We report on a case of multiple evanescent white dot syndrome (MEWDS) following the simultaneous administration of the human papillomavirus and meningococcal (conjugate) vaccines and two recurrences of MEWDS following the administration of the second dose of the human papillomavirus (HPV) vaccine and the COVID-19 vaccine and COVID-19 viral infection. A 17-year-old Hispanic female presented with a one-week history of photopsia and blurred vision in her left eye following the simultaneous administration of the human papillomavirus and meningococcal (conjugate) vaccines. Upon a comprehensive examination, her best-corrected visual acuity was 20/20 in the right eye and 20/100 in the left eye. A left fundus examination revealed multiple white dots in the macula and nasal periphery, consistent with a diagnosis of MEWDS. Ancillary testing, including fundus autofluorescence, fluorescein angiography, indocyanine green angiography, and optical coherence tomography, supported the diagnosis. One month following her initial diagnosis, the patient's symptoms had resolved without any therapy, and a fundus examination revealed multiple relatively ill-defined brown-colored subretinal lesions in the nasal midperiphery, corresponding to the location of the previous MEWDS lesions. Subsequently, she received the second dose of the HPV vaccine and then developed a mild COVID-19 infection. Four months after the initial presentation, she received the first dose of the BNT162b2 COVID-19 vaccine, followed by the second dose a month later. Eight months following her initial presentation, she presented with photopsia in the right eye. Her visual acuity remained 20/20 in the right eye and improved to 20/20 in the left eye, and white dots were identified nasal to the disk and surrounding the peripapillary region; the contralateral MEWDS diagnosis was confirmed by the previously mentioned ancillary tests. At her one-month follow-up, she presented new onset photopsia of the right eye. Her visual acuity remained 20/20 in both eyes, and a fundus examination revealed white lesions suggestive of active MEWDS temporal to the macula and brown-colored spots nasal to the disk, suggestive of recovering MEWDS, nasally. The aforementioned testing confirmed the coexistence of new and resolving lesions; nonetheless, the patient's symptoms resolved without any therapy, and she received the third dose of the BNT162b2 COVID-19 vaccine 11 months after her initial presentation. Our case suggests that vaccines may serve as immunological triggers of MEWDS. Recurrent MEWDS may occur when an individual is exposed to a powerful immune challenge, such as receiving a wide array of vaccinations in a short period of time. We believe this case constitutes a previously undescribed finding of multiple relatively ill-defined brown-colored subretinal lesions present in late MEWDS. Multiple evanescent white dot syndrome (MEWDS) is characterized by distinct small, round, white spots scattered over the posterior pole and midperiphery -3. As thMultiple evanescent white dot syndrome was first described by Jampol et al. in 1984 with two cases that were unilateral and monophasic ,6. At thA 17-year-old Hispanic female presented with a one-week history of photopsia and blurred vision in her left eye (OS). Her past medical history was remarkable for her having received the human papillomavirus (HPV) and meningococcal (conjugate) vaccines simultaneously 16 days before the onset of her symptoms. Her review of systems, as well as past social and family history, were otherwise unremarkable.Upon a comprehensive ophthalmic evaluation, her best-corrected visual acuity (BCVA) was 20/20 in the right eye (OD) and 20/100 OS with a manifest refraction of plano -0.75 x 105 OD and -1.50 -0.50 x 80 OS. The intraocular pressure was 19 mmHg in both eyes (OU). The pupils were round and reactive to light, and there was no afferent pupillary defect (APD). Color vision OU, as assessed by the Ishihara color plate test, revealed no defect. Extraocular movements were within normal limits. A slit-lamp examination was within normal limits, bilaterally, with no evidence of keratic precipitates, signs of inflammation in anterior chambers, or vitreous cells in either eye. The patient's right fundus was unremarkable; however, the left fundus revealed multiple white dots in the macula and nasal periphery Figure .The fundus autofluorescence (FAF) was within normal limits in the OD; however, in the OS, it was marked by hyperfluorescent spots in the macula and nasal periphery in a similar pattern as what was observed in the fundus examination Figure . The intProvided with the clinical and ancillary testing results, an assessment of MEWDS was made, and a workup was ordered to rule out secondary etiologies, such as syphilis and sarcoidosis. All the tests, including fluorescent treponemal antibody absorption, rapid plasma reagin, and a chest x-ray, were negative. The patient was placed under close observation without any topical or systemic therapy.One month following her initial diagnosis, the patient's symptoms had resolved. The patient's BCVA remained 20/20 OD and improved to 20/20 OS. A fundus examination revealed multiple relatively ill-defined brown-colored subretinal lesions in the nasal midperiphery corresponding to the location where the MEWDS lesions were present. The FAF and FA hyperfluorescent spots in the macula and nasal periphery had resolved. The corresponding OCT images of the OS showed that the numerous focal hyporeflective lesions previously found at the IS/OS junction had been resolved.The patient received the second dose of the HPV vaccine series two days after her follow-up. She later developed COVID-19 . Her symptoms were mild, including anosmia and nasal congestion; nevertheless, she evidenced no ocular symptoms during the course of the infection. Three months following her initial visit, a color fundus photograph, and FAF revealed that the lesions had resolved; she presented no further complaints at this time. Four months after the initial presentation, the patient received her first dose of the BNT162b2 COVID-19 vaccine, which was followed by the second dose a month later.Eight months following her initial presentation, the patient presented with flashes in OD. Upon ophthalmic examination, her BCVA was 20/20 OU, no APD was present, and the slit-lamp examination was within normal limits. A right fundus examination revealed multiple white spots nasal to the disk Figure . The FAFOne month following the initial presentation of the symptoms in the OD, the patient presented with a recurrence of flashes. The patient's BCVA remained 20/20 OU. A fundus examination revealed white lesions suggestive of active MEWDS temporal to the macula and brown-colored spots nasal to the disk, suggestive of recovering MEWDS nasally.The following month, the patient's BCVA remained 20/20 OU. The fundus of the OD was remarkable for brown-colored spots of recovering MEWDS in the temporal region Figure . An FA wIn the literature available about MEWDS, it is suggested that this disease may be triggered by infections or post-vaccination immune reactions -3,6,7. VMost patients with MEWDS present a single self-limited episode of disease activity, with resolution within a month; nevertheless, our patient presented a total of three episodes, two of which were in the same eye -3. The cAuthors have proposed two hypotheses as to why this disease may recur . The firThe difficulty in investigating MEWDS lies in the fact that it is characterized by mild and evanescent signs and symptoms -3,6,7. FOur case suggests that vaccines may serve as immunological triggers of MEWDS, which further supports the post-infectious or immune-mimicry etiology of this disease. Recurrent MEWDS may occur when an individual is exposed to a powerful immune challenge, such as receiving a wide array of vaccinations in a short period of time. The potential role of COVID-19 vaccines as triggers of recurrent MEWDS should be further studied. To better elucidate such underlying factors as may exist, a thorough vaccination history is of utmost importance when evaluating patients. We believe this case constitutes a previously undescribed finding of ill-defined brown-colored subretinal lesions present in MEWDS, which may prove useful for patients with late presentation of MEWDS.


