Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulating their pharmacokinetic-pharmacodynamic relationship (PK–PD). Therefore, in this study, a mechanism-based preclinical PK–PD model was developed to characterize the PK–PD relationship of nano-MSCs in orthotopic A549 human lung tumors in SCID Beige mice. The developed model leveraged literature information on diffusivity and permeability of PTX and PLGA NPs, PTX release from PLGA NPs, exocytosis of NPs from MSCs as well as PK and PD profiles of nano-MSCs from previous in vitro and in vivo studies. The developed PK–PD model closely captured the reported tumor growth in animals receiving no treatment, PTX solution, PTX-PLGA NPs and nano-MSCs. Model simulations suggest that increasing the dosage of nano-MSCs and/or reducing the rate of PTX-PLGA NPs exocytosis from MSCs could result in improved anti-tumor efficacy in preclinical settings. Friedenstein in early 1970s , especials.gov/) . MSCs exls.gov/) . The C-Xls.gov/) . These mls.gov/) ,14,15,16ls.gov/) ,18,19. MUnlike other targeted therapies, nano-MSCs take advantage of the inherent tumor homing capability of MSCs, to selectively and actively deliver potent chemotherapeutic drugs to tumor sites . HoweverA quantitative understanding of the dose-exposure-response relationship, via mechanism-based models, is a crucial step to optimize the preclinical efficacy of developmental therapeutics. Developed with integrated data from in vitro and in vivo studies as well as literature-derived parameter values, mechanism-based PK–PD models are able to extrapolate drug exposure and therapeutic effects, which is anticipated to reduce experimental attrition and facilitate the translation of complex therapeutics ,22,23. NConsidering there are different components responsible for the delivery of PTX to tumor cells using nano-MSCs , it beco® beige mice (Charles River Laboratories) through tail vein injection of A549-luc cells and tumor growth was monitored using in vivo bioluminescence imaging as described below.PK (tissue drug concentrations) and PD (tumor growth over time) data were obtained from our previously published study , which iThe tumor-bearing mice were randomized into 3 treatment groups, receiving a single 5 µg (0.25 mg/kg) intravenous (IV) injection of PTX solution, PTX-PLGA NPs, and nano-MSCs. Following the dose, mice (n = 3) were sacrificed at 2 h, and at 1-, 2-, 5- and 12-days post-treatment and blood, lung (tumor-bearing site), liver and spleen tissue samples were obtained. PTX concentrations were measured in these samples by LC/MS/MS as described before . Concent5–106 photon/sec. The tumor-bearing mice were randomized into 6 treatment groups receiving saline, untreated MSCs, MSCs with drug free blank NPs, PTX solution, PTX-PLGA NPs, or nano-MSCs. Mice in the PTX solution and PTX-PLGA NPs groups received 40 mg/kg of PTX on days 0, 4, and 8. Mice in the untreated MSCs, MSCs with blank NPs and nano-MSCs treatment groups received 1 × 106 MSCs  on day 0 and 0.5 × 106 MSCs every 14 days. For modeling purposes, animals receiving saline, untreated MSCs and MSCs loaded with blank NPs were pooled as the treatment-free group and used as control, given that PTX is the active tumor-killing cytotoxic drug. Tumor growth was monitored by measuring tumor-associated bioluminescence using the IVIS Spectrum in vivo Imaging System . Treatments were initialized when tumor size reached 10® version 7.4 software; ICON Development Solutions, Ellicott City, MD, USA) was performed for all analyses using the first-order (FO) and Laplacian methods for the development of the PK and PK–PD models, respectively. Since the PK study was conducted with a destructive sampling approach (one sample per subject), a naïve pooled approach was utilized. Thus, no between-subject variability (BSV) terms were estimated in the PK models, and all the variability was attributed to the residual unexplained variability (RUV). The PTX concentrations measured as ng/g were converted to ng/mL by assuming a 1 g/mL tissue density [2. Final NONMEM control streams for all analyses are provided in the ® interface [Nonlinear mixed-effect modeling  and tumor accessible fraction (PTXE) were assumed to be the same for all small molecules as shown in centralPTX, tumorPTX and peripheralPTX represent central, tumor and peripheral compartment for PTX free drug, respectively. PTXcentralA, PTXtumorA and PTXperipheralA describe the PTX amounts in central, tumor and peripheral compartment, respectively. The definitions of all the other parameters are shown in relK) was derived from a separate in vitro study conducted previously [relK and exoK Estimation below. Detailed PK model equations for PTX in the form of PLGA NPs are provided below (Equations (4)–(9)).centralNP, tumorNP, peripheralNP, centralPTX, tumorPTX and peripheralPTX represent the central, tumor and peripheral compartments for PTX in the form of PLGA NPs and central, tumor and peripheral compartments for PTX free drug, respectively in PTX-PLGA NPs PK model. NPcentralA, NPtumorA, NPperipheralA, PTXcentralA, PTXtumorA and PTXperipheralA describe the PTX amounts in central, tumor and peripheral compartments for PTX in the form of PLGA NPs and for PTX free drug, respectively. The definitions of all the other parameters are shown