytes. Not only this, ROS also triggers the secondary inflammation that undergoes intercellular signaling. However, the exact mechanism is still being researched to understand how SARS-CoV-2 directly induces inflammation. It has been found that immune compromised patients have dysregulated NLRP3 inflammasome resulting in severe tissue damage and cytokine storm , indicatCannabis sativa, which has been used for various medical purposes, has shown anti-inflammatory activity associated with COVID-19 infection [C. sativa extract fraction greatly reduced cytokines IL-6, and IL-8 as well as chemokines: C-C Motif Chemokine Ligands (CCLs)-2 and CCL7 levels, in an alveolar epithelial cell [Traditional folklore varieties of medicinal plants are reported to have anti-inflammatory activities, which can alleviate these pro-inflammatory mediators. The anti-inflammatory activity of medicinal plants can check the cytokine storm in the affected patients and inhibit viral entry and replication . Tangerenfection . C. satiial cell . Limonenial cell . Flavonoial cell .Different formulations and preparation have also demonstrated anti-inflammatory activities in COVID-19 associated inflammation. The Ayurvedic formulation, Divya-Swasari-Vati, was found to suppress the pro-inflammatory cytokine levels, TNF-α and IL-6 both in humanized Zebrafish model . ShufengBoerhavia procumbens, Cistanche tubulosa, Euphorbia hirta, Hyoscyamus niger, Capparis spinosa L., Carum copticum, which not only decrease the inflammasomes in viral infection but also alleviate the level of ROS built due to cytokine storm [Plants bestow antioxidant activities in a multifaceted manner, where their active ingredients work alone or in synergy to clear reactive oxygen species mainly by neutralizing them . Many nane storm . Number ne storm . Similarne storm ,99. ThisImmunity gets compromised in the later stages of this novel coronavirus disease. The decreased immune response causes increased secondary complications and resulting in organ failure in the suffering patients. Medicinal plants have always been used as a combinatorial medicine with other phytochemicals. Their antioxidative efficacy boosts up the immunity level in the patients to minimize further complexities in the COVID-19 disease. Ginseng plant has immunostimulating properties. They can induce cytokine productions activating the macrophages and enhancing the antibody productions . AchyranAllium sativum (garlic) have been reported to alleviate cytokine level and reverse the immunological abnormalities to comparatively safer situation in COVID-19 patients. Thus, A. sativum can be an important plant against SARS-CoV-2 infection [Echinacea spp., Boswellia spp., Glycyrrhiza spp., Curcuma longa, medicinal fungi, Pelargonium sidoides and Sambucus spp. are documented with immunomodulatory, immunostimulatory, and anti-inflammatory effects. These immune responsive properties of medicinal plants can help to prevent the viral infections [Compounds derived from nfection . Besidesfections . Thus, tIt is seen in many cases that COVID-19 patients experiences post-COVID complications. However, most of the patients recover in 1–2 weeks and have fairly any emerging complications. Post-COVID conditions are wide range of complications of different organs including but not limited to lungs, liver, kidney, heart, brain  that patRenal symptoms including acute kidney injury (AKI) is one of the most frequently occurring COVID-19 associated secondary complications . In a stInterestingly, kidney biopsies of Afro-American COVID-19 patients appeared to be collapsing focal segmental glomerulosclerosis with elevated level of APOL1, resulting in functional effect of podocytes due the viral replication ,149. HowNatural compounds have shown to be very helpful in the management of AKI induced by COVID-19. Quercetin, which is found in wide range of medicinal plants and dietary supplements, has found to be safe and potential candidate against AKI induced by different nephrotoxic agents. Using network pharmacology and molecular docking, it has been observed that quercetin exhibits renal protective effects on COVID-19-induced AKI through inhibiting the signaling pathways associated with apoptosis and inflammation. Quercetin also inhibits SARS-CoV-2 main protease 3CL and ACE2, suppressing the integral proteins and thus affects the viral life cycle . As incrSalvia multiorrhiza (family Lamiaceae) commonly known as Danshen is rich in tanshinones and salvionalic acids. Tanshinone IIA is well known for modulating TGF-𝛽 signaling pathway and anti-inflammatory effect. Using AKI model, Jiang and coworkers showed that Tanshinone IIA markedly reduces the expression of TGF-β1 and MCP-1 [Lingustrazine (tetramethylpyrazine), a natural product isolated from Chinese herb, significantly diminished the mRNA levels of TGF-β1 and also inhibited the loss of cytokeratin-18 expression hence attenuate renal tubulointerstitial fibrosis . Anothernd MCP-1 . Similarnd MCP-1 . As TGF-While the clinical exemplifications of COVID-19 disease are generally subjugated by respiratory symptoms, 8–12% of total patients were diagnosed with increased levels of cardiac troponine . A recenUlmus wallichiana plant extract has ability to decrease renin, Ang II, ACE activity as well as level of inflammatory molecules, which indicates its cardioprotective effect [Rosmarinus officinalis, exhibited cardioprotection on myocardial infarction-induced cardiac fibrosis in rat model through the suppression of ACE and angiotensin type 1 receptor (AT1R) expression [As overexpression of ACE2 receptor along with angiotensin in heart muscle cells causes systemic inflammation and myocardiac injury in COVID-19 patients, targeting these molecules by natural compounds can relive the infection associated cardiovascular illness. Studies conducted on rat model showed that e effect . Anotherpression . Ang II,pression . Besidespression . In anotpression . These sThe notable clinical manifestation of COVID-19 includes pneumonia, severe lung inflammation and acute respiratory distress syndrome (ARDS) leading to breathing problem in affected patients. Apart from this, the severity may outstretch to a complete shutdown of lung functions and induction of sepsis. Although a large proportion of clinical and experimental research are focusing on repurposing and combinatorial use of FDA approved drugs, efforts have been also made for the search of plant derived anti-viral compounds. SARS-CoV-2 enters into human host via the ACE2 receptor, which is highly expressed in lung tissue. Besides this, inflammation of the lungs is also the main factor leading to respiratory distress in patients with severe COVID-19.Andrographis paniculata and its active compound andrographolide directly inhibit the infectivity of SARS-CoV-2 in lung epithelial Calu-3 cells with an IC50 of 0.036 μg/mL and 0.034 μM, respectively [Cannabis sativa extracts decreases ACE2 expression levels [Prunus mahaleb L. fruit also downregulates the gene expression of ACE2 and TMPRSS2 in lung epithelial H1299 cells, suggests the potential role in inhibiting SARS-CoV-2 entry in the human host [C. sativa has also shown to reduce IL-6, IL-8, CCL2 and CCL7, expression in the lung epithelial A549 cell line and thus anticipated to prevent or treat COVID-19 infection [In view of this, attempts have been made to identify natural inhibitors of inflammation, ACE2 and 3CL protease. However, extract of ectively . Furthern levels . Prunus man host . Besidesnfection .A formulation tri-herbs, which contains ursolic acid, withanone, withaferine, cordifolioside A, magnoflorine, withanoside IV-V, betulinic acid, rosmarinic acid, and palmatine as phyto-metabolites, attenuated the inflammatory markers such as TNF-α and IL-6, and decreased the NF-κB/AP-1 transcriptional activity in lung cells, suggesting its potential use in SARS-CoV-2 infection . ShufengThe pre-Bötzinger complex (PBC) in the brain primarily functions as respiratory oscillator. It might be possible that during the infection, SARS-CoV-2 targets central nervous system and inhibits the PBC in the brainstem thus contributing respiratory breakdown . In COVIIt has been revealed that many of the traditionally used medicinal plants have the property to overcome COVID-19 associated neurological disorders. In this light, Ayurvedic plants not only boost the immunity but also directly affect the symptoms of depression or anxiety in COVID-19 patients . LuteoliGenerally the chronic liver disease (CLD) is correlated with immune dysregulation and inflammation, which may present a greater risk of COVID-19 mediated pathogenesis . Recent Therefore, natural products could have therapeutic potential in the management of COVID-19 affected liver injury. Based on the available evidence, glycyrrhizin preparations have been shown to be a useful therapeutic agent for SARS-CoV-2 infections, especially those complicated with liver damage . In a stn =2285) herbal medicine, and QingfeiPaidu decoction (n = 2053) led to improve on COVID-19-related symptoms like dry cough, headache, muscle pain, sore throat, dyspnea and loss of appetite. As corticosteroids have been administrated to severe patients with COVID-19, resulted in osteonecrosis of the femoral head (ONFH) disabling complication among convalescent SARS patients. However, Chinese herbal Huo-Gu formula therapy demonstrated beneficial effects on preventing femoral head collapse, delaying total hip arthroplasty, and maintaining physical function caused by ONFH in COVID-19 patients [Besides aforementioned secondary and post COVID-19 disease, many patients continue to experience symptoms such as anxiety, depression, fatigue, insomnia and also muscular sprain. However, facts from pre-pandemic observational and other related studies suggested that a nutraceutical may provide benefit to the patients with COVID-19 in managing these disorders  Ayurvedipatients . BesidesWithania somnifera, Ginkgo biloba, Citrus reticulata, Camellia sinensis, Glycyrrhiza glabra, Coffea arabica mentioned here in this review are rich in antioxidant and inflammatory activity. They show inhibitory action against integral proteins of SARS-CoV-2, whether it’s the spike protein or the inhibition of the RNA dependent polymerase, or papain like receptor and ACE-II receptor. So, further in-depth study on these medicinal plants with antioxidant and inflammatory activities can be studied for more putative compounds that can be promising leads in the development of newer therapeutic drugs.Hardly any country remains untouched by the menace of COVID-19 pandemic and its deleterious outcome. In this situation of crisis, it is utmost necessary to control the present ongoing condition. Where bringing out newer drugs is relatively harder it is very urgent to bring about a quick remedy for this disease. Medicinal plants have always been a huge repository presenting vivid range of natural products having both prophylactic and preventive activity against many serious complications. Where pooling the entire bioactivity data is a tedious job amidst lots of existing extracts variation and lack of proper standardization of the purified extracts, so direct anti-inflammatory, antioxidant and antiviral activity of such medicinal plants can be directed to understand their protective role in the mitigation of the various prevailing secondary complications associated with the COVID-19. Important plants like