Clinical trials remain the gold standard for evaluating efficacy, but there is increasing interest in using real-world evidence (RWE) to inform health care decision making. The aims of this observational study were to describe patterns of medical cannabis use, associated changes in symptom severity over time, and to evaluate change in cannabis dose over time for pain-related symptoms.™, an application that is HIPAA, PIPEDA, and PHIPA compliant. A total of 629 participants recorded data between May 2017 and August 2019. A total of 65 symptoms were grouped as Pain, Mental Health, Physical Symptoms, Seizures, Headaches/Migraines, and Other. Descriptive statistics and mixed-effects modeling were applied.Data were collected by StrainprintTHC-dominant products were more frequently consumed for symptoms of pain and sleep, while CBD-dominant products were more frequently consumed for anxiety and depression. Male and female participants demonstrated significant differences in the type of cannabis they consumed. Females more frequently consumed CBD-dominant products, and males more frequently consumed balanced (THC:CBD) products. Oil use was more prominent among females, while vaping was more common among males. Product use also varied by age tertiles . CBD-dominant products were more common among younger participants, <31 years, THC-dominant products were more common among the 31–39 years category and balanced (THC:CBD) products were common among older participants >41 years. Dosages of CBD-dominant and balanced (THC:CBD) products increased over time irrespective of symptom response. THC-dominant products demonstrated a significant relationship between dose and symptom reduction over time.Recognizing that RWE has important methodological limitations, we observed cannabis product preferences based on demographic characteristics, such as gender and age and the primary symptom treated such as pain and anxiety. Our study offers real-world insights into how participants use and respond to cannabis products and suggests important avenues and methodologies for future research. THC has been used as an analgesic agent, and is the major psychoactive ingredient in cannabis, whereas the nonintoxicating CBD has anxiolytic and anticonvulsant effects.5 THC administration has been shown to improve neuropathic pain,6 whereas CBD has been associated with improvements in anxiety and other neuropsychiatric disorders.8The pharmacologically active compounds in cannabis (cannabinoids) are known to moderate a range of physiological processes.9–15 However, randomized controlled trials (RCTs) are often too small and too short to draw definitive conclusions.16 In addition, studies use different cannabinoid preparations and modes of administration, making meta-analyses complicated.18 In the last few years, more than 300,000 Canadians have received an authorization for medical cannabis as part of their treatment plan,19 despite the absence of RCTs that would inform clinical use. Understanding real-world utilization of cannabis  may generate evidence on safety and effectiveness and inform future clinical trial designs.Several studies have observed that medical cannabis may have therapeutic benefit in patients with headache (including migraine), gastrointestinal pain, arthritis, and joint stiffness.20 There are several challenges with real-world data, including limitations of the data sources used and difficulties identifying and applying appropriate analytical tools to extract and interpret relevant information.21 Mobile applications (apps) are a form of innovative data collection, particularly for patient-reported outcomes.22 Development of these apps has led to increasing accessibility to large real-world datasets.The utilization of real-world evidence (RWE) is becoming accepted as an independent research approach complementary to RCTs. RWE is defined as clinical evidence about the usage and potential benefits or risk of a medical product derived from real-world data .(1)the characteristics of participants as a function of the symptom being treated and product selection;(2)the association of medical cannabis on self-reported symptom severity over time; and(3)to examine self-titration patterns over time and determine how these patterns differ as a function of product profile  among participants treating pain symptoms.Given the patient-driven basis of medical cannabis authorization, and the wide range of potential therapeutic uses, RWE offers an important option to gathering insights into medical cannabis use patterns. To inform research programs and patient perspectives, we conducted an observational study using archival data from a mobile app to describe:™, a mobile app that is HIPAA, PIPEDA, and PHIPA compliant. Strainprint™ helps individuals track their medical cannabis use by monitoring therapeutic regimens , and self-reported symptom scores. We examined Strainprint™ data collected prospectively from Canadian adults who had received a medical authorization to self-administer cannabis between May 2017 and August 2019. We included participants using data from one licensed producer (Spectrum Therapeutics) to standardize the exposure to products with known cannabinoid ratios.Data were collected using Strainprint™ app recorded cannabis variables by product name, cannabis type , mode of administration , and dosage  ; soft gels are reported in milligrams of THC and CBD (mg) per capsule; and oils are reported as milligrams of THC and CBD per milliliter of oil (mg/mL) . The Stror oils) . Due to Participants recorded data at several “sessions” defined as data entry on the app. During the initial session, participants recorded their demographics, including age, gender, province of residence, and medical conditions. Participants self-reported their symptoms and described their medical cannabis treatment regimen. Symptoms were identified from a list of 84 symptoms on the app. For the purposes of this study, symptoms were divided into 6 groups: Pain, Mental Health, Physical Symptoms, Seizures, Headaches/Migraines, and Other .™ users at the time of the study). These intervals are consistent with the known pharmacodynamic differences between these routes of administration.23 Following the prompt, participants rated symptom severity using the same 11-point scale . In the post-cannabis phase, participants entered data after cannabis use. Participants who inhaled cannabis were prompted 60 min post-administration, whereas those who ingested cannabis orally were prompted 90 min after administration . Summary statistics included the mean and standard deviation (SD) for continuous variables and counts and percentages for categorical variables.™, and (2) participants self-administered a cannabis product that was THC-dominant , CBD-dominant , or balanced (Blue).The aim of this analysis was to describe associated changes in symptom severity over time. Data were included for Analysis 2 if: (1) participants completed at least two sessions through Strainprintt-test. Due to considerable variability in the number of recorded sessions by participants, we made comparisons between the mean baseline measurement (first session pre-cannabis symptom severity score), and three post-cannabis symptom severity scores grouped as follows:Change in symptom severity from pre- to post-cannabis use was assessed with the paired-samples (1)the mean post-cannabis symptom severity score derived from the first session,(2)the mean post-cannabis symptom severity score derived from the last session, and(3)the mean post-cannabis symptom severity score showing greatest reduction.t-test and ANOVA analyses. Descriptive and inferential statistics were calculated using IBM SPSS® Statistics 24.25To determine whether there were any differences between symptom improvement and product used, three one-way between-group analyses of variance (ANOVAs) were run. These analyses used each of the aforementioned outcome variables , with product used  entered as the grouping variable. To control for alpha rate inflation due to multiple comparisons, we Bonferroni corrected the alpha rate to 0.017 for three comparisons for the The aim of this analysis was to examine self-titration patterns over time, and to determine how these patterns differ as a function of product profile among participants treating pain symptoms. Data were included for Analysis 3 if (1) participants indicated a symptom of pain, and (2) participants who exclusively ingested cannabis as an oil or soft gel that was THC-dominant (Red), CBD-dominant (Yellow), or balanced (Blue) . Data caAn effectiveness score was defined as the within-participant change in pain at each session. Effectiveness score was calculated as post-cannabis use symptom severity score − pre-cannabis use symptom severity score for each participant. As such, negative effectiveness scores reflected a reduction in symptom severity.26 Models included random intercepts and slopes to account for the correlated nature of the data within participant over time. Fixed effects of product, time (session), and effectiveness score were included, and all possible interactions among these variables. Nonsignificant higher-order interactions were removed from models to achieve maximal model fit. Relative model fit was evaluated using likelihood ratio tests to confirm model selection. Sequential instance of app use (sessions) was used as the time metric, which was treated as a continuous repeated measure. The CBD-dominant product was the reference category for the product predictor, and effectiveness score was mean centered. Owing to substantial positive skew, dose was log transformed. All parameter estimates are presented in the log-transformed scale in the text, but were back transformed to reflect predictor effects on the original dose scale in figures, to facilitate interpretation. Restricted maximum likelihood estimation was used to estimate and test individual parameters and full maximum likelihood estimation was implemented for evaluation of relative model fit. The “nlme” package in R version 3.6.1 was used for mixed-effects modeling.27To evaluate dose change over time, linear mixed-effects modeling was undertaken. These models have the advantage of using all available data to estimate parameters and allow for inclusion of cases with missing data under the missing-at-random assumption.™ (time from baseline to last session) ranged from 5 to 12 months.A total of 629 unique Spectrum product users who collectively entered 27,036 sessions over the 27-month period were included in Analysis 1. The participants' mean age was 38.3 years ±10.7 (range 18–74 years), and (58.7%) identified as female. The majority of users resided in Canada (97.1%), with the largest proportion from Ontario and Alberta . The median number of medical conditions identified per individual was 4, with anxiety disorder, back pain, and chronic pain as the most frequent . The num™ to record their therapeutic use of cannabis. In total, 65 symptoms were identified across the 629 participants. The most commonly treated symptoms were muscle pain (10.7%), anxiety (10.1%), joint pain (9.2%), insomnia (7.4%), and joint stiffness (6.8%). Insights on product preferences across symptoms are shown in The first analysis describes the characteristics of participants who used StrainprintMale and female participants demonstrated significant differences in the type of cannabis they consumed .ps<0.001). For Physical and Pain symptoms, all scores improved by a minimum of 2.6 points relative to baseline score. For Mental Health and Other symptoms, all scores improved by a minimum of 2.8 points relative to baseline score.ps>0.017).Results of the one-way ANOVA revealed no significant differences between selected product in terms of symptom improvement  ingested cannabis (oil or soft gel) over 3011 sessions and were included in the analysis. Participants' mean age was 40.8 years (range 18–74 years), evenly balanced by gender . The median number of days to complete 10 sessions was 16 (interquartile range: 8–40).ps<0.05). The model-predicted trajectories of dose change over time for each product, across all 10 sessions at levels of low (−0.41), average (−2.54), and high effectiveness score (−4.67) (ps>0.066).Evaluation of relative model fit indicated that the highest order model, including the three-way (time×product×effectiveness score) interaction yielded better fit than all other lower order models  . At sessb=0.03, t=2.11, p=0.035), and balanced product users followed the same trajectory of dose increase over time . In contrast, THC-dominant product users showed less of an increase in dose over time relative to the CBD-dominant product users, and in fact showed a decrease in trajectory . However, this effect was qualified by a higher-order three-way THC dominant×effectiveness×time interaction . High effectiveness (1 SD above average effectiveness) did not correspond to a significant increase in dose either for THC-dominant users , or CBD-dominant users . Average levels of effectiveness corresponded with a nonsignificant decrease in dose for THC-dominant users  and an increase in dose for CBD-dominant users . Low effectiveness (1 SD below average effectiveness) corresponded with a significant decrease in dose for THC-dominant users  and increase in dose for CBD-dominant users   .At average level of effectiveness score for CBD-dominant and balanced product, the models predicted trajectories suggesting an increase in dose across the 10 sessions of 0.21 and 0.22 mL, respectively. For the THC-dominant product, at low and average level of effectiveness score, there was a decrease in dose across the 10 sessions of 0.28, and 0.12 mL, respectively, and at high levels of effectiveness score, there was an increase in dose across the 10 sessions of 0.10 mL.We completed an observational analysis of prospectively collected archival data on patterns of medical cannabis use and self-reported symptom reduction in participants with a variety of conditions.We observed that THC-dominant product use was frequently selected for the treatment of sleep and pain , while CBD-dominant product use was frequently selected for the management of mental health conditions, such as anxiety and depression. The current study is unable to determine how products were selected. It will therefore be important for future work to examine if physician, patient preferences or a combination of the two drives product selection. Product and administration differences were also observed by age and gender. These observations suggest that there are subsamples of the population, such as age and gender that differ in product selected. For example, CBD-dominant products were more common among younger participants (<31 years of age), THC-dominant products were more common among the 31–39 years category, and balanced (THC:CBD) products were common among older participants (>41 years).29 One possible explanation for these observations therefore would be the presence of a significant and prolonged placebo effect. Patients with chronic diseases may have a high degree of expectation and this may effect a significant bias on the results. While there is emerging scientific rationale to suggest responses of anxiety disorders to CBD30–32 and pain to THC,11 robust large-scale trials are lacking, and we are only just beginning to explore complex patterns of poly-cannabinoid use for complex chronic disorders. Clearly there is a need for additional focused trials to examine cause and effect relationships, but in addition, efforts are needed to identify appropriate control groups for large well-phenotyped observational studies to better explore the relationship between medical cannabis use and therapeutic response in real-world settings.While our analyses show a significant reduction in symptom severity over time among participants, we first acknowledge that there are considerable limitations in interpreting these findings. Positive effects were observed across all cannabis types and symptoms. Such a robust response to a complex array of cannabinoids on a range of symptoms is difficult to interpret based on classical single-agent pharmacology. Indeed, recent reviews conclude that there, is at best, weak evidence for cannabinoids being effective in managing specific symptoms.™. A total of 66 (9.5%) participants only completed one session on the app. The unit of puff for inhalations lacks the necessary detail  for granular analyses of these data, limiting our self-titration results to oils and soft gels. In addition, there was considerable attrition in the sample , which may have biased parameter estimates. Overall, while we have a large and unique dataset to explore, loss to follow-up and the limitations of self-reported use data restrict the conclusions we can draw from the analyses completed. Tolerance to therapeutic effect and tolerance to adverse effects may have impacted treatment outcomes. As such, we cannot advance conclusions as to the causes of the effects observed here. Delineating the underpinning mechanism of the dosing changes found in this study is an area of future research.There are other limitations to consider. Stemming from the use of real-world data, the design of this analysis lacks a control group. Evidently, there is a sampling bias, which overrepresents participants who find medical cannabis effective, since participants who do not find medical cannabis effective would be unlikely to continue to use StrainprintNotwithstanding the limitations outlined above, what lessons can we take away? The data were obtained from authorized medical cannabis users, which required a physician approval. Furthermore, a wide variety of products were used by a large sample to treat different symptoms in a real-world setting. These results may therefore have ecological validity and represent how medical cannabis is being used in everyday life. Symptomatic improvements were described as early as the first session, which suggest that subjects self-report a quick onset of symptom relief with the initial cannabis dosage. Moreover, reductions in symptom severity up to 12 months from their first session were noted in participants with longer follow-up data, suggesting that, for these patients, therapeutic benefit was sustained over time.6 found that THC-dominant products, as compared with CBD-dominant, were more frequently selected in treating pain. If THC-dominant products are effective analgesics, it would explain why we observed a tendency for participants to select THC-dominant products in the treatment of pain. Gulbransen et al.8 observed that CBD-dominant cannabis was associated with improvements in pain, anxiety, and depression, in patients with noncancer pain and mental health symptoms, although their study design also precludes stronger inferences on correlation. Black et al.33, points out the scarce evidence for cannabinoids in improving depressive disorders and symptoms, requiring further high-quality studies. While CBD has been found to be relatively safe,34 it is not risk free, and potential drug/drug interactions must be considered when recommending it to patients.35Our findings on patient preference are consistent with others; Li et al.36 We found overall increases in dosage and effectiveness score over time for participants treating pain symptoms. Changes in cannabis dosage over time varied by effectiveness score, suggesting that participants titrated dosages based on perceived effectiveness. This effect differed by the cannabinoid content of the cannabis consumed. This may be interpreted as reward-seeking behavior: by increasing the amount of cannabis consumed, participants aim to enhance previous effectiveness. The observation may also be an effect of tolerance, whereby increasing dosages are required to yield a satisfactory effectiveness.Our data on dosage of cannabis and changes in dosage over time are also consistent with other studies.When the effectiveness in reducing symptoms was low, dosages of THC-dominant product decreased, whereas dosages of CBD-dominant and balanced increased over time. This effect may be explained as participants' aversion to the effects of THC-dominant products found to be ineffective at symptom reduction, discouraging an increase in dosage. However, as CBD-dominant and balanced products would not be expected to give rise to the same psychoactive experiences as high dosages of THC products, participants may have been more comfortable to increase the dosage of the former to improve effectiveness.Analyses of real-world data on medical cannabis use may reveal patterns of use and effectiveness across individuals in natural conditions that could inform treatment decisions and stimulate future research. Improvements in app design and compliance would conceivably increase the quality of RWE available in the future. Safety monitoring plays a crucial role in understanding various aspects of usage patterns . Systematic collection of adverse events on apps would further strengthen future RWE analyses.This study provides real-world insights into patterns of use for medical cannabis, self-titration trends, and responses to various cannabis products within the first month of initiating treatment for different symptoms. While recognizing that RWE studies have limitations, the study builds upon evidence of safety, efficacy, pharmacokinetics, and therapeutic indications for medical cannabis. In this study, we specifically observed product preferences based on the symptoms treated  and demographic characteristics . An early onset of symptom improvement was noted with cannabis use, and it was sustained over time. Upon first use of medical cannabis oil for pain symptoms, participants reported pain reduction irrespective of the dose and product used. Only THC-dominant products demonstrated a statistically significant relationship between dose and effectiveness score over time. In the ongoing quest for producing the best evidence-based medicine, we suggest that both RCT and RWE data hold unique value and complement each other.


Diagnostics, vaccines, and drugs are indispensable tools and control measures employed to overcome infectious diseases such as coronavirus disease 2019 (COVID-19). Diagnostic tools based on RT-PCR were developed early in the COVID-19 pandemic and were urgently required for quarantine . Vaccines such as mRNA vaccines and virus-vectored vaccines were also successfully developed using new platform technologies within one year after identifying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the causative agent of COVID-19. Drug development has been conducted in various ways including drug repurposing, convalescent plasma therapy, and monoclonal antibody development. Among the above efforts, this review examines COVID-19 drug development along with the related and upcoming challenges. Coronavirus disease 2019 (COVID-19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . AdvanceSARS-CoV-2 is very similar to SARS-CoV, which was identified in China in 2002~2003, with both viruses showing approximately 80% resemblance in their viral genome sequences . Like otCoronaviridae family, seven coronaviruses are known to infect humans  and SARS-CoV-2) and they were identified after the year 2000 except for 229E and OC43, which were reported in the 1960s. Among these human coronaviruses, only three coronaviruses  are known to cause severe respiratory diseases and were reported in 2002, 2012, and 2019, respectively. The recent, frequent emergence of these highly pathogenic coronaviruses emphasizes the need for concerted global efforts to better prepare for these recurring challenges.While there are numerous viruses belonging to the The lung is a main target of SARS-CoV-2 infection and the incubation period between virus exposure and symptom onset is approximately 4 ~ 5 days, although it varies between 2 and 14 days. The viral load increases as the virus replication continues until the immune response of the infected person starts. In most cases, the viral load decreases as a result of the immune response and the infected person recovers spontaneously without therapeutic intervention. However, people with high risk factors may suffer from severe COVID-19 and need treatment. Treatment of patients with COVID-19 cannot be achieved with any single drug because COVID-19 is known to be a bi-phasic (or multi-phasic) disease which needs differential therapeutic approaches . The firMany laboratories and companies simultaneously began developing drugs for COVID-19 very early in the pandemic and most of this drug development can be summarized in the following four categories: 1) drug repurposing (or repositioning), 2) monoclonal antibody development, 3) convalescent plasma therapy, and 4) new drug development.In general, drug development requires a very long period of research and investment . It usually starts from basic research and proceeds to preclinical trials , followed by phase 1, 2 and 3 clinical trials (testing in humans) prior to FDA approval. Despite these efforts, the chance of successful drug development is very low (less than 10%) . TherefoDrug repurposing is a rapid and effective approach to reposition drugs that have already been approved for use in other indications, for treatment of COVID-19 . A main 10While remdesivir, lopinavir/ritonavir, and chloroquine (or hydroxychloroquine) were developed as drugs with antiviral mechanisms against SARS-CoV-2, others, such as dexamethasone, tocilizumab, and baricitinib, were developed as anti-inflammatory drugs. After several large-scale clinical trials, the clinical efficacy of these drugs was demonstrated, and they were approved for patients with severe COVID-19 -18.Screening for drug repurposing was also conducted by many laboratories and some results were published as early as March, 2020, which was only 2 months after identification of SARS-CoV-2 as the causative agent of COVID-19 , 20-22.20i.e., injection).Monoclonal antibodies can be developed more rapidly than small molecule inhibitors and several of them have already been successfully developed and authorized for use in patients with mild COVID-19  23]. As. As23]. 