in eviously , as descexoK) was derived from a separate in vitro study conducted previously [relK and exoK Estimation below. The rate constant of PTX free drug release from nano-MSCs is assumed to be the same as the PTX free drug release from PLGA NPs layer and described via a first order drug release rate constant, relK. The assumption is based on the relatively fast efflux of PTX free drug from MSCs. Detailed PK model equations for PTX in the form of nano-MSCs are provided below (Equations (10)–(18)).eviously  as descrcentralMSC, tumorMSC and peripheralMSC represent the central, tumor and peripheral compartments, respectively, for PTX in the form of nano-MSCs. centralNP, tumorNP, peripheralNP, centralPTX, tumorPTX and peripheralPTX represent the central, tumor and peripheral compartments for PTX in the form of PLGA NPs and for PTX free drug, respectively. MSCcentralA, MSCtumorA and MSCperipheralA, NpcentralA, NptumorA and NpperipheralA, PTXcentralA, PTXtumorA and PTX peripheralA describe the PTX amounts in central, tumor and peripheral compartments for PTX in the form of nano-MSCs, PLGA NPs and PTX free drug, respectively. The definitions of all the other model parameters are presented in In the above equations, rel,K free PTX release from PLGA NPs was assumed to follow a first order release process and the in vivo PTX release kinetics from PLGA NPs was assumed to be comparable to in vitro PTX release kinetics. The in vitro PTX release from PLGA NPs study conducted by Sadhukha et al. [relK. A first order association model was fitted using least square method with GraphPad Prism 7. Additionally, the efflux of free PTX from nano-MSCs was assumed to happen instantaneously and therefore drug release from PLGA NPs within the cells was considered the rate-limiting step for free PTX release from nano-MSCs. Thus, the derived relK was used for describing free drug release from both PLGA NPs and nano-MSCs. To estimate a et al.  was usedexoK, exocytosis of PLGA NPs from nano-MSCs was assumed to follow a first order exocytosis process. Moreover, the in vivo PLGA NP exocytosis was assumed to be comparable to in vitro exocytosis. The in vitro NPs exocytosis study conducted by Layek et al. [exoK). A first order decay model was fitted using least square method with GraphPad Prism 7. To estimate k et al.  was usedThe estimated PK parameters from free PTX, PTX-PLGA NPs and nano-MSCs–PKmodels were fixed and made available in the NONMEM control stream for the tumor growth model. The predicted PTX concentrations for free drug, PLGA NPs and nano-MSCs were assumed to inhibit tumor growth as shown in PTXKkill, NPKkill and MSCKkill are the tumor killing rates caused by PTX free drug, PTX in the form of PLGA NPs and PTX in the form of nano-MSCs, respectively. VT represents the tumor volume and TV represents the tumor compartment with the unit consistent with tumor bioluminescence. The conversion between TV and VT was derived from a separate animal study as described in the section Correlation between Tumor Weight and Tumor Bioluminescence. The definitions of all the other PD model parameters are provided in In the above equations, The tumor bioluminescence profiles from animals receiving no treatment, PTX solution, PTX–PLGA NPs and nano-MSCs were fitted simultaneously with a population model. In order to account for the potentially early dropouts of animals having a high tumor burden, a modified M3 method-based approach proposed by Martin et al. was utilized . In this6 cells) through the intravenous (tail vein) route. The tumor bioluminescence (photon/sec) and tumor weights (g) were reported for A549 tumor mice (n = 8) before and after euthanasia, respectively. Assuming the density of tumor tissue as 1 g/mL, the relation between tumor bioluminescence in photon/sec and tumor volume in mL can be investigated. In order to prevent the existence of negative tumor volume during the PD modeling process, a power function (Equation (23)) was used to investigate the association between tumor volume and tumor bioluminescence with Microsoft Excel.VT is tumor volume in mL; and TV is tumor bioluminescence in 106 photon/s.The animal studies were conducted according to the protocols approval by Institutional Animal Care and Use Committee (IACUC) at the University of Minnesota (Protocol ID: 1605-33821A). Six to eight-week-old female Fox Chase SCID Beige mice were purchased from Charles River Laboratories. The orthotopic human lung cancer model was developed in these mice by the injection of A549-luc cells , the stability of the model, and goodness-of-fit plots. The precisions of the final model parameters were evaluated using relative standard error (RSE) generated from covariance steps and sampling-importance-resampling (SIR)-based 95% confidence intervals (CIs) ,39. The 6 MSCs  on day 0 and 0.5 × 106 MSCs every two weeks; 106 MSCs on day 0 and 0.25 × 106 MSCs every week; 106 MSCs on day 0 and 0.125 × 106 MSCs every 3.5 days); (ii) different doses with the same dosing interval . The effect of different relK  and exoK  values on tumor growth were also simulated with the original dosing regimen of 106 MSCs on day 0 and 0.5 × 106 MSCs every two weeks. All the simulations were performed with mrgsolve package in R. The median and 10th and 90th percentiles of simulated