There is significant variability in neutralizing antibody responses (which correlate with immune protection) after COVID-19 vaccination, but only limited information is available about predictors of these responses. We investigated whether device-generated summaries of physiological metrics collected by a wearable device correlated with post-vaccination levels of antibodies to the SARS-CoV-2 receptor-binding domain (RBD), the target of neutralizing antibodies generated by existing COVID-19 vaccines. One thousand, one hundred and seventy-nine participants wore an off-the-shelf wearable device (Oura Ring), reported dates of COVID-19 vaccinations, and completed testing for antibodies to the SARS-CoV-2 RBD during the U.S. COVID-19 vaccination rollout. We found that on the night immediately following the second mRNA injection (Moderna-NIAID and Pfizer-BioNTech) increases in dermal temperature deviation and resting heart rate, and decreases in heart rate variability (a measure of sympathetic nervous system activation) and deep sleep were each statistically significantly correlated with greater RBD antibody responses. These associations were stronger in models using metrics adjusted for the pre-vaccination baseline period. Greater temperature deviation emerged as the strongest independent predictor of greater RBD antibody responses in multivariable models. In contrast to data on certain other vaccines, we did not find clear associations between increased sleep surrounding vaccination and antibody responses. Vaccines for COVID-19 have been remarkably effective in preventing severe disease, with reductions in the risk of severe disease in the 90% range . ExistinPrior data suggest that sleep duration just before and after vaccination is associated with the level of antibody responses to vaccination. For example, in an experimentally induced sleep restriction model, less sleep in the nights prior to influenza vaccination predicted lower responses to vaccination . SimilarCOVID-19 vaccinations result in physiological responses that are short in duration but can be quite noticeable, including fever, chills, and fatigue . These pWe sought to shed light on these questions by analyzing data from the second TemPredict study, which took place in the spring of 2021, just as COVID-19 vaccinations were becoming widely available. In this study, we tested whether a wearable device (Oura Ring), which collects data on dermal temperature, heart rate, heart rate variability, and various sleep metrics  sleep duration) could be used to detect the early period of COVID-19 disease. Prior data suggest that wearable devices can detect changes in physiology that follow mRNA vaccination against COVID-19 . Most paWe initiated the second TemPredict study in December of 2020 to assess whether an algorithm derived from physiological metrics collected by an off-the-shelf wearable device (Oura Ring) could be used to detect COVID-19 infection in real-time. An additional aim of this study was to assess whether data from this device could predict antibody response quantified as antibodies to SARS-CoV-2 spike protein receptor binding domain (RBD), which is the focus of the current report.Recruitment. We recruited participants residing in the United States who already possessed Oura Rings by sending them email invitations. These email invitations included a link to an online consent survey. We also recruited participants who worked at participating sites  by enlisting leadership at these sites to assist in recruitment. We mailed these sites recruitment materials, including study flyers and Oura Ring sizing kits, which contained plastic rings for prospective participants to try on to determine their size. We provided Oura Rings to interested individuals at these sites after they provided their size information to study coordinators.Eligibility and Consent. Eligible participants were at least 18 years of age, possessed a smartphone that could pair with their Oura Ring, resided in the United States, did not previously have COVID-19 infection (verified through laboratory testing during enrollment), and could communicate in English. For this analysis, of the 2055 participants who completed the overall study, we first excluded participants who had a positive SARS-CoV-2 nucleocapsid antibody test at the end of the study, indicating COVID-19 infection during the study period (n = 56). We then excluded participants who were not fully vaccinated at least 7 nights prior to their final blood draw (n = 715). We then excluded participants who did not have at least 7 nights of physiological data within the timeframe used to develop the pre-vaccination baseline period .The University of California San Francisco (UCSF) Institutional Review Board  and the U.S. Department of Defense (DOD) Human Research Protections Office  approved of all study activities, and all research was performed in accordance with relevant guidelines and regulations. All participants provided electronic (written) informed consent, and this research was conducted according to the principles expressed in the Declaration of Helsinki. Participants to whom we provided Oura Rings kept the devices following their participation; we did not otherwise compensate participants for participation.Questionnaires: Beginning in December 2020, participants completed several online surveys. They first completed a baseline survey that collected demographic and health information. They also completed daily and monthly surveys on which they reported COVID-19 symptoms, COVID-19 diagnosis, and COVID-19 exposures. Within these surveys, participants also reported whether they had been vaccinated against COVID-19, and if so, which vaccine they received  as well as their injection dates. After participants reported on vaccine type and dates of vaccine injections, their surveys were customized such that they were not asked these questions in duplicate on future dates.Antibody testing. We tested participants for antibodies to the SARS-CoV-2 nucleocapsid protein  during enrollment (December 2020 through early April 2021) and at the end of their participation (April and May 2021). The SARS-CoV-2 nucleocapsid antibody test becomes positive following COVID-19 infection, but vaccination does not cause individuals to generate antibodies to this part of the virus. Participants were required to have a negative nucleocapsid antibody test at enrollment as we excluded participants with evidence of prior COVID-19 infection. At the end of the study period (late April and May 2021), we also tested participants for antibodies to the SARS-CoV-2 RBD with the LabCorp Semi-Quantitative Total Antibody, Spike assay , which used the Roche Elecsys Anti-SARS-CoV-2 S assay performed on a COBAS e602 module  stages 1 and 2), deep sleep (NREM stages 3 and 4), rapid eye movement (REM) sleep, and total sleep time. We examined these metrics  in the present analyses.Vaccination. Participants reported the dates on which they received injections of one of the three vaccines available in the United States  between December 2020 and May 2021.Outcome. For correlation analyses, we treated values of “>2500 IU/mL” as 2500 IU/mL (n = 474). We omitted participants who received a value of “>250 IU/mL;” n = 51) from primary analyses. However, we reported analyses including these values as 250 in Predictors. We used device-generated values of each metric two nights before and three nights after each injection . We established a pre-vaccination baseline period for each participant from 14 nights to 4 nights prior to the first vaccine injection (night −14 to night −4). We calculated values of each device-generated metric adjusting for this pre-vaccination baseline period by converting each physiological metric to a z-score using participants’ respective individual means and standard deviations from the pre-vaccination baseline period . We examined device-generated metrics from all nights surrounding each injection  and device-generated metrics adjusted for the pre-vaccination baseline period as predictors of RBD antibody responses. Notably, all device-generated metrics reflect values solely from the prior night, except the temperature deviation metric . The temperature deviation metric adjusted for the pre-vaccination baseline period, therefore, reflects a difference in two deviation metrics: the difference between a participant’s (1) deviation on a particular night surrounding injection and (2) average deviation during the pre-vaccination baseline period.If a participant was missing device-generated metrics from a particular night, we did not include them in analyses for that night. We excluded participants who had a positive SARS-CoV-2 nucleocapsid antibody test at the end of the study, who did not receive their second injection (Moderna-NIAID and Pfizer-BioNTech) at least 7 nights prior to their final blood draw, who did not have at least 7 nights of physiological data within pre-vaccination baseline period (night −14 to night −4), and who had a threshold value of “>250 IU/mL” on the outcome.Statistical