24Using convalescent plasma for treatment of infectious diseases is not a new concept and it is often considered as an option when there are no other therapeutics available. Convalescent plasma is a source of neutralizing antibodies and the mechanism of action is very similar to that of monoclonal antibodies. However, unlike monoclonal antibodies, using convalescent plasma has limitations because it has to be donated from patients who recovered from COVID-19 and standardization of convalescent plasma is not easy since the neutralizing antibody titers vary depending on the different sources. While there have been some promising case reports, the result of a recent large-scale clinical trial failed to show any clinical efficacy of convalescent plasma in high-risk patients with COVID-19 .Although new drug development is not practical in a pandemic situation, some drugs are being actively developed based on their previous investigation results. Drugs being developed by Merck and Pfizer are representative examples that fall into this category . Merck i30pro or Mpro). This protease activity is essential in the coronavirus life cycle since it cleaves the viral polyprotein into individual, mature proteins. Without this protease activity, the coronavirus life cycle cannot proceed and ultimately virus replication stops. PF-07321332 is also not a new drug as it was being developed during the SARS outbreak in 2002~2003, although this outbreak lasted less than 8 months. Since there are no longer reports of patients with SARS, the drug was never tested in clinical trials and therefore the SARS drug discovery program was halted. When the COVID-19 pandemic started, this program was revived because SARS-CoV-2 and SARS-CoV are similar to each other.On the other hand, the drug being developed by Pfizer (PF-07321332) belongs to a different class of antiviral drugs . As an oi.e., RNA-dependent RNA polymerase and viral protease) and there have been many successful examples of HIV and HCV (hepatitis C virus) drug development targeting these viral proteins [Being orally available is a common key feature of these two drugs and this is very important in a pandemic situation as exemplified by oseltamivir, which played a significant role in the past flu pandemic. In addition, these two drugs inhibit the two well-known antiviral targets , but others have had mixed results, showing both success and disappointment .As discussed above, many different approaches have been taken to develop therapeutics against COVID-19. Some have been successful so far  it can be taken orally, 2) it prevents progression to severe COVID-19, 3) it is affordable and easily accessible even by people in low-income countries, and 4) it works against SARS-CoV-2 variants and potentially even against related coronaviruses such as MERS-CoV and SARS-CoV.Vaccines will play a major role in terminating the current pandemic. But the importance of drugs should not be ignored, as demonstrated by the antiviral drugs developed against HIV or HCV. Both are the causative agents of chronic infectious diseases  and also causes of substantial global socioeconomic burden. Even after decades of intensive investigations, no effective vaccine has been successfully developed for these infectious diseases. However, antiviral drug development has been very successful to the extent that these diseases have become manageable. Surprisingly, we are now even expecting to see the eradication of HCV from the planet by antiviral drugs.We have witnessed the frequent emergence of highly pathogenic coronaviruses since the year 2002, and yet more coronavirus outbreaks could potentially occur in the future due to spillover events . Thus, p


The cardiovascular complications of Coronavirus Disease 2019 (COVID-19) may be attributed to the hyperinflammatory state leading to increased mortality in patients with COVID-19. HMG-CoA Reductase Inhibitors (statins) are known to have pleiotropic and anti-inflammatory effects and may have antiviral activity along with their cholesterol-lowering activity. Thus, statin therapy is potentially a potent adjuvant therapy in COVID-19 infection. This study investigated the impact of statin use on the clinical outcome of critically ill patients with COVID-19.A multicenter, retrospective cohort study of all adult critically ill patients with confirmed COVID-19 who were admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were classified into two groups based on the statin use during ICU stay and were matched with a propensity score based on patient's age and admission APACHE II and SOFA scores. The primary endpoint was in-hospital mortality, while 30 day mortality, ventilator-free days (VFDs) at 30 days, and ICU complications were secondary endpoints.P = 0.004] and 30-day mortality  were significantly lower in patients who received statin therapy on multivariable cox proportional hazards regression analysis. Moreover, patients who received statin therapy had lower odds of hospital-acquired pneumonia , lower levels of inflammatory markers on follow-up, and no increased risk of liver injury.A total of 1,049 patients were eligible; 502 patients were included after propensity score matching (1:1 ratio). The in-hospital mortality [hazard ratio 0.69 , The use of statin therapy during ICU stay in critically ill patients with COVID-19 may have a beneficial role and survival benefit with a good safety profile. Since the spread of the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), leading to Coronavirus Infectious Disease 2019 (COVID-19) in 2019, over six million people have died worldwide . EvidencIn non-COVID-19 patients, statin therapy has been associated with lower Cardiovascular risk and mortality . StatinsThe clinical evidence about the benefit of statins is inconsistent , 25. MulThis was a multicenter, retrospective cohort study including adult critically ill patients with confirmed COVID-19 who were admitted to the intensive care units (ICUs) from March 01, 2020, until March 31, 2021. Eligible patients were then classified into two groups based on statin therapy use during ICU stay (non-statin vs. statin users). Statins were prescribed in the ICU as part of the medication reconciliation process if they had been prescribed in the pre-ICU period or were initiated in the ICU for various indications at the discretion of the ICU treating team and stopped based on physicians' clinical judgment. The King Abdullah International Medical Research Center (KAIMRC) authorized the study in January 2021 (Reference number: NRC21R/015/R). Due to the study's retrospective observational nature, informed consent from study participants was waived.Adult (age 18 years and older) critically ill patients who were admitted to ICUs at four centers with confirmed COVID-19, regardless of their comorbid conditions, were included in the study. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) nasopharyngeal and/or throat swabs were used to diagnose COVID-19. Patients were excluded if they had an ICU length of stay (LOS) of 1 day or less, died within 24 h of admission, or were designated a “Do-Not-Resuscitate” status within 24 h of their ICU admission . All patThis study was conducted at four centers in Saudi Arabia: King Abdulaziz Medical City (Riyadh), King Abdullah bin Abdulaziz University Hospital (KAAUH) (Riyadh), King Abdulaziz University Hospital (Jeddah), and King Salman Specialist Hospital (Hail). We included both tertiary and secondary centers. The selection of these centers was based on the geographic distribution, availability of electronic records and the center's willingness to participate in this national project. King Abdulaziz Medical City (Riyadh), a tertiary care center that includes more than 1500 beds and more than nine ICU units, was the primary site for this multicenter retrospective study.® software hosted by the King Abdullah International Medical Research Center (KAIMRC). We collected demographic data, comorbidities, vital signs, laboratory tests, severity scores , Nutrition Risk in Critically ill (NUTRIC), and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores), Glasgow Coma Score (GCS), receipt of mechanical ventilation (MV) and MV parameters , use of prone positioning, and acute kidney injury within 24 h of ICU admission. Moreover, liver function tests (LFTs), coagulation profile , renal profile, and inflammatory markers  within 24 h of ICU admission were collected. For the eligible patients, HMG-CoA Reductase Inhibitors (statin therapy) (type and dose), tocilizumab and corticosteroids use were recorded. We also included information on the use of inotropes and vasopressors during the first 24 h of ICU admission, as well as information on the use of nephrotoxic drugs and DVT prophylaxis during ICU admission. If administering oral tablet was not feasible, then statin tablet was crushed and given to the patient through the feeding tube, according to hospital policy.Each patient's data were collected and handled using RREDCaps , secondary fungal infection, acute kidney injury, and liver injury] were considered secondary endpoints  at 30 days, and ICU-acquired complicationndpoints .t-test for normally distributed continuous data and the Mann-Whitney U-test for non-normally distributed continuous variables. The normality assumptions were assessed for all numerical variables using graphical representation  and statistical tests . Hosmer-Lemeshow goodness-of-fit test was used for model fit assessment.We reported continuous data as mean and standard deviation (SD), or median with the lower quartile (Q1) and upper quartile (Q3), as appropriate, and categorical variables as number and percentage. The baseline variables of the two study groups were compared (statin and non-statin users). We employed the Chi-square or Fisher's exact test categorical data. On the other hand, we used the student Propensity score matching  was used to match patients who received statin medication (active group) to patients who did not (control group) based on patient's age and baseline illness severity scores (APACHE II and SOFA scores) within 24 h of ICU admission. A greedy nearest neighbor matching approach was utilized, such that one patient who received statin medication (active) was paired with one patient who did not (control), resulting in the least within-pair difference among all available pairs of treated patients. The difference in the logits of the propensity scores for pairs of patients from the two groups was matched only if it was ≤0.5 times the pooled estimate of the standard deviation. To validate the propensity score model, baseline characteristics for the matched cohort were compared between the two groups.P-value of < 0.05 was considered statistically significant.By considering the PS score as one of the covariates in the model, regression analysis was done based on the patient's age and baseline severity scores (APACHE II and SOFA) within 24 h of ICU admission. For the 30-day and in-hospital mortality, multivariable cox proportional hazards regression analyses were performed, and the proportionality assumption was assessed before fitting the cox model. Visual assessment was performed to assess the assumption by plotting log(-log) plot and by testing the correlation of scaled Schoenfeld residuals with rank-ordered time. Multivariable and negative binomial regression analysis were used for all other outcomes considered in this study. The hazard ratio (HR), odds ratios (OR), or estimates with the 95% confidence intervals (CI) were reported as appropriate. Since the patients in our study were not selected randomly, no imputation was performed for missing data. All statistical analyses were performed using SAS version 9.4 and a A total of 1,049 patients met our inclusion criteria. Of these patients, 279 (26.6%) received statins during their ICU stay. After propensity score matching, 502 patients were included (1:1 ratio) according to the selected criteria. Most of the patients (86.4%) received statins as a continuation due to underlying coexisting illness . Only 20 patients (8.6%) required statin discontinuation during ICU stay. The most common cause for statin discontinuation was rhabdomyolysis (nine patients), followed by liver damage (eight patients). Atorvastatin (81.3%) with a median daily dose of 20 mg was the most often used statin, followed by rosuvastatin (14.1%) with a median daily dose of 20 mg.Most of the included patients in both arms were males (68.9%) with a mean age of 61.6 years (SD ± 14.8). Diabetes mellitus (59.0%) was the predominant underlying comorbidity, followed by hypertension (55.2%) and dyslipidemia (19.3%). There were some notable differences between the two groups before propensity score matching. Following the propensity score (PS) matching, most of the baseline and