tumor bioluminescence were calculated and plotted using R.After the development of PK model for nano-MSCs, simulations were performed following the administration of 5 µg (0.25 mg/kg) PTX equivalent nano-MSCs as a single IV bolus dose into the central compartment of the nano-MSCs layer. PK profiles of the total PTX, PTX in the form of free drug, PLGA NPs and nano-MSCs were simulated in both plasma and lung. In addition, following the development of the full PK–PD model, simulations (n = 100) were carried out for animals receiving nano-MSCs, using typical values and BSV estimated in the final models. Different dosing scenarios were simulated to reflect: (i) different dosing intervals of the same total dose (10The drug exposure in the lung (tumor-bearing tissue) following a single dose of nano-MSCs is much higher compared to that with PTX solution and PTX-PLGA NPs with comparable plasma drug exposure A. The turelK and exoK were estimated with data acquired from in vitro drug release and NPs exocytosis studies [relK as 0.0085 h−1 with R2 of 0.845  of the other model parameters. Hence, we tested different exoK values ranging from 0.080 to 0.085 h−1 and found that fixing exoK to 0.081 h−1 provided a reasonable RSE% for all model parameters and gave the lowest objective function value (OFV). The association between tumor weight and tumor bioluminescence is shown in Given the limited PK data, the rate constant  studies ,36. The of 0.845 A, whereaof 0.734 B. Since TX/mg NP . The resThe total PTX concentrations in plasma and lung following the administration of PTX solution, PTX-PLGA NPs and nano-MSCs were reasonably predicted using the developed PK models in both plasma and tumor-bearing lungs . The PK The overall goodness-of-fit plots indicated little evidence to reject the PK–PD model . The preSimulations were performed to examine the anticipated PK profiles following the administration of nano-MSCs. Following the administration of 5 µg PTX equivalent nano-MSCs, total PTX concentration, PTX concentrations in the form of PTX solution, PLGA NPs and nano-MSCs in both plasma and lung were simulated . Our simrelK  led to unsuccessful convergence of the model. As shown in In preclinical studies, subcutaneous tumor models are often used to study tumor growth for the purpose of optimizing the therapeutic benefits of newly developed cancer therapies. In these studies, calipers are frequently used to monitor tumor growths ,54,55, wNPperipheralV and NPKmax were estimated with relatively poor precision as shown in One limitation of the PK–PD model was that a few parameters related to PTX-PLGA NPs such as Given the complex composition of nano-MSCs, examining the PK profiles of different PTX components of this therapy experimentally is extremely difficult. Our simulations performed using the developed nano-MSCs–PK model provided mechanistic insights about the disposition of the three different forms of PTX as well as total PTX, following nano-MSCs administration. In tumor-bearing mice, following nano-MSCs administration, the relatively fast targeting, retention and extravasation of MSCs quickly deplete nano-MSCs from plasma to peripheral tissues, especially tumor-bearing sites. Nano-MSCs deliver large amount of PTX to tumor-bearing organ despite premature release of free PTX and PTX-PLGA NPs in systemic circulation . Subsequ6 nano-MSCs may increase the chance of forming cell clots within blood vessels and cause immediate death of experimental animals [6 MSCs  was simulated. It has to be noted that if animals can tolerate such multiple doses, it would result in complete tumor remission. However, the goal should be to improve the payload capacity of nano-MSCs so as to minimize dosing frequency to further improve their effectiveness. We believe that efficacy studies conducted with the simulated maintenance doses are needed to evaluate the practicability of the predicted dosing regimens and to validate the model predictions. We expanded our simulations of the PK–PD model to examine properties that may optimize the therapeutic potential of nano-MSCs. Achieving more sustained release of chemotherapeutic drugs could improve their therapeutic efficacy [Simulations performed using the developed PK–PD model can be useful in optimizing preclinical dosing regimens for nano-MSCs. Previous studies have suggested that cancer therapies, such as gefitinib and trametinib, can achieve a better therapeutic efficacy in treating certain types of cancer when administered in multiple low doses compared with a single high dose ,59. Howe animals ,61. Thusefficacy ,63. HoweThe mechanistic model developed closely captures the complex PK–PD behavior of nano-MSCs in an orthotopic A549 lung carcinoma model. The developed model provides an opportunity to examine the effect of various parameters to further optimize the therapeutic potential of nano-MSCs. The model also provides mechanistic insights regarding the in vivo kinetics of nano-MSCs and can help guide future preclinical study design. The modeling workflow illustrated by the development of the current PK–PD model can serve as a platform for developing a mechanistic model for nano-MSCs in other tumor models. This will further help to optimize the therapeutic efficacy and clinical translatability of nano-MSCs.