analyses. We conducted analyses separately for each type of vaccine . We also analyzed the data from both mRNA vaccines combined (Moderna-NIAID and Pfizer-BioNTech). First, we conducted Spearman rank-order correlations between RBD antibody responses and device-generated metrics, before and after adjusting for the pre-vaccination baseline period. We also examined correlations between metrics assessed during the pre-vaccination baseline period and RBD antibody responses. We repeated these analyses retaining participants (n = 51) with RBD values of “>250 IU/mL” as “250 IU/mL” and include these results in p-values < 0.1. Due to the proportion of observations with right-censored values of the outcome variable, we adopted a semi-parametric approach using Cox regression models [Second, we used the results of the bivariate correlational analyses to inform variable selection for multivariate regression models that assessed which device-generated metrics independently predicted RBD antibody responses. Based on results from the Spearman correlations, we combined data from the mRNA vaccine recipients (Pfizer-BioNTech and Moderna-NIAID) from night 0 after the second injection to predict RBD antibody responses from device-generated metrics before and after adjusting for the pre-vaccination baseline period. We included device-generated metrics that had associations in Spearman correlation analyses (in the combined mRNA sample) before and/or after adjusting for the pre-vaccination baseline period with the RBD antibody responses with n models , using tn models . We founWe enrolled 2392 participants in the second TemPredict study . After eChanges in device-generated metrics during night 0 (the night immediately following the second injection) tended to show a stronger pattern of associations with RBD antibody responses than these metrics the night immediately following the first injection . In somep = 0.012; temp deviation: rho = 0.123, p = 0.026) and Pfizer-BioNTech  were associated with greater RBD antibody responses (p = 0.022), and these associations were in the same direction, but not statistically significant, for Moderna-NIAID . The associations between RBD antibody responses and HR (Pfizer-BioNTech only) and temp deviation (Pfizer-BioNTech and Moderna-NAIAD) were also evident the following night (night 1) after the second injection. Correlations between device-generated metrics and antibody responses were in the same direction and often had similar rho values for participants who received the Johnson & Johnson-Janssen vaccine, but none of these correlations were statistically significant in the smaller group that received this vaccine.Greater HR and temp deviation on night 0 after the second injection for both the Moderna-NIAID . In analyses combining participants who received either of the two mRNA vaccines, there was a statistically significant inverse correlation between deep sleep on night 0 after the second injection and RBD antibody responses . The associations between RBD antibody responses and HR, RR, and temp deviation were also evident the following night (night 1) after the second injection.Analyzing the two mRNA vaccines in combination (Moderna-NIAID and Pfizer-BioNTech) yielded similar associations between device-generated metrics and RBD antibody responses . HR, temReplicating these analyses retaining participants whose RBD antibody responses were “>250 IU/mL” as 250 IU/mL showed similar patterns of results . Repeatip = 0.007; temp deviation: rho = 0.158, p = 0.004) and Pfizer-BioNTech  were associated with greater RBD antibody responses. Additionally, on night 0 after the second injection, larger decreases in HRV and deep sleep, and a larger increase in RR, were associated with greater RBD antibody responses for Moderna-NIAID  and Pfizer-BioNTech . Pfizer-BioNTech also demonstrated an additional association between larger decreases in deep sleep and greater RBD antibody responses . The associations between RBD antibody responses and both RR and temp deviation for each Pfizer-BioNTech and Moderna-NAIAD were also evident the following night (night 1) after the second injection. We did not observe these patterns for Johnson & Johnson-Janssen.Adjusting for the pre-vaccination baseline period strengthened associations between device-generated metrics and RBD antibody responses revealed significant associations between RBD antibody values and additional metrics . Specifip = 0.024).When we combined participants who received either of the two mRNA vaccines (Moderna-NIAID and Pfizer-BioNTech), the associations between device-generated metrics adjusted for pre-vaccination baseline and RBD antibody responses demonstrated greater statistical significance . HR, HRVReplicating these analyses retaining participants whose RBD antibody responses were “>250 IU/mL” as 250 IU/mL showed similar patterns of results . Repeatip < 0.05) correlations using Spearman rank order or Kendall rank correlation coefficients between baseline values of sleep duration, REM sleep, deep sleep, HRV, HR, RR, or temperature deviation and antibody responses. Among participants who received the Moderna-NIAID vaccine, we observed a correlation between temperature deviation and antibody response such that lower temperature deviation was associated with greater antibody response . Among participants who received the Pfizer-BioNTech vaccine, we observed a correlation between respiration rate and antibody response such that lower respiration rate was associated with greater antibody response .Among participants who received the Johnson & Johnson-Janssen vaccine, we did not observe any statistically significant  participants. In Cox regression models, temp deviation on night 0 after the second injection was a statistically significant predictor of RBD antibody responses in models before and after adjusting for the pre-vaccination baseline period . In the We found that physiological metrics from an off-the-shelf wearable device on the two nights following the second dose of an mRNA-based COVID-19 vaccine were associated with RBD antibody responses. Using the device-generated metrics adjusted for the pre-vaccination baseline period, we found that both increased temperature deviation and heart rate (HR) and decreased heart rate variability (HRV) the night immediately following the second mRNA vaccine injection correlated with higher RBD antibody responses. In bivariate analyses using a standardized difference from the pre-vaccination baseline period for each physiological metric, we found that increased HR, temperature deviation, and RR, as well as decreased HRV and deep sleep, were each associated with higher RBD antibody responses for individuals who received the mRNA vaccines. We did not, however, find a meaningful pattern of associations between participants’ device-generated metrics during the pre-vaccination baseline period and antibody responses. Although one earlier study did not find an association between vaccine-related side effects and antibody levels , a seconafter receiving an mRNA-based vaccine against COVID-19, both in absolute terms and relative to one’s pre-vaccination levels, was associated with greater antibody responses. Rather than implicating reduced deep sleep after vaccination as a mechanism driving antibody response, a more likely explanation is that individuals experiencing more noticeable discomfort, such as arm pain, fever, chills, or other symptoms that can follow COVID-19 vaccination [In a multivariate model predicting RBD antibody responses from device-generated metrics, we found that increased HR and temperature deviation independently predicted greater RBD antibody values for individuals who received the mRNA vaccines. In an identical model adjusting for the pre-vaccination baseline period, we found that dermal temperature was the sole statistically significant independent predictor of greater RBD antibody values in this same sample. Prior research has focused on identifying the roles of behavioral and psychological factors, in particular, sleep parameters, in vaccine responses. Short sleep duration prior to vaccination against influenza reduces antibody responses in both observational and experimental sleep deprivation models ,23. ThesMediators of systemic inflammatory responses, such as COX-2, are associated with fever as well as with the development of certain vaccine responses . As antiPsychological factors, including psychological stress, can impact immunological responses to vaccination, and clarifying their impact on COVID-19 vaccination may be important for developing interventions to optimize antibody response . For exaOur data have several limitations. We did not collect information on antipyretic or other medication use surrounding the time of vaccine injections, and thus cannot directly assess any effects of antipyretics on vaccine responses. We also did not collect detailed self-report information on post-vaccination symptomology, and we did not collect anthropometric information  from participants as this study was completed by mail and internet only. Future research should collect such information, as emerging data suggests that health metrics, such as body mass index, may be associated with antibody responses . The RBDIn conclusion, we found that several physiological metrics generated by an off-the-shelf wearable device in the nights following a second mRNA vaccination against COVID-19 were associated with subsequent levels of RBD antibody levels. In multivariate analyses, we found that elevated temperature was the strongest independent predictor of antibody responses. These findings suggest that off-the-shelf wearable devices collect data that could be useful in predicting immune responses to COVID-19 vaccination, though the clinical implications remain uncertain. Our data suggest that further investigation of the effects of antipyretics on COVID-19 vaccine responses is warranted.Patent application US App. No. 63/287,914 was filed on December 9 by the University of California San Francisco. The application covers use of wearable device data to predict the development of antibodies against COVID-19 following vaccination against COVID-19. A.E.M. and B.L.S. are listed as co-inventors on these applications.