demographic characteristics were similar between the two groups. Summary of the patients' baseline characteristics is available in P = 0.17) or 30-day mortality  between the statin and the control group, respectively , P = 0.03] compared with the control group (P = 0.09); however, it did not reach to a statistical significant difference. The overall survival probabilities were higher during hospital stay among patients who received statin therapy before and after propensity score-matching , P = 0.007], and . On the other hand, statin users had higher odds for secondary fungal infection  compared with the control group. Other complications during ICU stay were reported in P = 0.001] and higher odds for secondary fungal infection [OR 1.93 , P = 0.02; Patients who received statins had statistically significantly lower odds of hospital-acquired pneumonia  [OR 0.48 , p-value < 0.001), procalcitonin , and total WBC count  were significantly lower during ICU stay in patients who received statins compared with the control group. In contrast, CPK and ferritin levels were similar among the groups, as described in The follow-up biomarkers such as D-dimer  even though the investigators reported >30% ICU admission in their cohort . This finding is consistent with previous data, which could be related to a proposed antibacterial effect for statins –38. On tBesides the observed survival benefits in our study with statin use in critically ill patients with COVID-19, we did not observe any safety concerns related to statins' side effects or complications. Even though earlier reports from a cohort of 1,099 patients with COVID-19 from China showed that up to 39.4% had aspartate aminotransferase (AST) >40 U/L and 28.1% had Alanine aminotransferase (ALT) >40 U/L, most of these elevations occurred in critical COVID-19 cases . We did We believe that our multicenter cohort study is one of few studies that evaluated statins' clinical and safety outcomes in critically ill patients with COVID-19 using PS matching and multiple regression analysis to minimize the bias. Nevertheless, we also determined some limitations in our study. The retrospective nature of our study may have been affected by missing documentation that could be translated to unmeasured confounders. Also, the medication history before admission might be affected by limited reconciliation during COVID-19 pandemics. Thus, collecting data regarding the length of statin use prior to admission or data related to baseline lipid profile was limited. Furthermore, although we did not include a full list of the medications used in the ICU, we did report, and adjust for, the use of COVID-19 related medication including tocilizumab and corticosteroids. In addition, we included information on the use of nephrotoxic drugs, inotropes, vasopressors, and DVT prophylaxis during the ICU stay. Even though we observed mortality benefits, due to limited follow up period we were unable to assess statin intensity and the long-term benefit of statin use after COVID-19 survival. Furthermore, we were unable to evaluate each type of infection independently since we included both viral and bacterial infections in the same outcome category for pneumonia. Thus, a large randomized controlled trial is needed to investigate the efficacy and safety of statin use in critically ill patients with COVID-19.The use of statins during ICU stay in critically ill patients with COVID-19 was associated with lower mortality with no safety concerns. Thus, the use of statins in patients with COVID-19 during ICU stay might be a reasonable approach unless contraindicated. The result of this multicenter retrospective study motivates further prospective clinical studies to confirm our findings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study was approved in January 2021 by King Abdullah International Medical Research Center Institutional Review Board, Riyadh, Saudi Arabia (Ref. #NRC21R/015/R). Participants' confidentiality was strictly observed throughout the study by using anonymous unique serial numbers for each subject and restricting data only to the investigators. Informed consent was not required due to the research's method as per the policy of the governmental and local research center.All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas, took part in drafting, revising, or critically reviewing the article, gave final approval of the version to be published, have agreed on the journal to which the article has been submitted, and agree to be accountable for all aspects of the work.This study was supported by Princess Nourah Bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R78), Princess Nourah Bint Abdulrahman University, Riyadh. Saudi Arabia.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


After an initially mild course of the disease, he developed multiorgan failure requiring periodic respiratory and dialysis therapy. Covid-19 disease was complicated by multiple infections such Clostridioides difficile infection, Streptococcus epidermidis bacteriemia, Klebsiella pneumoniae and Candida glabrata urinary tract disease, cytomegalovirus infection and oral candidiasis. In a short period, he was readmitted to the hospital twice with recurrent Klebsiella pneumoniae urosepsis. One of those hospitalizations was also complicated by another COVID-19 infection that was confirmed with non-reactive neutralizing antibody. Due to severe infections the patient required individualized modification of immunotherapy; however, due to their recurrence it was finally decided to be discontinued. The patient was also reintroduced to hemodialysis therapy and no infections occurred since then. A forty-seven-year-old recipient in late period after kidney transplantation with chronic estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m Infections, besides cardiovascular complications and cancers, are the most common cause of morbidity and mortality in patients after kidney transplantation (KTx) . The immWe present a case of a patient in long term after KTx with severe course of SARS-CoV-2 infection complicated by multi-pathogenic infections. 2), with artificial mitral valve because of endocarditis in 2004 (treated with vitamin K antagonists) and with history of arterial hypertension. His maintained immunosuppression regimen consisted of tacrolimus , mycophenolate mofetil , and prednisone (5 mg a day). He was vaccinated against COVID-19 with two doses of Pfizer (on April and May 2021) and third dose of Moderna (September 2021). Nevertheless, in November 2021 he was diagnosed with COVID-19 infection (PCR test was positive) with initially mild symptoms . He was treated symptomatically at home, but after 2 weeks a significant deterioration of general condition occurred and he was admitted to the covid unit with cough, hemoptysis, dyspnea, fever up to 40 °C, chills, and decreasing urination. Due to hemodynamic instability and multiorgan failure: tachycardia 130–140/min; hypotension (60/49 mmHg), and saturation 77% (with no oxygen therapy) he was admitted to ICU. His laboratory tests revealed respiratory failure, serious anemia, low platelets, elevated C-reactive protein (CRP) and pro-calcitonin (PCT) levels with high IL-6 level , deep coagulation disturbances, and significant deterioration of graft function  chronically 25–35 mL/min/1.73 mEnterococcus faecium, Klebsiella pneumoniae) and fungal (Candida glabrata) infection in the urinary tract as well as blood infection (Staphylococcus epidermidis). Targeted antibiotics  were administered. CMV DNA was also detected and valganciclovir was started. Throughout the whole hospitalization, the patient required rehabilitation and nutritional treatment with gradually expanded oral diet. The therapy resulted in improvement of his general status with disappearance of inflammation signs and dyspnea. During hospitalization RT-PCR COVID-19 tests were performed four times as per local standards—all were negative; IgM and IgG concentrations were not assessed. The patient had diuresis (2 L/day) with satisfactory stable graft function (serum creatinine [sCr] 2.5–3.2 mg/dL) and immunosuppressive treatment was implemented again, first TAC with trough level around 5 ng/mL and dexamethasone was converted to prednisone. Then MMF treatment was restarted in reduced dose (500 mg/day) on discharge on day 39 of hospitalization.His chest computer tomography (CT) showed wide areas of bilateral ground-glass opacities with segmental areas of crazy paving and local inflammation . Respira2) with 2.5 L/d diuresis so HD was suspended. Apart from that all control laboratory tests results were improving . Our patient developed severe COVID-19 disease despite taking three doses of vaccination and was diagnosed with COVID-19 for a second time after experiencing SARS-CoV-2 infection although without symptoms. His exact serological status before SARS-CoV-2 was unknown but immunocompromised patients, including KTx recipients usually have worse response to vaccination ,9. HowevFurthermore, in less than two months after the first infection, during a routine check-up of patients hospitalized in Nephrology Department our patient had a positive result from the swab PCR test. Due to the lack of specific symptoms of SARS-CoV-2 infection and the possibility that the residual genes from previous coronavirus infection remained in the blood circulation , we identified antibodies as well as neutralizing antibodies that both confirmed the new infection. That result clearly indicated lack of neutralizing effect despite the previously acquired immunization. It should be noted that the SARS-CoV-2 neutralizing antibody prevents invasion of human cells by SARS-CoV-2 by inhibiting or even neutralizing the biochemical effects of the virus. The SARS-CoV-2 neutralizing antibody reduces the infectivity of the virus by binding to surface epitopes of virus particles and blocking virus entry into the infected cell. Detection of SARS-CoV-2 neutralizing antibodies may reflect the body’s immune response to SARS-CoV-2 and ultimately determine whether there is antibody protection or immunity. Some SARS-CoV-2 binding antibodies may not have neutralizing activity. Therefore, detection of SARS-CoV-2 neutralizing antibodies is an important way to assess the immune status of SARS-CoV-2. It should be noted that both the type of vaccine used and the mutation of the virus do not affect the results of the test used ,22. The COVID-19 infection and probably its treatment and long hospitalizations were the cause of multi-pathogenic co-infections in the immunocompromised individual. The main risk factors of developing such complications aside from immunosuppressive treatment are ICU hospitalization with intubation and graft failure with a later HD treatment, high doses and long treatment with dexamethasone and long wide-spectrum antibiotics therapy, presence of central and Foley catheter, blood transfusions, cachexia, and general long hospitalization. Some studies show that among solid organ transplant recipients with COVID-19 infection, bacterial co-infections are most common (50%), followed by CMV  and fungal infections (8.3%) . Our patIt is difficult to differentiate whether all those infections were complications of hospitalization itself or the state of immunosuppression together with severe course of COVID-19 illness followed by multiorgan dysfunction and development of malnutrition despite nutritional treatment. Nevertheless, despite presenting nearly all epidemiological and laboratory factors of poor prognosis followed by multiple infectious complications the patient survived. Decreasing immunosuppression treatment should be the first step in infection therapy although it may increase the risk of graft rejection. In the presented case, after taking into account the overall clinical picture of recurrent severe multi-pathogenic infections in the patient treated with immunosuppressive therapy with significantly impaired graft function and with an implanted artificial heart valve, it was decided to discontinue the immunosuppressive treatment and reintroduce HD therapy. The applied treatment improved the patient’s general condition. Now the patient has been HD for ten months, he is in good clinical condition, no signs of infection have been observed, and he is prepared for a second kidney transplantation. Patients after kidney transplantation are at high risk of developing severe infections, and the presence of one pathogen paves the way for other infections, therefore the patient should be carefully monitored and the coexistence of other infections should be taken into account, especially in patients with COVID-19 infection. In KTx patients with severe course of infections, the reduction of immunosuppression or even discontinuation in patients with impaired graft function and return to hemodialysis should be considered. Consequently, such may not only save the patient’s life but also give the prospect of another kidney transplant in the future.


Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT).n = 118, 49.2%) or usual CR alone . Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores  = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term  follow-up data.We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR  patients.NCT03999359. In a randomized controlled trial, Adrian Wells and colleagues test the effectiveness of adding self-help metacognitive therapy to cardiac rehabilitation in reducing anxiety and depression. One-third of cardiovascular disease (CVD) patients suffer anxiety and depression symptoms, but psychological support in cardiac rehabilitation (CR) is limited and produces small effects.Treating anxiety and depression is important because they are associated with worse health outcomes and impair quality of life.Previously, a recent treatment called metacognitive therapy (MCT) significantly improved anxiety and depression in patients undergoing CR when delivered by cardiac staff.Home-based self-help MCT was previously found to be feasible and acceptable to deliver alongside CR, hence a full-scale trial was required to test the effectiveness of this self-help intervention.We used a single-blind parallel randomised trial to test the effectiveness of self-help MCT.A total of 240 CR patients with elevated anxiety and/or depression received either usual CR or usual CR plus self-help MCT.The addition of self-help MCT significantly improved anxiety and depression ) compared to CR alone (standardised mean difference (SMD) = 0.38). In CR alone, 36% of patients met criteria for minimal clinically important improvement, compared to 59% achieving this status under MCT self-help.MCT self-help plus CR was also found to improve post-traumatic stress symptoms to a greater extent than CR alone. An unexpected finding was that MCT self-help was also associated with a reduced rate in worsening of anxiety and depression during CR.Anxiety and depression in CVD can be effectively managed with self-help MCT.Self-help MCT has the potential in the future to improve health outcomes, reduce the risk of psychological deterioration in CVD, and improve access to evidence-based psychological care.The current findings do not address long-term outcomes, but they support a future policy of managing the psychological needs of patients undergoing CR with a menu of MCT options that includes home-based self-help. Cardiovascular disease (CVD) is the leading cause of death globally . HoweverWhile CR improves anxiety and depression, the effects are small, limiting the benefits that CR alone might have on improving psychological health. This is important because anxiety and depression are common among heart disease patients , are assn = 678) [While CR services offer home and centre-based CR programmes that are exercise and lifestyle based, less emphasis has been placed on offering effective home-based/self-help psychological support for CR patients. When home-based psychological therapies are offered, cognitive behavioural therapy (CBT) techniques are used but the effectiveness is limited ,12. Matcn = 678) , angina n = 678) ,15, and n = 678) . In mostn = 678) ,18. Howen = 678) ,20. The A candidate treatment approach is metacognitive therapy (MCT ), which The present study is to our knowledge, the first large-scale trial of a self-help, home-based MCT in patients with CVD. We evaluated if the addition of home-MCT to usual cardiac rehabilitation improved anxiety and depression. The trial tested the primary hypothesis that the addition of home-MCT to usual CR is more effective than CR alone in alleviating symptoms of anxiety and depression in patients with CVD between baseline and 4-month follow-up. We set a minimal inclusion criterion as presence of mild symptoms of anxiety, depression, or both, based on HADS scores, which could include individuals with current or previous psychological disorders.clinicaltrials.gov, NCT No. NCT03129282 and No. NCT03999359. The study began as a feasibility and acceptability trial (NCT No. NCT03129282) that was conducted April 2017 to June 2020). The trial was then granted a variation to contract (VTC) by the funder in March 2019 to progress from a pilot feasibility study (n = 108) to a definitive RCT. The trial registration for the progression to a definitive trial can be found here: NCT No. NCT03999359. The definitive RCT was conducted between May 2019 and August 2020. The results of the feasibility study are reported elsewhere [A multicentre two-arm, single-blind randomised, controlled trial with 4-month follow-up comparing home-MCT plus usual CR (Home MCT+CR) with usual CR alone was conducted between April 2017 and March 2020. Patients were recruited between April 20, 2017 and April 6, 2020. Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Patients were recruited from CR services at 5 National Health Service (NHS) hospital trusts  across the North West of England. Ethical approval was obtained from the North West—Greater Manchester West Research Ethics Committee (REC Reference 16/NW/0786), along with site-specific approval. The trial is registered with lsewhere . The VTClsewhere . A separlsewhere  to whichThe trial included participants referred to CR services who met the Department of Health or British Association for Cardiac Prevention and Rehabilitation CR eligibility. As part of the CR program, all patients referred to CR are sent a National Audit of Cardiac Rehabilitation assessment pack , which iPatients were randomised via telephone/email link to the Centre for Biostatistics at the University of Manchester. Within each site, participants were stratified by sex and screening HADS score , then allocated to trial arms in a 1:1 ratio using randomised blocks of size 4 and 6. The chief investigator, RAs, and trial statisticians were masked to treatment allocation throughout data collection and analysis. Instances of accidental unmasking were recorded to assess their frequency and severity, which was routinely reviewed by the Trial Steering Committee.Usual CR consists of 8 to 10 weeks of group-based exercise classes and educational seminars. Educational seminars focused on health and medical risk factor management. The extent of psychological components varied by site. All sites included educational seminars on stress management and relaxation, which focused on breathing techniques and progressive muscle relaxation. At 3 sites stress management sessions also incorporated 2 cognitive therapy strategies . In addition, 1 site offered a 4-week stress management course as part of CR that included generating and sharing a CBT case formulation based on Greenberger and Padesky , mindfulHome-MCT  was deliPatients also received 3 brief scripted telephone support calls delivered by CR staff who had received basic training in delivering the calls. There were 7 support staff, 3 from Bolton and 4 from Liverpool. The support staff were predominantly CR nurses, with 1 site including a physiotherapist. They completed a workshop delivered by the developer of MCT (AW). Training included didactic teaching, role play, discussion, and studying the treatment manual to facilitate an understanding of the MCT approach and the purpose of the techniques in the manual. In addition, they piloted home-MCT support calls with 5 volunteers each , after which an additional 1-day workshop was delivered, which focused on enhancing support skills.The first scripted call was 10 to 15 minutes and introduced the structure of the manual and helped users think of a timetable for completing the modules. The second and third calls (approximately 30 minutes each) reviewed the modules completed to date and helped participants consolidate what they had learned from the exercises, encouraging widening of practise of techniques, reviewing unhelpful coping behaviours, and increasing motivation to change them. The support calls did not consist of actively delivering MCT intervention techniques  but patients were asked questions to help them reflect on changing beliefs about worrying  and changing behaviours.As depicted in The primary outcome was the HADS  total scFour other measures were used to evaluate the secondary outcomes. The Impact of Event Scale–Revised (IES-R)  was usedAdverse events were monitored throughout by healthcare professionals delivering CR and reported and assessed as related or unrelated to the study. Adverse and serious adverse events were reviewed on a quarterly basis at the study executive committee meetings.The trial was designed to detect a standardised mean difference (SMD) between trial arms of 0.4 in HADS total score at 4-months follow-up with 90% power, where 0.4 is in the middle of the range of effect sizes reported for other forms of psychological interventions for depression . We assup-values for this outcome were validated in a sensitivity analysis using bootstrapped standard errors based on 10,000 repetitions.Analysis was conducted in accordance with a prespecified analysis plan detailing the analytical models, primary and secondary outcomes, choice