To estimate statewide presentation delay, misdiagnosis rate, inter-hospital transfer times and testicular salvage for testicular torsion patients treated in our state’s public health system. Case series of consecutive testicular torsion patients treated in our state’s public health system between 2012-2018. Predictors included presentation delay , facilitie’s level-of-care , first diagnosis , Doppler-enhanced ultrasound request (Doppler-US) and inter-hospital transfer times, with surgical organ salvage as the main response. We used Bayesian regression to estimate the effect of first examining facilitie’s level-of-care, first diagnosis, and Doppler-US on transfer time. 505 patients were included, most  with presentation delay >6 hours. Misdiagnosis at first examining facility raised transfer time from median 2.8 to 23.4 (epididymitis) and 37.9 hours (other) and lowered testicular salvage rates from 60.3% (torsion) to 10.7% (epididymitis) and 18.3% (other). Doppler-US had negligible effects on transfer time once controlling for misdiagnosis in the regression model. Although organ salvage in patients presenting before 6 hours at the tertiary facility was high , the overall salvage rate was more modest (46%). Our low overall testicular salvage rates originated from a large proportion of late presentations combined with long transfer times caused by frequent misdiagnoses. Our results indicate that efforts to improve salvage rates should aim at enhancing population-wide disease awareness and continuously updating physicians working at primary and secondary levels-of-care about scrotal emergencies. Intravaginal testicular torsion (henceforth testicular torsion) occurs when the testis rotates upon its axis inside the tunica vaginalis, twisting the spermatic cord or mesorchium   , 2  intSince irreversible ischemic injury swiftly follows testicular torsion, supplemental imaging studies are not required after clinical diagnosis. One must admit, however, the possibility of diagnostic uncertainty, mainly acute epididymitis and torsion of testicular appendages   , 5 . InWhile the time interval between symptoms and first medical assessment, i.e. presentation delay, rests upon the patient’s awareness of the disease and medical care availability   - 13 , dSince our tertiary unit is the referral center for testicular torsion patients within the public health network of our state - which grants database access for each patient’s entire medical history within the network, with time-stamps for each medical assessment - we may begin to fill this void in the urological literature. In this study, we set a two-fold goal. Firstly, to evaluate the relative roles of presentation delay and inter-hospital transfer time on testicular salvage; and secondly, to investigate the influence of the patient’s first clinical diagnosis and Doppler-US request on inter-hospital transfer time, especially on those examined shortly after symptoms, where expedient treatment is most decisive.After Institutional Board Review, all consecutive patients surgically diagnosed with testicular torsion in our tertiary facility between January 2012 and January 2018 were retrospectively identified from our unit’s data repository and were initially included in the study’s database. We retrieved each patient’s complete medical file - including assessments made outside our unit - for variable recovery. Since we did not have access to the time-stamps of patients first examined at private facilities or outside state borders, these were excluded from further analysis.Continuous predictors included patient’s age in years, and the following time intervals: presentation delay, defined as the time between symptom’s onset and first examination, and transfer time, defined as the time between first examination and assessment at the tertiary facility. The arithmetic sum of these sub-intervals was named treatment delay. Categorical predictors included: The level-of-care of the facility where the patient was first examined (first examining facility), as defined by the Brazilian Health Authority   : primarContinuous variables were summarized by their medians and interquartile range (IQR), and categorical variables by their frequencies. Differences between continuous variables were assessed with Kruskal-Wallis´ (KW) and Dunn’s tests, and we evaluated differences between categorical variables with Pearson’s Chi-Square (Chi-Square) or Fisher’s Exact (Fisher) tests, with statistical significance set at <0.05.Bayesian hierarchical linear regression models were implemented using level-of-care, first diagnosis, and Doppler-US as predictors and transfer time as the response variable. The posterior distributions of the parameters were graphically presented and summarized by their medians and 0.95 Highest Posterior Density intervals (HPDI).Computations took place within the R language statistical environment   , suppleIn this report we followed the Preferred Reporting of CasE Series in Surgery (PROCESS)   , 20  guSix-hundred and three patients were treated for testicular torsion during the study period. We excluded 72 (11.9%) patients examined in private institutions and 26 (4.3%) patients