Knee trauma can lead to poor health-related quality of life (HRQoL) and osteoarthritis. We aimed to assess HRQoL 3–12 years following youth sport-related knee injury considering HRQoL and osteoarthritis determinants. Generic  and condition-specific  HRQoL were assessed in 124 individuals 3–12 years following youth sport-related knee injury and 129 uninjured controls of similar age, sex, and sport. Linear regression examined differences in HRQoL outcomes by injury group. Multivariable linear regression explored the influence of sex, time-since-injury, injury type, body mass index, knee muscle strength, Intermittent and Constant Osteoarthritis Pain (ICOAP) score, and Godin Leisure-Time Exercise Questionnaire (GLTEQ) moderate-to-strenuous physical activity. Participant median (range) age was 23 years (14–29) and 55% were female. Injury history was associated with poorer KOOS QOL  but not EQ-5D-5L  or EQ-VAS . Injury history , worse ICOAP score , and anterior cruciate ligament tear  contributed to poorer KOOS QOL. Worse ICOAP score contributed to poorer EQ-5D-5L  and higher GLTEQ moderate-to-strenuous physical activity to better EQ-VAS . Knee trauma is associated with poorer condition-specific but not generic HRQoL 3–12 years post-injury. Traditionally, osteoarthritis has been considered a disease, largely defined by structural findings seen on imaging. However, there is an inconsistent relationship between imaging findings and outcomes associated with the personal , whereas not returning to sport, higher BMI, and subsequent surgery are linked to poorer condition-specific HRQoL  in adults experiencing knee difficulties  5–20 years post-ACL reconstruction  were calculated for all participant characteristics and outcomes by study group (knee injury history or not).2), normalized peak knee extensor and flexor strength (Nm/kg), intermittent knee pain , and moderate-to-strenuous physical activity (GLTEQ weekly METs) were considered. Biological sex [p-value <0.05 were retained and the most parsimonious model was reported. All assumptions for linear regression analyses were assessed and met.Univariable linear regression models (95%CI), accounting for clustering on sex  and main sport type , were used to assess the association between previous injury history (yes/no) and HRQoL outcome . To better understand what factors might influence the relationship between injury history and HRQoL outcomes, separate multivariable linear regression models (95%CI), accounting for clustering on sex and main sport type, including sex, time since injury (years), type of injury (ACL tear or other), BMI  and 55% of the participants were females . Soccer For generic HRQoL, the median EQ-5D-5L index score for the uninjured and injured participants was 0.911 (range 0.634–0.949) and 0.911 (range 0.561–0.949), respectively, and the median EQ-VAS score for the uninjured and injured participants was 85 (range 20–100) and 80 (range 10–100), respectively. For condition-specific HRQoL, uninjured participants had a median KOOS QOL score of 100 (range 83–100) whereas injured participants had a median score of 92 (range 64–100). One injured participant did not complete the EQ-5D-5L and three injured participants did not complete the EQ-VAS.Univariable associations between injury history and HRQoL outcomes are summarized in Multivariable linear regression models that considered the influence of sex, time since injury, type of injury, BMI, knee extensor and flexor strength, intermittent knee pain, and moderate-to-strenuous physical activity on the relationship between youth sport-related knee injury history and HRQoL outcomes are summarized in Currently, most of what is known about risk factors for osteoarthritis is relative to markers of osteoarthritis disease , not osteoarthritis illness . This contrasts the fact that it is the illness that motivates people to seek healthcare and drives the individual and societal burden of osteoarthritis.We present a novel examination of generic and condition-specific HRQoL in individuals with a previous youth sport-related knee injury compared to uninjured controls of similar age, sex, and sport. Our findings indicate that a 3–12 year history of a youth sport-related knee injury is not associated with generic HRQoL but is negatively associated with condition-specific HRQoL. Exploratory analyses revealed that more intermittent knee pain or less self-reported moderate-to-strenuous physical activity are associated with worse generic HRQoL, as measured by the EQ-5D-5L index and EQ-VAS scores, respectively. Regarding condition-specific HRQoL (KOOS QOL), injury history, a previous ACL tear, and more intermittent knee pain were associated with a poorer outcome. These data imply that there may be distinct determinants of generic and condition-specific HRQoL following a youth sport-related knee injury; therefore, these two outcomes, although related, need to be considered as unique parts of a broad construct. Furthermore, these preliminary analysis suggests that risk factors for osteoarthritis illness, including intermittent knee pain and participation in moderate-to-strenuous physical activity, may differ from osteoarthritis disease.n = 2493, mean age 34 years) at a mean of nine years following ACL reconstruction who reported similar or even better generic HRQoL (Short-Form 36) compared to population norms [n = 147, mean age 48 years) with radiographic osteoarthritis [n = 24,513, mean age 64.7 years) with radiographic and/or symptomatic osteoarthritis [The finding that generic HRQoL was not associated with a 3–12 year history of a previous youth sport-related knee injury is consistent with a systematic review examining adults , psychon = 120, mean age 19 years) [n = 100, mean age 53.1 years) diagnosed with post-traumatic osteoarthritis compared to athletes with no knee surgery history [Current evidence indicates that individuals who have undergone an ACL reconstruction and those who have post-traumatic osteoarthritis may demonstrate deficits in condition-specific HRQoL. Specifically, reduced KOOS QOL scores have been observed at two years post-ACL reconstruction compared to uninjured controls (9 years)  and pers9 years) . Reduced history . Our finIntermittent pain was identified as a possible determinant of condition-specific HRQoL, likely due to similar physical, psychological, and social manifestations as those mentioned above. It is also important to consider there is a moderate correlation between the KOOS QOL and pain subscales (Pearson’s correlation coefficient 0.603) , indicatAside from a past ACL tear, we found no association between other established risk factors for osteoarthritis disease  confirmed at the time of injury. In contrast, this study was not specifically powered for our research questions. However, these preliminary findings can be used to inform an adequately powered study to fully address related objectives. Many of the participants in the Alberta Youth PrE-OA cohort may be from middle-to-high socioeconomic status given the recruitment sources and their ability to access organized sport, post-secondary education, and healthcare which limits the generalizability of our findings. Future studies should seek diverse and inclusive samples to better understand what happens to people from all backgrounds following a youth sport-related knee injury. It is important to highlight that the KOOS QOL subscale only consists of four items which may not capture the breadth and complexity of condition-specific HRQoL. Although only limited to people with an ACL injury, a possible alternative is the Anterior Cruciate Ligament-Quality of Life questionnaire (ACL-QOL)  which coMore research is required to better understand osteoarthritis illness, particularly in individuals who have sustained a previous youth sport-related knee injury. Further investigation of both generic and condition-specific HRQoL outcomes as it relates to osteoarthritis prevention is needed as they likely represent related yet separate constructs. Future studies should confirm and continue to explore the determinants of generic and condition-specific HRQoL and assess how these outcomes change in the short-, medium-, and long-term after a youth sport-related knee injury. In addition to building upon previous evidence, we recommend engaging patients as research partners to ensure relevant constructs related to HRQoL and osteoarthritis illness are examined. This information can be leveraged to develop osteoarthritis prevention programs that target aspects of both osteoarthritis disease and illness.The findings of this study suggest that generic and condition-specific HRQoL are distinct from one another and, therefore, both should be measured in research and clinical practice. Injury history appears to be associated with condition-specific but not generic HRQoL. Based on exploratory analyses, intermittent knee pain and moderate-to-strenuous physical activity may be factors that influence generic HRQoL whereas injury history, injury type, and intermittent knee pain may be factors that influence condition-specific HRQoL. Targeting intermittent knee pain and physical activity, particularly in youth and young adults who have sustained an ACL injury, may help optimize HRQoL. This study provides preliminary evidence that risk factors for osteoarthritis illness may differ from osteoarthritis disease. This finding can inform the design of future studies and osteoarthritis prevention strategies.


Recent reports of the transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by fully vaccinated people  do not uOver 12,000 mutations have been catalogued in SARS-CoV-2 genomes –5.Vaccines provide short-term relief from COVID-19, but rapid evolution of resistant viral variants necessitates additional supportive strategies, including broad-spectrum antiviral agents coupled with innovative prophylactic and therapeutic processes. Antiviral agents against SARS-CoV-2 should have been repurposed drugs, but of all the drugs tested, those effective in the later stages of infection, such as dexamethasone, are the main ones granted approval for emergency use . One excThe main entry of SARS-CoV-2 occurs in the ciliated epithelium lining the nose –11. The Most SARS-CoV-2 vaccines are injected and mainly induce serum immunoglobulin G1 (IgG1), which enters and protects the lungs, leaving the nasal epithelia and upper respiratory tract largely unprotected. Any serum immunoglobulin A1 (IgA1) produced by vaccination is not effectively transported to the secretions of the upper respiratory tract including those of the nasal mucosa . The dynThe nose is therefore likely to remain a source of infective virus transmission even after parenteral vaccination, which fails to completely eliminate the virus in the nose ,17. A siDrugs for nasal pharmacological prophylaxis against COVID-19 are under development and include (1) those blocking virus attachment to the host entry receptors without involving host immunity; and (2) intranasal vaccines or immune stimulants eliciting antiviral antibodies and memory cells at the mucosal surface.Category 1: Include povidone-iodine [co-glycolic acid) nanoparticles to deliver and confine drugs specifically to treat the nasal sinuses with slow release over one week [e-iodine , nitric e-iodine , ethyl le-iodine , astodrie-iodine ,23, iotae-iodine –26, and one week . StringeCategory 2: Intranasal vaccines are also being developed, inducing IgA since dimeric forms of these antibodies are particularly potent and found at the mucosal surfaces where SARS-CoV-2 targets the cells [he cells .Previous studies to develop nasal therapy for respiratory viruses have met with variable success. For example, a live attenuated flu nasal spray vaccine, called Flu Mist, has been approved by the US Food and Drug Administration (FDA), although the results of clinical trials have been discordant . DevelopIn conclusion, nasal therapy has great potential to prevent and treat a variety of respiratory viruses. As patients present at different stages of COVID-19 or with other viral infections, we will need a selection of therapeutic strategies from vaccines to broad-spectrum antiviral drugs, delivered in different ways from injection, sprays/inhalations, and tablets alone or in combinations, to counter these threats.