of covariates, sensitivity analyses, and all other key aspects of the analysis. The plan was finalised and approved by the Trial Steering Committee prior to data analysis or unmasking. The primary analyses used intention-to-treat principles. For each of the continuous outcomes, a linear mixed effects regression model was applied incorporating both time points . Prespecified covariates in the model were the design stratification actors of hospital site and sex, plus age and medication for depression or anxiety (never taken/currently taking/taken in the past). All other potential covariates  were belp < 0.05. A Cronbach alpha of 0.91 derived from the control sample at 4 months was used as the estimate of reliability for a usual CR population, since baseline HADS scores had restricted variance due to being a study eligibility criterion. We calculated that a reduction of 7 points in an individual’s score represented statistically reliable improvement, while an increase of 7 points represented reliable deterioration in symptoms.To aid interpretation, we computed effect sizes in the form of SMDs between groups. For consistency with Cochrane reviews and to enable cross-study comparisons, these were computed as the adjusted mean difference between groups from the mixed effects model divided by the pooled standard deviation of change scores from baseline . A generBeing based on statistically significant change within an individual, the RCI can be conservative. We therefore conducted an equivalent analysis based on a published minimal clinically important difference (MCID) for the HADS anxiety and depression subscales of 2 points . To operWe observed a higher attrition rate by 4-months follow-up in the MCT+CR arm. Sensitivity analysis based on MI assumes data is missing at random, which is unlikely in this case. We therefore conducted 2 additional sensitivity analyses to account for differential attrition. The first assumed that patients who dropped-out experienced no change in their outcome scores between baseline and 4 months (a last observation carried forward (LOCF) analysis). The second sensitivity computed the mean 4-month score required among drop-outs to reduce the treatment effect between arms to zero, for each outcome. This score was expressed as a percentile of the outcome’s score distribution among controls at 4 months to aid interpretation. Analyses were conducted using Stata version 14.p < 0.001). There were 8 incidents of unmasking, which involved RAs accidently being unblinded to patient allocation. There were no cases of the trial statisticians or chief investigator being unmasked.A total of 1,839 patients were referred to CR between April 2017 and March 2020, of which 596 had an elevated HADS score and were screened for eligibility see . Approxip = 0.005, SMD = 0.38). Results of the main analysis of primary and secondary endpoints are summarised in p = 0.032, SMD = 0.29), plus a lower HADS depression subscale mean score . Most other secondary outcomes also favoured the MCT intervention: IES-R ; MCQ-30 total scores ; negative beliefs subscale scores  and the CAS-1R . EQ-5D utility scores demonstrated no statistically significant difference ; similarly, the difference on the EQ-5D-VAS was not significant . Sensitivity analysis using MI changed only the result for HADS anxiety which ceased to be statistically significant. The use of a bootstrapped standard error did not alter the result for the skewed utility outcome.Patients in the MCT+CR arm achieved significantly lower mean HADS anxiety subscale score . Attendance at CR educational sessions was lower (medians: CR 4 (IQR 1 to 6), MCT+CR 4 (IQR 0 to 6)) and did not differ between groups (p = 0.657). Approximately 76% of participants in the Home-MCT arm entering treatment completed 4 or more Home-MCT modules, our criteria for a clinically effective exposure [p = 0.139); however, the numbers involved were small.Patients in both trial arms attended routine CR sessions at their site as members of larger groups (of up to 15) including patients with CVD not part of the trial. Among patients returning the 4-month follow-up questionnaire, attendance at CR exercise sessions was high in both groups, with a median of 5 (IQR 2 to 6) out of 10 sessions attended by CR arm patients and 5 (IQR 2 to 7) by MCT+CR patients, a nonsignificant difference  in CR compared to 10% (1 in 10 patients) in MCT+CR . Based oSafety and adverse events  associated with the treatments were monitored throughout the trial. No adverse events were reported.This trial showed that the addition of a home-based self-help MCT significantly reduced overall anxiety and depression symptoms  in CVD patients undergoing cardiac rehabilitation. Significantly greater improvement was observed in the primary outcome, HADS total at 4-months and in most secondary outcomes. Post-traumatic stress symptoms  appeared to respond particularly well in the self-help MCT condition. These outcomes showed for the first time that self-help MCT was an effective intervention when added to CR, across anxiety, depression, and trauma symptoms in patients with CVD.An analysis of separate HADS subscales indicated greater improvements in both anxiety and depression symptoms in the MCT group. However, it should be noted that the treatment effect on anxiety was smaller and not significant under MI and LOCF sensitivity analyses accounting for attrition. All other significant effects were robust against sensitivity analyses.The HADS effect sizes were lower than those obtained in our previously published face-to-face group based MCT trial of CR patients . The curCompared to treatment as usual, the home-based treatment had a significantly greater effect on underlying psychological mechanisms considered to contribute to excessive and chronic anxiety and depression symptoms. We found greater improvements in worry, rumination, and unhelpful coping behaviours, as well as greater reductions in maladaptive metacognitive beliefs . It is notable that while the controlled effect for metacognitive beliefs is only slightly smaller in this study compared to our earlier group-MCT intervention study, the effect on the cognitive attentional syndrome (CAS) measure is seemingly lower here. In the present study, the SMD for CAS was 0.43 and this compares with an SMD of 0.73 in our earlier therapist delivered group intervention. The reduced impact on causal mechanisms  might account for the reduced effectiveness of self-help MCT on HADS compared with the effects observed in our earlier study of face-to-face group MCT.n = 50). They found that 60% of patients completed 4 out of the 7 modules, with only 24% completing all 7 modules.Twenty-four percent of participants returning the end of treatment questionnaire completed less than 4 Home-MCT modules and attrition from the study was significantly higher in the MCT+CR arm. Hence, it appears that Home-MCT did not appeal to some patients. Nevertheless, the completion rates of Home-MCT compare favourably to previous studies of psychological guided self-help interventions. For example, Lundgren and colleagues  evaluateThe results we obtained compare favourably with the results of other studies that have used a range of treatment techniques. In a study similar to the present study, Lewin and colleagues  examinedp-value approached significance.We failed to find a significant effect on EQ-5D utility scores, although the The strengths of the current study include the recruitment of a large sample size, clearly specified a priori outcomes and analysis plan, recruitment from multiple treatment sites, and blinding of investigators. We used an evidence-based model and treatment on which to base the self-help intervention.The main limitation is the absence of longer term  follow-up data. This study was an extension of a pilot feasibility study of self-help MCT that was approved under variation to contract and we did not have the time and resource to collect the longer term follow-up data. We cannot determine the effects of MCT alone in this study as it was designed to address a question of the “added effect” of self-help MCT when offered alongside CR. It is possible that combining MCT with psychological techniques included in some CR packages may impair rather than enhance MCT effects, because they rely on opposing mental processes .Self-help metacognitive therapy significantly improved total anxiety and depression symptoms when added to usual cardiac rehabilitation. The treatment also resulted in significantly improved traumatic stress symptoms and impacted on hypothesised psychological causal variables. An important incidental finding was preliminary evidence that the addition of self-help MCT might also reduce rates of psychological deterioration in CVD patients. The implication is that self-help MCT could be offered to distressed CVD patients as an effective psychological intervention in addition to or as an alternative to group-based therapist-led MCT.S1 Statistical Analysis Plan(DOCX)Click here for additional data file.