examined outside state boundaries from our analysis. Most remaining 505 patients  were first examined at secondary facilities , with significant differences between primary  and secondary facilities , and between primary or secondary versus tertiary facilities . Fifty-six (11.1%) were first diagnosed with epididymitis and 104 (20.6%) received another first diagnosis. Torsion was more often first diagnosed at the tertiary facility , compared to primary  and secondary facilities , more often in primary  and secondary facilities  than in the tertiary facility . Doppler-US was less frequently requested when the first diagnosis was torsion .Globally, Doppler-US requests were associated with longer presentation delays , a pattern reproduced at primary  and secondary level-of-care facilities . Longer - but not statistically significant-presentation delays were also associated with Doppler-US requests at the tertiary level .Transfer time was similar between primary and secondary facilities . Transfer times diverged, however, considering first diagnosis: Median transfer time for patients diagnosed with torsion was 2.8 hours (IQR 1.8-5.7), compared to 37.9 hours  for epididymitis and 23.4 hours  for other diagnoses. Transfer time was longer when Doppler-US was requested, rising from median 3.5 hours (IQR 1.9-11.1), when not requested, to 10.5 hours (IQR 4.2-53.8), when requested .The testis was surgically salvaged in 233 patients (46.1%). Although salvage rates were similar across levels-of-care , rates differed regarding patient’s subsets presenting before 6 and 3 hours: In the former time frame, 35/37 (94.6%) patients first examined at the tertiary facility had their organs salvaged, compared to 24/39 (61.5%) first examined at primary and 100/131 (76.3%) first examined at secondary facilities . Similar differences were observed in the subset of patients with presentation delay <3 hours, where all 11 patients first examined at the tertiary facility had their organs salvaged, contrasting with 18/25 (72%) and 50/65 (76.5%) in those first seen at primary and secondary facilities .Most patients first diagnosed with torsion had their organs salvaged , in contrast with those first diagnosed with epididymitis  or other . Salvage rates for 160 patients first diagnosed with torsion and presentation delay <6 hours were 73.3%, 90.3% and 94.3% for those respectively seen at primary, secondary and tertiary facilities. In the subset of patients first diagnosed with testicular torsion with presentation delay <3 hours, Doppler-US was associated with significantly lower salvage rates: 28/126 (22.2%) organs were salvaged when Doppler-US was requested, compared to 205/378  when it was not requested.Models were implemented for the whole dataset and patient’s subsets with presentation delay <6 and <3 hours, with 300.000 to 400.000 posterior distribution samples generated for each model. Testicular torsion misdiagnosis increased overall median transfer times by 53.2 hours . The highest salvage rates were observed among patients first examined at the tertiary facility shortly after symptoms.Most of our patients (59%) were first examined after 6 hours of symptom’s onset. Presentation delay has been reported as the leading cause of organ loss in testicular torsion   , havingEven if the patient rapidly seeks medical attention, the organ can still be lost if the first examining physician does not contemplate the diagnosis of testicular torsion. In our series, misdiagnosis was second only to presentation delay in determining the organ’s prognosis-especially in patients presenting before 6 hours of symptoms-by increasing median transfer time by more than a day on average. This influence of patient’s first diagnosis on transfer time remained even after accounting for Doppler-US in the regression model. Since the request for supplemental imaging studies must chronologically follow the patient’s first examination and initial diagnosis, this finding suggests that Doppler-US mainly acted as a mediator of the effects of first diagnosis on the outcome.Difficulties with the differential diagnosis of acute testicular disease could be addressed by the dissemination of a predictive tool such as the Testicular Workup for Ischemia and Suspected Torsion (TWIST) score   , 23 , wInter-hospital transfer may further delay treatment, with repercussions on salvage rates. In our study, even patients with presentation delay <3 hours and correctly diagnosed at primary or secondary facilities had salvage rates 10% lower than those first presenting at the tertiary facility. These findings agree with Bayne’s   , that rOur results show that there is much to improve in the care of our testicular torsion patients. Despite addressing the main cause of organ loss-long presentation delay-attempts to instruct the public about testicular torsion can be complex and expensive to implement, likely requiring large-scale information campaigns. Alternatively, educational efforts aimed at the medical community to increase knowledge about the disease and to improve its diagnosis could be less costly and produce faster results, as envisioned by Friedman and associates   . These In our