TA-HEVs have been proposed to play important roles in lymphocyte entry into tumors, a process essential for successful antitumor immunity and lymphocyte-mediated cancer immunotherapy with immune checkpoint inhibitors, vaccines or adoptive T cell therapy. In this review, we highlight the phenotype and function of HEVs in homeostatic, inflamed and tumor-draining lymph nodes, and those of HEV-like blood vessels in chronic inflammatory diseases. Furthermore, we discuss the role and regulation of TA-HEVs in human cancer and mouse tumor models.High endothelial venules (HEVs) are specialized blood vessels mediating lymphocyte trafficking to lymph nodes (LNs) and other secondary lymphoid organs. By supporting high levels of lymphocyte extravasation from the blood, HEVs play an essential role in lymphocyte recirculation and immune surveillance for foreign invaders  and alterations in the body’s own cells (neoantigens in cancer). The HEV network expands during inflammation in immune-stimulated LNs and is profoundly remodeled in metastatic and tumor-draining LNs. HEV-like blood vessels expressing high levels of the HEV-specific sulfated MECA-79 antigens are induced in non-lymphoid tissues at sites of chronic inflammation in many human inflammatory and allergic diseases, including rheumatoid arthritis, Crohn’s disease, allergic rhinitis and asthma. Such vessels are believed to contribute to the amplification and maintenance of chronic inflammation. MECA-79 Endothelial cells play critical roles in physiology and physiopathology, and are involved in many important diseases, including cardiovascular diseases, chronic inflammatory diseases and cancer. Although all vascular endothelial cells share certain common functions, considerable structural and functional heterogeneity exists along the length of the vascular tree and in the microvascular beds of various organs. One of the most striking examples of organ-specific endothelial cell differentiation occurs at the level of high endothelial venules (HEVs), specialized post-capillary venules found in lymph nodes (LNs) and other secondary lymphoid organs Fig.  which me6 lymphocytes migrate through the HEVs of the human body every second [The most obvious characteristic of HEV endothelial cells (HECs) revealed by light-microscopic examination is their morphology. HECs have a plump, almost cuboidal appearance very different from the flat appearance of endothelial cells that line other vessels. This cuboidal appearance provides the basis for the name of high endothelium. Thome first noted the plump morphology of HECs in LNs in 1898 . Thome wy second .HEVs are present in all secondary lymphoid organs with the exception of spleen, including hundreds of LNs dispersed in the body, tonsils, adenoids, Peyer’s patches in the small intestine, appendix, and small aggregates of lymphoid tissue associated with the mucosal surfaces of the respiratory, gastrointestinal and urogenital tract. HECs range from 7 to 10 μm in width and 5–7 μm in height and are much less regular in outline than the term cuboidal would suggest. They exhibit great deformability and irregularity of shape . The inc2) in many tissues and disease states [Evidence accumulated over the past 40 years indicates that blood vessels with HEV features develop in non-lymphoid tissues in many human chronic inflammatory diseases , 6, 22. n = 273) and primary melanomas (n = 225), the density of tumor-associated HEVs (TA-HEVs) was highly correlated with the density of CD3+ T cells (including CD8+ cytotoxic T cells) and CD20+ B cells, indicating that TA-HEVs may function as major portals of entry for lymphocytes into human solid tumors [Ten years ago, we reported that blood vessels with HEV characteristics are frequently found in the stroma of many human solid tumors including melanomas, breast, ovarian, colon and lung carcinomas , 29. Thed tumors , 29. Intd tumors . Blood vd tumors . StudiesThere are comprehensive reviews about the role of HEVs in LNs and other secondary lymphoid organs, to which the reader is referred –6. In ouIn mammals, HEVs are present not only in LNs and other secondary lymphoid organs –6 but alX GlcNAcβ1-R), is abundantly produced in HEVs and is present on both N-glycans and extended core 1 and 2 O-glycans decorating HEV sialomucins [X structures on extended core 1 O-glycans [+ antigens and MECA-79+ blood vessels may be more appropriate designations than PNAd outside of peripheral LNs. MECA-79 is a fantastic tool for HEV studies. It is a very robust mAb for immunohistochemistry and immunofluorescence studies, which reacts specifically with HEVs in both humans and mice (no cross-reaction with other blood vessels in the body), and in both lymphoid and non-lymphoid organs [The first interaction between naive lymphocytes and HEVs is initiated by lymphocyte L-selectin  that recognizes a family of sulfated mucin-like glycoproteins known as HEV sialomucins , 6. Althlomucins –49. The lomucins –46, 50. -glycans . The MEC-glycans . Howeverd organs . Importad organs .+ HECs by differential expression and subtractive hybridization strategies [+ HECs displayed a unique transcriptional program clearly distinct from that of all other endothelial cell subsets in the LN [Glycam1), CC-chemokine ligand 21 , and critical HEV enzymes  [Cd34, Emcn, …), were not differentially expressed in HECs. These transcriptomic analyses confirmed that the unique capacity of HECs to capture large numbers of lymphocytes is based on the coordinated expression of the different enzymes involved in the decoration of HEV sialomucins with high affinity 6-sulfo sialyl LewisX L-selectin ligands [Enpp2, Spns2, Sphk1) that were previously or subsequently identified through in vivo studies in mice [Glycam1 and Ccl21a exhibit differential expression in HECs. In a subset of HEVs, some MECA-79+ HECs expressed high levels of Glycam1 (or Ccl21a) mRNAs, although adjacent cells expressed none [+ HECs in the LN paracortex had higher expression levels of GlyCAM-1 protein than MECA-79+ HECs located close to the medulla. The functional consequences of this HEC heterogeneity are currently unknown, but it reveals the highly plastic nature of the HEV phenotype. The spatial localization of HECs within the LN microenvironment might dictate accessibility to factors regulating HEV gene and protein expression and thereby contribute to the remarkable heterogeneity of HECs at steady state.Crucial insights about the HEV phenotype came from genome-wide transcriptomic analyses of HECs from mouse peripheral LNs , 53, 54 rategies –58. MECAn the LN , 53, 54.St3gal6) , 59, 60, ligands , 53. Tra in mice –65. AnotX motifs decorating HEV sialomucins , which binds to intercellular adhesion molecule 1 and 2 (ICAM1 and ICAM2) expressed on endothelial cells, is the major integrin for T and B cell arrest in peripheral LN HEVs. In mesenteric LNs and other gut-associated lymphoid tissue (GALT), including Peyer’s patches, the integrin α4β7, a major ligand of mucosal addressin cell adhesion molecule 1 (MAdCAM-1), is also critical for lymphocyte recruitment through HEVs , 76. ThePioneering studies performed more than 30 years ago revealed that LN afferent lymphatic vessel ligation results in HEV dedifferentiation . This pr+ dendritic cells (DCs) are critical for maintenance of HEV phenotype and function in homeostatic LNs [+ DCs induces a reversion to an immature HEV phenotype characterized by reduced expression of MECA-79 antigens, downregulation of HEV-specific genes  and upregulation of the mucosal addressin MAdCAM-1, a marker of immature HEVs in neonatal peripheral LNs [Eventually, we discovered that CD11catic LNs . Indeed,eral LNs . The funeral LNs , 97. Interal LNs , 98.Glycam1, Fut7, Chst4, Gcnt1), demonstrating that many HEV-specific genes are LTβR-dependent genes [Chst4 requires lower levels of LTβR-dependent signals for expression than the other HEV genes  [Chst4), showing that LTβR ability to induce the non-canonical NF-kB signaling pathway is essential for the regulation of HEVs [The lymphotoxin-β receptor (LTβR) and downstream non-canonical nuclear factor kB (NF-kB) signaling pathway are essential for HEV maintenance and lymphocyte homing to adult LNs –102. Endnt genes . scRNA-s, Gcnt1) . LTβR st, Gcnt1) . Neither, Gcnt1) , 101. On of HEVs , 101.