Langerin-expressing DCs can be further subdivided into numerous subtypes based on the co-expressed receptors, but here, we identify commonalities across these subtypes that point to the major role of langerin. Better understanding is required to clarify key disease pathways and determine potential new therapeutic approaches.Dendritic cells (DCs) are “frontline” immune cells dedicated to antigen presentation. They serve as an important bridge connecting innate and adaptive immunity, and express various receptors for antigen capture. DCs are divided into various subclasses according to their differential expression of cell surface receptors and different subclasses of DCs exhibit specific immunological characteristics. Exploring the common features of each sub-category has became the focus of many studies. There are certain amounts of DCs expressing langerin in airways and peripheral lungs while the precise mechanism by which langerin Later,  as well . The dis as well , 5.+ DCs were also found in tissues apart from skin including the lung, liver, kidney, and lymphoid tissue  DCGM4 staining , 9. Langpression . LCs werpression , 11. Evepression . Accordipression , 13, 14.pression . It diffpression , 17. Spepression .+ CD83− LCs from both CD14-negative and CD14-positive precursors -RA receptor (RARα) axis in a concentration-dependent manner  inhibits the growth of Lewis' lung carcinoma tumors expressing gp33 (LL-LCMV), leading to reduced cytotoxic CD8+ T cell activity. This highlights the importance of langerin in antigen cross-presentation of tumor peptides  we analyzed the expression of langerin in Lung Squamous Cell Carcinoma (LUSC)  and Lungclass Ib ,D. These+ DCs from the lung to the draining lymph node and LPS-exposed langerin+ DCs instructed CD4+ T cells toward a Th2 response. Selective depletion of langerin+ DCs prevented LPS-induced eosinophil recruitment and T-cell activation  2-cell sensitization but also for maintaining effector Th2-cell responses during ongoing allergic disease . In a motivation . In additivation . Moreove2.5-fold . These rhigh CD11chigh-DC population which express high levels of langerin and act to enable efficient antigen uptake and presentation  and non-specific interstitial pneumonia, importantly the characteristics of the immature DCs that infiltrate during fibrosis and epithelial hyperplasia in these diseases are similar . Intraepeillance . High leeillance .+ and langerin+ cells than the subjects with sarcoidosis and IPF  occurs predominantly in young smokers or ex-smokers (>90% of cases) with a peak incidence between the ages of 20 and 40 , 76. Pat and IPF .+ and langerin+ cells in LCH lesions is more than two-fold that in interstitial pneumonia  in areas of highest density indicates that the number of CD1aneumonia . Additiopatients , providipatients , but itspatients  which prpatients , 87. AllThere is a significantly higher expression of langerin mRNA in human COPD lung tissue compared with those from healthy control subjects . The pri+ DCs in langerin-DTR mice aggravates the severity of infection .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In this review, we aim to summarize the evolution of care for the solid organ transplant recipient (SOTR) with COVID-19 disease, based on the current published guidelines and our center’s experience.Oral antiviral medications and monoclonal antibodies are now used with the goal to prevent severe disease. Immunomodulating drugs in addition to antivirals have been used in the treatment of severe COVID-19.With the ongoing pandemic and unique challenges posed by the SOTR, understanding the risk and advancing management and treatment of COVID-19 infections are imperative to the successful care of a transplant recipient. There are many ongoing clinical trials being conducted in hopes of developing novel therapeutics towards COVID-19. As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is now entering its third year, treatment and prevention methods have evolved and multiplied. Numerous medications for the treatment of coronavirus disease 19 (COVID-19) have been studied, and some have received emergency use authorization (EUA) and Food and Drug Administration (FDA) approval, allowing for improved outcomes in the fight against this infection . In genePrevention options for SOTR have become a priority to stop the spread of COVID-19 •. With tThis review will highlight the evolution of clinical developments in the treatment of COVID-19, particularly in infected transplant recipients. It will include discussions on prevention techniques and treatment options. Throughout this review, when discussing severity of COVID-19 disease, definitions will be consistent with the National Institutes of Health (NIH) COVID-19 Panel guidelines on the treatment of COVID-19 ••. It shEarly in the pandemic, remdesivir, an adenosine nucleotide pro-drug, was seen to be effective against COVID-19 . In ApriTreatment duration with remdesivir was investigated in two large open-label trials. The SIMPLE Trial randomized hospitalized patients on supplemental oxygen to either 5- or 10-day courses of remdesivir and found that a 5-day course of treatment was equally beneficial to a longer course by day 15 ••, 11•. Based on preliminary early data, the FDA granted emergency use authorization (EUA) for remdesivir as of May 1, 2020 . FurtherIt should be noted that benefits of remdesivir were not definitive in many trials, and no trial revealed a mortality benefit. In the ACTT-1 trial, patients who required high-flow oxygen, mechanical ventilation, or ECMO saw no difference in time to recovery.•• The SoSOTRs were not explicitly excluded from the major trials of remdesivir. While transplant medications may have represented a contraindication to treatment arms, SOTR enrollment in these trials is not explicitly stated. The ACTT-1 trial did not specify how many SOTR were included; however, it is noted that of the 1062 participants, 6.9% had some type of immune deficiency, either acquired or innate , 19. As One early retrospective cohort of SOTR include 90 patients, but remdesivir was utilized in only two patients, one with severe disease and one with moderate disease . This inHowever, now that remdesivir has been extensively used in this pandemic, practitioners have developed an anecdotal body of evidence to comfortably implement its frequent use in SOTR. Prior to extensive use of remdesivir, early caution for liver and kidney donors was advised due to remdesivir adverse effects. Indeed, in Wang et al. as well as in the ACTT-1 trial, elevations in transaminases more than five times the upper limit of normal as well as renal impairment with glomerular filtration rate (GFR < 30 mL/min) or renal replacement therapy were exclusion criteria for the trials ••, 26. FAs of the end of 2021, the FDA granted EUAs for two different oral antivirals, nirmatrelvir/ritonavir , and molnupiravir  , 29. DueCorticosteroids were not initially recommended in the treatment of SARS-CoV-2 due to the theoretical concern regarding delayed viral clearance . HoweverGiven these findings, the type of steroid and dose of steroids have been examined in a few large trials. Hydrocortisone did not reduce treatment failure at day 21; however, this study was terminated early, leading to an underpowered study •. LikewiSOTRs were not specifically evaluated in sub-group analyses of these trials. Early case studies of transplant recipients noted that patients were already on low-dose steroids for immunosuppression and had similar outcomes of COVID-19 . As the IL-6 inhibitors, specifically tocilizumab and sarilumab, have been examined in large, randomized controlled trials and have exhibited a beneficial effect among patients with progressive moderate to severe COVID-19 who are not yet on mechanical ventilation •, 46. ThDespite these trials demonstrating advantages of tocilizumab, the REMDACTA double-blind RCT of tocilizumab and remdesivir in hospitalized patients with severe COVID-19 pneumonia found that the combination of remdesivir plus tocilizumab did not shorten time to discharge and there was no difference in mortality between arms . NeverthIn STOR, use of tocilizumab has been evaluated in observational studies, calling into question the safety and efficacy of additional immunosuppression in this population . In an oOf the kinase inhibitors currently in use, there are randomized clinical data only for baricitinib and ruxolitinib in COVID-19. The ACTT-2 trial randomized over 1000 hospitalized patients to receive remdesivir plus baricitinib or remdesivir plus placebo ••. The tData on baricitinib in SOTR is sparse. Bodro et al. discuss use of baricitinib in 33 kidney transplant recipients (KTR) admitted to the hospital in the early stages of the pandemic . This stIn randomized controlled trials of the various monoclonal antibodies, outcomes were not stratified by organ transplant recipients specifically. Yet all of them were able to demonstrate improved outcomes among patients with risk factors for more severe COVID-19 disease and hospitalization, namely, reducing hospitalization rates .Bamlanivimab was studied in the Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trials, double-blind RCT with three phases. The first phase compared bamlanivimab versus placebo, with a post hoc analysis of high-risk patients revealing lower hospitalizations in the study drug arm . Phase 2Casirivimab/imdevimab (brand name Regeneron) was studied in a three-phase RCT. Regeneron significantly decreased viral level from day 1 through day 7 when compared to placebo . This efSotrovimab is currently being used against Omicron variant. Sotrovimab targets a portion of the receptor binding domain, which remains highly conserved in the Omicron variant . OngoingBebtelovimab is the most recent monoclonal antibody available to treat COVID-19 and works by binding to the COVID-19 spike protein similar to other monoclonals. To date, bebtelovimab seems to retain activity against both the omicron variant and the BA.2 omicron subvariant , 77.Vaccination against COVID-19 has helped limit the spread of the disease. Available vaccines in the USA include the mRNA vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer), and Ad26.COV2.S (J&J). Recommendations for SOTR are to prioritize the mRNA vaccine, as they appear to mount a stronger humoral response compared to adenovirus vector vaccines, such as the J&J vaccine ••. CurreSOTR response to vaccination has been widely researched and variable in the literature. Antibody response in SOTR after receiving COVID-19 has evaluated spike protein IgG or receptor-binding domain IgG , 82, 83.Pre-exposure prophylaxis is now a consideration with the arrival of tixagevimab + cilgavimab (Evusheld) . EvushelNotably, certain medications have been investigated as preventive measures from contracting COVID-19. Ivermectin, an anti-parasitic medication, inhibits replication of viruses in vitro. Meta-analysis of numerous trials does not show any benefit to ivermectin , 97.Data on the use of chloroquine and hydroxychloroquine have not been shown to benefit COVID-19. The FDA EUA was revoked for both drugs due to ineffectiveness, and both have potential to prolong QTc and cause harm  that may reduce cytokine production as demonstrated in mouse models . In the COVID-19 therapeutics have gone through several iterations since the beginning of the pandemic in 2020. SOTRs have often been one of the populations most affected by this disease, and evidence on specific treatment in this population is limited. In our clinical practice, remdesivir remains the antiviral of choice for those hospitalized with moderate COVID-19. Additional treatments for moderate to severe disease include corticosteroids, tocilizumab, or baricitinib. Outpatient treatment for mild COVID-19 includes shorter courses of remdesivir, or oral antivirals, or monoclonal antibodies. As new therapeutics evolve for this virus, it is imperative that immunocompromised patients, specifically SOTRs, are included in studies. Providers should continue ongoing vaccination campaigns for those who remain unvaccinated or partially vaccinated. Prevention with pre-exposure prophylactic medications could provide protection for many who cannot mount an immune response to the vaccine. The progress in the treatment of COVID-19 should include SOTR as the medical community navigates the future of this pandemic.