series, only patients that presented at the tertiary facility shortly after symptoms had salvage rates >90%, which we attribute to our experience with this disease. Yet, we could not help wondering about the possibility of reproducing these results at the secondary level-of-care, as testicular torsion’s diagnosis is eminently clinical and its surgical treatment is not complex. Matter-of-fact, it was often performed by general surgeons before the consolidation of urologic specialty   . PatienThis study has many limitations. The main one, shared by all retrospective studies, is selection bias, since our database contained only surgically treated testicular torsion patients and did not provide means to identify those clinically treated for other acute scrotal diseases. Selection bias was manifested in the overall low proportion of Doppler-US requests, especially at the tertiary facility, where patients were first assessed by a team attentive to the recommendation to waive supplemental studies after testicular torsion was clinically diagnosed. Recall bias regarding presentation delay should also be considered, since information about symptom’s onset is patient/parent-provided, with inherent uncertainty that increases with time. Lastly, since our data comes from the smallest Brazilian state with the highest per capita income, further endowed with a structured public health network, we advise caution in generalizing our results.In this large statewide case series, we observed that most testicular torsion patients first presented, after considerable delay, at primary or secondary level-of-care facilities, where they were often clinically misdiagnosed. Misdiagnosis led to the increase in inter-hospital transfer time, and the cumulative effect of these extended presentation delays and transfer times led to a low overall organ salvage rate.This study provides relevant and previously unavailable contemporary information to apprise our medical - especially urological - communities to the real-world state-of-affairs of testicular torsion assessment and treatment at our public health care system. We hope that this study motivates other investigators to replicate our initiative, in order to provide a wider view of the current situation of testicular torsion care and determine where we should act to improve testicular torsion outcomes.


To determine possible modes of virus transmission, we investigated a cluster of coronavirus disease cases associated with a shopping mall in Wenzhou, China. Data indicated that indirect transmission of the causative virus occurred, perhaps resulting from virus contamination of common objects, virus aerosolization in a confined space, or spread from asymptomatic infected persons. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), is presumed to spread primarily via respiratory droplets and close contact. However, these transmission modes do not explain all cases. To determine how the virus may have spread among a cluster of COVID-19 cases associated with a shopping mall in Wenzhou (a city with 8 million residents), China, we monitored and traced close contacts and hypothesized possible transmission modes. We analyzed clinical and laboratory data for cases by using real-time reverse transcription PCR  sought care at a hospital after 11 days of fever and headache. On January 21, COVID-19 was confirmed for patient E and his co-worker, patient G. The Wenzhou Center for Disease Control and Prevention traced and tested their contacts, and by January 28, COVID-19 was confirmed for 7 persons (patients A–G) from the same office (on floor 7).https://www.medrxiv.org/content/10.1101/2020.02.06.20020974v1). Asymptomatic carrier transmission has been reported for SARS-CoV-2  days.The mall has 8 floors above ground and several basement levels; floors B1 to 6 are commercial shopping space, and floor 7 contains shopping and office space. We created an illustration showing the floors where the eventual COVID-19 case-patients worked or shopped, along with dates of symptom onset, potential incubation periods, symptom durations, confirmed times of positive diagnosis, and times of discharge , panel AExcept for those who had been on floor 7, all other case-patients denied direct close contact with other case-patients. The possibility of customers being infected from other sources cannot be excluded. However, most customers reported early symptom onset in a concentrated time frame , panel BUntil now, no evidence has shown that SARS-CoV-2 can survive outside the body for long. However, Middle East respiratory syndrome coronavirus demonstrates high robustness and a strong capability to survive outside the body and can remain infectious for up to 60 minutes after aerosolization  spreading the virus. However, according to screening protocols implemented by the Wenzhou Center for Disease Control and Prevention, we traced all close contacts and included all patients with positive PCR results, including the asymptomatic carrier (patient A), in this study. Our findings appear to indicate that low intensity transmission occurred without prolonged close contact in this mall; that is, the virus spread by indirect transmission.