+ DC are a major source of LTβR ligands, lymphotoxin α (LTα), lymphotoxin β (LTβ) and LIGHT, and that DC-derived lymphotoxin is critical for HEV-mediated lymphocyte recruitment to homeostatic LNs [In fact, we demonstrated that CD11catic LNs . Becauseatic LNs –107, we LNs can be regarded as immune hubs strategically positioned in the organism to provide regional immune surveillance . These h+ endothelial cells are present in capillaries whereas HECs do not express the receptor. However, Apln-reporter mice revealed that many HECs and capillary endothelial cells are positive for the reporter three weeks after an immune challenge, showing that Alpln-expressing CRPs can also contribute to inflammation-induced HEV neogenesis, in addition to HECs themselves [Soon after the initial inflammatory stimulus, the LN blood vasculature undergoes substantial enlargement and remodeling which includes expansion of the primary feed arterioles and HEV network, a process that is thought to increase influx of lymphocytes and therefore the efficiency of screening for rare antigen-specific lymphocytes –114. Mecemselves .Glycam1, Fut7, Gcnt1), maintenance of strong MECA-79 expression, and upregulation of inflammatory proteins  and immature HEV marker MAdCAM-1 [DC mobilization increases during the initial phase of LN swelling . DC accuMAdCAM-1 , 120–123MAdCAM-1 , 124–127MAdCAM-1 , 120. InMAdCAM-1 .The tumor-draining lymph node (tdLN), which is the first regional lymph node draining established tumors, is considered as the major activation site of tumor-specific lymphocytes . The TdLBecause they mediate naive lymphocyte entry to tdLNs, HEVs indirectly participate to the priming of naive lymphocytes specific for cancer antigens and are consequently crucial components of T-cell-dependent antitumor responses. In fact, HEV-mediated homing of naive lymphocytes to tdLNs is even targeted by the primary tumor which reduces expression of CCL21 on HEVs, thereby reducing lymphocyte adhesion to the endothelium . This prbona fide HEVs or profoundly abnormal venules that have lost their HEV function remains unclear. Metastasis is more likely to occur through de-differentiated HEVs that are no longer functional for lymphocyte recruitment.The participation of the tdLN in the dissemination of cancer cells to distant organs is a widely accepted hypothesis . EfferenInflammation is an evolutionary conserved process characterized by the activation of immune and non-immune cells to protect the host from foreign invaders during tissue injury, infection and cancer . Acute i+ HEV-like blood vessels express the post-capillary venule marker Duffy antigen receptor for chemokines (DARC) [+ blood vessels encompass a wide range of venules with distinct degree of maturation regarding the HEV phenotype. Histological examinations of HEV-like blood vessels in human chronically inflamed tissues precludes definitive conclusions on their functionality and their ability to mediate lymphocyte recruitment. In contrast, mouse models of chronic inflammation, which recapitulate several features of human diseases including the development of HEV-like blood vessels, allow for in vivo functional investigations. A comprehensive list of mouse inflammatory conditions in which MECA-79+ HEV-like blood vessels develop is included in Table + HEV-like blood vessels in close association with T and B cells, before the onset of T cell lymphoma [+ HEV-like blood vessels are involved in lymphocyte trafficking to the hyperplastic thymus. Indeed, injection of blocking amounts of MECA-79 or anti-L-selectin mAb MEL-14 abolished the recruitment of adoptively transferred lymphocytes, revealing the functional significance of MECA-79 expression on HEV-like blood vessels [+ HEV-like blood vessels are observed in several tissues [+ HEV-like blood vessels are functional, and second, that the L-selectin-MECA-79 antigens axis is involved in lymphocyte trafficking to various chronically inflamed tissues. In contrast to MECA-79 antigens, MAdCAM-1 is not involved in the recruitment of adoptively transferred lymphocytes to the inflamed lacrimal glands and BALT of NOD mice [The HEV-specific mAb MECA-79 recognizes HEVs from lymphoid tissues, but also HEV-like blood vessels from extra-lymphoid tissues in both mice and humans, making it a very useful tool for the identification of ectopic HEV-like blood vessels. Indeed, systematic surveys involving large numbers of independent samples revealed that HEV-like blood vessels are recognized by MECA-79 in various human chronic inflammatory diseases affecting many different organs , 157. MEs (DARC) , similars (DARC) , suggests (DARC) . HEV-liks (DARC) . In manylymphoma . Short-t vessels . Similar tissues . After s tissues . These rNOD mice , 190.TabHEV-like blood vessels of chronically inflamed tissues can be observed close to diffuse non-organized lymphoid infiltrates, but they are also frequently associated with highly organized lymphoid clusters defined as tertiary lymphoid structures (TLSs) Table  6, 147,,147, 227HEV-like blood vessels are nearly always present when pronounced lymphocyte infiltration is present over the course of chronic inflammation, suggesting an important role of lymphocytes in the development of these specialized blood vessels. Interestingly, a growing body of evidence indicate that several mechanisms occurring during the development of physiological HEVs in lymphoid tissues are involved in the development of ectopic HEV-like blood vessels, with an especially strong participation of cytokines and chemokines.+ HEV-like blood vessels are induced in the skin and lungs during diseases associated with lymphocyte infiltration, such as psoriasis and bronchial asthma, but they are absent during diseases characterized by neutrophil infiltration, like vasculitis in the skin or adult respiratory distress syndrome in the lung [As mentioned in the introduction, initial morphometric studies made by Ziff with electron microscopy revealed that HEV-like blood vessel “plumpness”, which can be regarded as a surrogate of HEV maturity, is associated with the number of perivascular lymphocytes . Anotherthe lung , 157. Th+ HEV-like blood vessels are induced in pancreatic islets or thyroid in response to ectopic expression of TNF/lymphotoxin cytokines, CCL21 or CXCL13 [+ HEV-like blood vessels exhibit mostly abluminal expression of MECA-79 antigens due to the absence of the sulfotransferase GlcNAc6ST-2 (Chst4) responsible for MECA-79 luminal expression [+ HEV-like blood vessels expressing GlcNAc6ST-2 and high levels of luminal MECA-79 antigens [+ HEV-like blood vessels but that LTβR signaling is required to generate vessels with increased HEV maturity and that might have an improved ability to capture L-selectin-expressing lymphocytes  of the gastric mucosa that fosters local tissue inflammation and increases the risk of extranodal marginal zone lymphoma of MALT type (MALT lymphoma) [+ HEV-like blood vessels positively correlated with the progression of inflammation in the gastric mucosa [H. pylori by treatment with antibiotics and a proton pump inhibitor is associated with the disappearance of HEV-like blood vessels and minimal lymphocyte infiltration, suggesting that local post-capillary venules reacquire a normal phenotype after treatment and are no longer able to sustain extensive lymphocyte recruitment. Therapeutic agents also have an impact on HEV-like blood vessels in other diseases. For instance, in RA and psoriatic arthritis, reduced inflammation in the synovium after TNFα blockade with different biological agents  was associated with reduced numbers of MECA-79+ HEV-like blood vessels [+ HEV-like blood vessels are preferentially induced in the active phase of the disease [The presence of MECA-79ymphoma) –237. By c mucosa . Further vessels , 238. In vessels , 157–161 disease , 161. Fi disease , 183, in+ HEV-like blood vessels in the lung, Rosen et al. showed that intravenous administration of MECA-79 antibody prevents airway hyper-responsiveness induced by allergen challenge and inhibits the accumulation of leukocytes in bronchoalveolar lavage fluid [+ HEV-like blood vessels can have therapeutic efficacy [+ HEV-like blood vessels after treatment with LTβR-Ig is associated with improved function of salivary and lacrimal glands [+ HEV-like blood vessels in several murine tissue sites, including inflamed pancreatic islets, heart transplant allografts, and inflamed aorta during atherosclerosis in apoE−/− mice  but also the marker DARC, indicating that they likely derive from post-capillary venules similar to HEV-like blood vessels in chronic inflammation [+ TA-HEVs exhibit a cuboidal appearance reminiscent of the plump morphology of LN HECs  [+ TA-HEVs can spontaneously develop in the tumor microenvironment in the absence of any treatment [+ TA-HEVs generally do not exhibit the HEV-specific cuboidal shape and they are characterized by a flat morphology associated with reduced expression of MECA-79 in comparison with LN HEVs [+ TA-HEVs are associated with the recruitment of naive lymphocytes into tumors [+ TA-HEVs correlated with increased infiltration of naive and central memory T cells [MECA-79ammation , 29. EndECs Fig. , but the (Tregs) –285. Howreatment . Importareatment , 287. In LN HEVs , 286. Ne+ TA-HEVs in > 74% of primary breast tumors (n = 127) [n = 225) [+ TA-HEVs are often found in T-cell rich areas containing DCs but no B cell follicles  , whereasn = 127) . In primn = 225) , whereasn = 225) . Indeed,les Fig. b [29, 24n tumors . Jansen n tumors , but thepothesis , 29, 253+ TA-HEVs are associated with a favorable clinical outcome in most cancer types [Importantly, although TLSs containing MECA-79er types , they maer types . In facter types , 292. ThInduction of TA-HEVs in solid tumors highlights the remarkable capacity of immune cells to modify their target tissue to maximize the immune response, even in highly hostile microenvironments. Despite similarities with HEV-like blood vessels of chronic inflammatory diseases, the mechanisms regulating TA-HEV development also have distinctive features related to the particular nature of solid tumors. Determining the cellular actors and molecular signals triggering the HEV differentiation program in tumor blood vessels is essential to better define their role in antitumor immunity, and to provide important insights for the design of novel therapeutic approaches based on TA-HEV induction.