The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs  combined with co-medications . Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm . After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib  and erlotinib . The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy . Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of primary lung cancers. In addition, most patients with NSCLC present with advanced or metastatic disease at the time of diagnosis. Recent research aiming at the treatment of NSCLC has been focused on the inhibition of epidermal growth factor receptor (EGFR) mutations through the administration of EGFR-tyrosine kinase inhibitors (TKIs). In terms of geographical distribution, the Asia–Pacific subgroup exhibited the higher frequency of EGFR mutation in patients with NSCLC (47%)2. Within this region, the highest and lowest frequencies of EGFR mutation in patients with NSCLC were observed in Taiwan (57%) and Singapore (40%), respectively. In NSCLC, > 90% of the known EGFR-activating mutations are exon 19 deletions and Leu858Arg mutations (L858R)3. EGFR mutations may result in constitutive activation of EGFR-tyrosine kinases, leading to cell proliferation or anti-apoptosis, regardless of the presence of extracellular ligands.Lung cancer is one of the leading causes of cancer death, with limited treatment options available for advanced-stage disease4. Three oral EGFR-TKIs, namely gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Giotrif), have recently been approved for first-line use in advanced patients with NSCLC harboring EGFR mutations. Gefitinib and erlotinib are first-generation EGFR-TKIs that reversibly inhibit EGFR. In contrast, afatinib is an irreversible EGFR-TKI, considered as a second-generation EGFR-TKI4. These three TKIs have shown improved response rates and progression-free survival (PFS) compared to first-line conventional platinum-based chemotherapy7. A recent phase III, randomized, controlled trial8, (LUX-Lung 7), revealed that afatinib exerted significant benefits in PFS compared to gefitinib in NSCLC patients with EGFR-activating mutations . However, phase III, randomized, controlled trials mainly enroll lung cancer patients with a good performance. Therefore, the effectiveness of TKI use in NSCLC patients presenting with impaired performance status (PS) in real-world clinical practice remains unclear. Other drugs that affect metabolism, such as statins9 and metformin10, have also been reported to have antitumor effects on NSCLC. Previous reports12 showed that antacids and corticosteroids use may compromise the clinical efficacy of EGFR-TKIs in advanced NSCLC patients. However, the real-world effects of co-medications use in patients with NSCLC receiving EGFR-TKI therapy remains unclear. The objective of the present study was to analyze the distinct effects of the three TKIs and co-medications use in NSCLC patients with EGFR mutations in a real-world setting.EGFR-TKIs have become the cornerstone therapy for patients with NSCLC harboring EGFR mutations, and are recommended as first-line treatment for patients with advanced NSCLC positive for EGFR mutationsThis study was conducted at Taipei Veterans General Hospital, a 3,000-bed tertiary referral hospital in Taiwan, treating approximately 800 newly-diagnosed cases of lung cancer per year. The stage of NSCLC was determined according to the 7th edition of the American Joint Committee on Cancer (AJCC) TNM staging system. Classical EGFR mutations were exon 19 deletion and point mutation of exon 21 (L858R). Other EGFR mutations included any other mutations of exon 18, 19, and 21. All three EGFR-TKIs have been reimbursed by the Taiwan National Health Insurance (NHI) program for the first-line treatment of patients with advanced NSCLC (stage IIIB or IV) with EGFR-activating mutations. Gefitinib, erlotinib, and afatinib have been used as first-line therapy since June 2011, November 2013, and May 2014, respectively. All methods were performed in accordance with the Declaration of Helsinki. Informed consent was waived because of the retrospective design and the analysis used anonymous clinical data. The present study was approved by the Institutional Review Board of Taipei Veterans General Hospital (VGHIRB NO: 2018-06-013CC).13. Following the re-evaluation, EGFR-TKIs could have been prescribed and reimbursed again by the Taiwan NHI program.The information of NSCLC patients treated with EGFR-TKIs reimbursed by the NHI program was externally reviewed by the NHI organization every 3 months. Chest computed tomography (CT) combined with other medical imaging modalities  were used to re-evaluate the disease status. The status of NSCLC was considered under control  according to the New Response Evaluation Criteria in Solid Tumors (RECIST) guidelinesWe conducted a retrospective analysis to evaluate the effects of three EGFR-TKIs as first-line treatment in patients with advanced NSCLC harboring EGFR mutations from January 2011 to December 2016. All patients underwent treatment at the Taipei Veterans General Hospital. Patient inclusion criteria were: (I) new or recurrent stage IIIB/IV NSCLC; (II) presence of somatic EGFR mutations; and (III) treated with EGFR-TKIs as first-line therapy for ≥ 3 months. Patient exclusion criteria were: (I) age < 20 years; (II) diagnosis of other cancer prior to lung cancer diagnosis or within 1 year after lung cancer diagnosis; and (III) negative or lack of EGFR mutation analysis. All patients were followed up until the date of death, or 31 December 2017, or the end of the 2-year follow-up period, whichever occurred first.In the analysis of the effects of EGFR-TKI administration on