+ TA-HEVs are lost in tumors grown in lymphocyte-deficient Rag2−/− mice [+ T cells is sufficient to induce development of MECA-79+ TA-HEVs in Rag2−/− mice, indicating that CD8+ T cells could be major inducers of TA-HEVs in tumors. In contrast, Tregs, which are known as major immunosuppressive cells in the tumor microenvironment, seem to limit TA-HEV development in tumors as revealed by the induction of MECA-79+ TA-HEVs following depletion of Foxp3-expressing cells in Foxp3DTR mice [+ T cells was shown to abrogate MECA-79+ TA-HEV induction consecutive to Treg depletion [+ T cells in the regulation of TA-HEVs. The increased MECA-79 staining of TA-HEV endothelial cells in close proximity with CD3+ T cells in human primary melanoma , vaccines or adoptive T cell therapy (ACT) –321. Tum to ICIs –325. How+ T cells may be critical for antitumor immunity at baseline and also for response to cancer immunotherapies with ICIs [+ T cells designated stem-like CD8+ T cells because of their capacity to self-renew while being able to generate more differentiated effector CD8+ T cells. Interestingly, analyses of T cells in patients treated with ICIs revealed that continuous recruitment of fresh and less exhausted T cells from the periphery into the tumor may be important for clinical response [+ T cells into tumors could result in increased numbers of patients responding to ICIs. As specialized blood vessels for lymphocyte trafficking, TA-HEVs may be major gateways for entry of stem-like CD8+ T cells into tumors, and their therapeutic modulation could enhance the infiltration of these critical cells, thus increasing the efficacy of ICIs. Infiltration of naïve and central memory CD8+ T cells, CD4+ T cells and B cells through TA-HEVs may also play important roles in the response to ICIs [Checkpoint blockade therapy with anti-PD-1 and anti-CTLA-4 antibodies provides remarkable and durable responses for many patients across different types of cancer , 320. Hoith ICIs , 326–328response , 330. To to ICIs , 305 and+ TA-HEVs in various mouse tumor models [+ TA-HEV and to enhance lymphocyte infiltration in distinct mouse tumor models, and treatment with anti-LTβR enabled response to anti-VEGFR2 and anti-PD-L1 combination therapy in a recalcitrant glioblastoma model [+ TA-HEV and to eradicate established tumors [+ tumor blood vessels are identical to MECA-79+ TA-HEVs induced through LTβR stimulation warrants further studies, but in both instances, neogenesis of TA-HEVs correlated with a robust lymphocyte-mediated antitumor response. Intriguingly, other agents targeting signaling pathways not related to HEV biology induce TA-HEVs. For instance, intratumoral injection of STING agonists (ADU-S100) or treatment with a PARP inhibitor (BMN 673) both induce MECA-79+ TA-HEVs in mouse tumor models [As expected, LTβR agonists are potent inducers of TA-HEVs in tumors. Targeting LIGHT directly to tumor blood vessels via fusion to vascular targeting peptides (VTP) induces MECA-79r models , 297. Sir models . LIGHT-ir models . Notablyr models , 331. LTma model . Differema model . Along wd tumors , 284. Whr models , 299. To+ T cells within transferred cells, demonstrating the crucial role of these particular CD8+ T cells in cell-based immunotherapies in human cancer [+ T cells  elicit better antitumor responses during therapeutic ACT in mouse tumor models [Therapeutic induction of TA-HEVs in tumors might enhance trafficking of endogenous lymphocytes but also of adoptively transferred lymphocytes. If cell-based immunotherapies with chimeric antigen receptor (CAR) T cells are showing great promises in the treatment of hematological malignancies (e.g. CD19-targeted CAR T cells for B-cell acute lymphocytic leukemia), they are usually ineffective for treatment of solid tumors . Pre-conn cancer . In addir models –337. TheBlood vessels that are structurally and phenotypically similar to HEVs from lymphoid organs appear in non-lymphoid tissues during chronic inflammation and cancer. HEV-like blood vessels in chronically inflamed tissues and TA-HEVs in tumors are associated with lymphocyte infiltration similar to lymphoid tissue HEVs, indicating that induction of specialized blood vessels for lymphocyte trafficking is a universal property of tissues exposed to intense lymphocyte activity. In chronic inflammatory diseases, HEV-like blood vessels facilitate influx of pathological lymphocytes, leading to amplification and maintenance of chronic inflammation. In contrast, TA-HEVs are generally beneficial in cancer, showing that the clinical significance of ectopic HEV-like blood vessels is highly dependent on the pathological context.+ blood vessels versus MECA-79− blood vessels will be important to confirm the increased capacity of HEV-like blood vessels and TA-HEVs to mediate lymphocyte recruitment into tissues. Recent transcriptomic analyses of mouse MECA-79+ HECs delineate the HEV phenotype in homeostatic and inflamed LNs [In the past 30 years, there has been considerable progress in our understanding of the mechanisms regulating the phenotype and function of HEVs in LNs, both at steady state and following immune challenge. However, several questions remain regarding the phenotype and functionality of HEV-like blood vessels and TA-HEVs. For instance, the use of intravital microscopy, which is the only experimental approach enabling visualization of lymphocyte recruitment through blood vessels in vivo , will beamed LNs , 53, 54.+ TA-HEVs could not only increase lymphocyte trafficking quantitatively, but also qualitatively by enabling the entry of specific lymphocyte subsets that may be critical for antitumor immunity. These may include naive, central memory and stem-like CD8+ T cells, but also CD4+ T cells and B cells [Great promises stem from the potential of TA-HEVs to increase lymphocyte trafficking into tumors, especially for cancer immunotherapy, which has to face unmet clinical needs. Because of their unique ability to mediate the recruitment of L-selectin-expressing lymphocytes, therapeutic induction of MECA-79 B cells , 338. Ho+ HEV-like blood vessels accurately accompany lymphocyte-dependent activity and disease progression. Similar findings in solid tumors mean that MECA-79+ TA-HEVs go along with antitumor immune response and may represent a biomarker to identify highly immunogenic tumors that are more likely to respond to cancer immunotherapies. Indeed, it is important to identify biomarkers predicting response to ICIs because they are widely used for metastatic patients who are frequently non-responsive and develop severe immune-related adverse events [+ TA-HEVs are present in metastatic lesions, there is an urgent need to investigate their capacity to predict response to ICIs in cancer patients.In chronic inflammation, MECA-79e events , 339. SiIn this article, we presented a comprehensive review on HEVs and HEV-like blood vessels in immunity, inflammation and cancer. HEVs in lymphoid organs have fascinated many researchers over the past century. We are convinced that HEVs and HEV-like blood vessels will continue to attract the interest of scientists and clinicians in the next decades, particularly those working in the areas of vascular biology (angiogenesis), immunology, inflammation, cancer biology (tumor microenvironment) and cancer immunotherapy. Although many aspects of HEV-like blood vessels are still to be discovered, their therapeutic modulation already offers promising avenues, especially for cancer treatment.


This review summarizes various therapeutic immune approaches representing their targets, the efficacy and toxicity in the treatment of acute myeloid leukemia. In particular, immune checkpoint inhibitors, bispecific T-cell engager antibodies and chimeric antigen receptor-T-cell approaches are highlighted. The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data. Acute myeloid leukemia (AML) is characterized by medullary or peripheral presence of immature, undifferentiated blast cells. Per its definition, AML is characterized by ≥20% blast cells in the bone marrow or peripheral blood, and the infiltration of extramedullary tissues is also possible. The accumulation of various somatically acquired genetic changes in hematopoietic progenitor cells that alter normal mechanisms of self-renewal, proliferation, and differentiation leads to its genetic heterogeneity . CurrentAML is typically a disease of the elderly with a median age of 72 years at diagnosis and an incidence of 3–4 per 100,000 adults per year. Overall, outcome is poor with a 5-year survival rate of ~40%, which is rapidly declining with increasing age at diagnosis. Outcome is influenced by multiple factors, both patient-dependent, such as pre-existing comorbidities, and disease-dependent, such as cytogenetics, molecular abnormalities and response to initial therapy. Nevertheless, ~50% of younger (≤60 years) and about 80–90% of older patients relapse after achieving their first complete remission (CR). Despite intensive consolidation therapy, the majority of relapsed patients succumb to their disease . CD33-CAR-TThe approach of CAR-T cells targeting CD33 is also under examination as a potential immune-based therapy. Currently, a phase I/II trial using a CD33-CAR-T cell is being evaluated in children and young adults with r/r AML (NCT03971799). The construct, using linutuzumab-CD28/CD3ζ, has shown robust in vitro and in vivo activity against cell lines and patient-derived xenograft models .CAR-T-38The antigen CD38, expressed on mainly leukocyte subtypes and well known as suitable target for the therapy of multiple myeloma, is also a target for CAR T-cells in r/r AML. Currently, this approach is being evaluated in a phase I/II trial (NCT04351022). Currently, results on six relapsed AML patients after allo-HSCT are available . All patUniCARA modification on the CAR-T cell approach is the universal CAR-T platform (UniCAR), in which a universal adapter molecule with a short half-life is being continuously infused intravenously. This allows for quick cessation of CAR-T side effects such as CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) and is currently being explored in a phase I trial (NCT04230265) ,61. VeryAnother approach is to use T-cell receptor (TCR)-modified T-cells, which do not express a CAR, while also targeting a specific antigen. One such antigen is the preferentially expressed antigen of melanoma (PRAME), which has been shown to be a potential target for AML therapy in concurrence with specific human leukocyte antigen (HLA) restrictions. A phase I/II trial (NCT03503968) using such T-cells is currently underway.CAR natural killer cellsFinally, an alternative approach is to exploit and take advantage of the potential of natural killer cells (NK-cells). An active, recruiting phase I trial (NCT04623944) uses allogeneic, genetically engineered CAR NK-cells (NKX101), which have been modified to express several co-stimulatory and signaling receptors as well as membrane bound interleukin-15 used as an autocrine growth factor . PreclinAnother strategy to combat AML presented here is the use of vaccination-based ideas in order to harness the immune systems’ ability to recognize leukemia-specific antigens through common pathways mediated by dendritic cells and T lymphocytes, among others. The most challenging issue for tumor vaccinations remains antigen selection. A recently published trial (NCT03697707) investigated the use of two different vaccination regimes using allogeneic dendritic cells in 12 advanced-stage elderly AML patients who were in CR, but MRD-positive. The study was based on a 3 + 3 dose escalation design. Patients received four biweekly intradermal DCP-001 injections at different dose levels . The treatment was well tolerated. SAEs occurred in six patients, with a possible relationship to study treatment in one (diabetes insipidus). A median OS of 36 months  was observed in patients with no circulating blasts in comparison to patients with circulating blasts, who died within 6 months. Maintained T cell levels and multi-functional immune responses were associated with long-term survival .Immune-based therapeutic approaches are an important asset in the fight against AML. Currently, there are many substances in development. However, most of the clinical data are mainly available in meeting presentations, since these trials are still in progress. Nevertheless, these preliminary data suggest an acceptable safety profile with promising efficacy. As expected, CRS is one of the most frequently observed AE, whereas neurotoxicity does not seem to be common. Currently, the only approved immune-based therapies are GO for AML and tagraxofusp for BPDCN. Further agents, used as monotherapy or in combination with chemotherapy or venetoclax + HMA, might provide long-term disease control including MRD negativity. However, more studies are needed to evaluate the impact on patient outcomes.


This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases. The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global health crisis emphasizes the importance of understanding the coordination and crosstalk between alveolar epithelial cells (AECs) and alveolar macrophages (AMs) in maintaining lung physiology during viral illness . GranuloThe alveolar epithelium is essential for gas exchange in the lung and serves as a physical barrier between the lumen and the underlying submucosa . The alvPseudomonas aeruginosa has also been shown to cause disruption of tight junctions in patients with cystic fibrosis , AM or AEC monocultures, or fibroblast co-cultures of either AMs or AECs do not . During id cells . Infecteid cells . Epithelid cells ; therefoALI and acute respiratory distress syndrome (ARDS) have been considered events along a clinical spectrum, although the 2012 Berlin definition does not include a separate definition for the less severe ALI . Trigger2 (PGE2) and surfactant protein A, thus reprogramming AMs to an anti-inflammatory phenotype  such as influenza and SARS-CoV-2 to prevent their spread. Here, we focus on the interaction between AECs and AMs in responding to these two viruses. A more comprehensive review of RVIs is denoted in AECs are the primary target for human influenza infection, characterized by loss of alveolar barrier function and edema, with persistent inflammation resulting in greater capillary/alveolar leakage, culminating in severe hypoxemia and ARDS. Following viral clearance and initiation of AEC repair, local progenitor cells replicate, and the integrity of the epithelial layer is restored. Virus elimination and immune-mediated pulmonary injury are balanced by the immune response to minimize respiratory tract damage .COVID-19 is caused by SARS-CoV-2, resulting in respiratory illness including pneumonia, ARDS, respiratory failure, shock, multi-organ failure and death in severe cases .SARS-CoV-2 binds to the angiotensin-converting-enzyme 2 receptor via the viral spike protein that is cleaved by proteases to allow fusion of the viral and cellular membranes, and subsequent internalization and release of the viral RNA . CurrentAfter the virus infects the lining of the nose, bronchi, and bronchioles, it then infects the alveoli in the distal lung, in particular AECII . AEC injAspergillus airway overgrowth with pulmonary infection is characterized by mixed airway inflammation and bronchial invasion known as COVID-19−associated pulmonary aspergillosis (CAPA)  . The incs (CAPA) .Many patients with COVID-19 contract a secondary bacterial infection which frequently leads to worse outcomes . For ins+ DCs  mice induced AECII hyperplasia, increasing lung size and demonstrating a role for GM-CSF in the regulation of AECII proliferation and differentiation  when more of these cells are needed to fight infection, and governs emergency myelopoiesis, expanding and mobilizing progenitor myeloid cells when needed . GM-CSF Stillborn infants lack AMs, suggesting that these cells develop postnatally, similar to observations in mice . This is−/− mice are prone to respiratory infections, and experimental data show that restoring GM-CSF expression reverses this susceptibility. GM-CSF−/− mice have increased susceptibility to bacterial infection due to defective pulmonary clearance and abnormal cytokine production in response to infection, demonstrating the role of GM-CSF in fending off infection mediated partly by AM innate immune functions , whereas intraperitoneal injection did not impact survival  without side effects in patients with severe ARDS  significantly improved oxygenation  demonstrated that subcutaneous sargramostim restored immune function and significantly reduced mechanical ventilation time compared with placebo   .Six patients with pneumonia-associated ARDS received inhaled sargramostim . Sargram2] to the fraction of inspired oxygen  below 350 mmHg) the efficacy and safety of 5 days of inhaled sargramostim (125 μg/m2 twice daily) with standard of care (SOC) vs. SOC alone were assessed at day 6 (p = 0.0459). Treatment adverse events, including signs of cytokine storm, were not different between groups. Serum concentrations of pro-inflammatory cytokines in trial patients at day 6 were not increased over baseline levels. Analysis of immune cells suggests inhaled sargramostim impacted B-cell responses and SARS-CoV2–specific CD8 T-cell responses as evidenced by significant increases in circulating switched memory B-cells and CD38+ HLA-DR + effector memory CD8 T-cells after 5 days of sargramostim inhalation vs SOC alone.In the multi-center, open-label, randomized, controlled SARPAC trial, 81 non-ventilated hospitalized COVID-19 patients with acute hypoxemic respiratory failure  by supporting the tissue-resident AM population and maintaining the best physiologic ratio of resident AMs . Producther RVIs .