disease control, age, sex, smoking status, AJCC TNM stage, EGFR mutation types, baseline brain metastases (BM), Eastern Cooperative Oncology Group PS (ECOG PS) score at the time of lung cancer diagnosis, initial radiotherapy (RT), DCCI, and co-medications were considered to be potential confounders.Baseline BM was used to identify patients with BM prior to the administration of EGFR-TKIs or within 1 month after receiving EGFR-TKI treatment. Initial RT meant that patients received RT within 3 months after the administration of EGFR-TKIs. Comorbidities were defined as those diagnosed in patients prior to the initiation of EGFR-TKI therapy.14.Information on co-medications was extracted to analyze the effects of EGFR-TKI therapy on disease progression and mortality. The four groups of co-medications were: glucocorticoids ; antacids ; statins ; and metformin. Patients prescribed ≥ 28 cumulative defined daily doses (cDDDs) of each group of co-medication within the first 3 months of receiving EGFR-TKI therapy were assigned to respective co-medication groups. The DDD of each co-medication was estimated in accordance with 2017 ATC/DDD WHO IndexIn this study, NSCLC was pathologically confirmed by a bronchoscopic- or computed tomography (CT)-guided biopsy, and/or surgical resections. The EGFR mutation status of tumors was determined through analysis of DNA extracted from formalin-fixed, paraffin-embedded, archival tumor tissues. EGFR mutation analysis was performed using polymerase chain reaction-direct sequencing and scorpion/amplified refractory mutation system technology. The diagnosis of NSCLC in this study was externally reviewed by the NHI organization. Moreover, the EGFR mutation status must be reviewed by the NHI organization. Therefore, in this study, the diagnosis of NSCLC and the EGFR mutation status was reliable and exhaustive.The primary endpoint was time to treatment failure (TTF). TTF was defined as the time from the first day of EGFR-TKI administration to the date of treatment failure. In this study, treatment failure was defined as the date of EGFR-TKI discontinuation, judged by the treating physicians. The secondary endpoints were overall survival (OS) and BM-free survival. OS was defined as the time from the first day of EGFR-TKI treatment initiation to all-cause death or lost to follow-up, or the end of the follow-up period. BM-free survival was defined as the time from the first day of EGFR-TKI treatment initiation to the day of detection of new BM in NSCLC patients without baseline BM at the time of enrollment.2 test. Survival was assessed using the Kaplan–Meier curves, and the log-rank test was used to compare differences between groups. The HR and 95% CI of the risk of treatment failure and mortality and new BM among different EGFR-TKI groups were calculated using the Cox proportional hazards regression analysis. The factors used as covariates in the multivariate Cox proportional hazards model are shown in Supplementary Table All data are expressed as mean ± standard deviation (SD) or percentage (%), unless otherwise stated. Differences in continuous variables between the three EGFR-TKI groups were compared using analysis of variance. Differences in categorical variables were compared using Pearson’s χWe identified 1,285 patients with NSCLC diagnosed between 1 January 1997 and 31 December 2012, who received EGFR-TKIs as first-line treatment for ≥ 3 months. Patients with other types of cancer prior to or within 1 year after the diagnosis of NSCLC (n = 278), those aged < 20 years, and those with negative or lack of EGFR mutations analysis (n = 154), were excluded from the analysis. The final study population consisted of 853 NSCLC patients, who received first-line treatment with gefitinib (n = 534), erlotinib (n = 220), or afatinib (n = 99)  and most patients had stage IV disease (96.1%) and adenocarcinoma (94.1%). Among the study groups, patients receiving gefitinib (66.8 years) were significantly older than those treated with erlotinib (63.0 years) or afatinib (64.1 years). There were no differences in the stage of disease, pathology report, initial RT, and DCCI between the groups. The gefitinib group had a higher prevalence of females and an ECOG PS score ≥ 2 compared to the other groups. The erlotinib group had a higher prevalence of L858R mutation, baseline BM, and initial RT compared to the other groups. The afatinib group had a higher prevalence of smokers and exon 19 deletion compared to the other groups.The co-medications prescribed to the three groups are shown in Supplementary Table Other EGFR mutations , and ECOG PS ≥ 2 , and baseline BM  were identified as independent risk factors of treatment failure in NSCLC patients with EGFR-activating mutations who received EGFR-TKIs as first-line treatment. In contrast, age ≥ 65 years  and female sex  were associated with significantly lower risks of treatment failure  and erlotinib  in NSCLC patients with EGFR-activating mutations. However, there was no difference observed in risk of treatment failure between gefitinib and erlotinib in NSCLC patients with EGFR-activating mutations  in patients treated with afatinib compared to those observed following treatment with gefitinib as first-line therapy in NSCLC patients harboring EGFR-activating mutations (HR 0.73). The results of the present study are consistent with those of the LUX-Lung 7 trial. The administration of afatinib was associated with prolonged TTF versus gefitinib . In addition, use of afatinib was associated with prolonged TTF in NSCLC patients with exon 19 deletion versus those with L858R . This finding was also consistent with the results of the LUX-Lung 36, LUX-Lung 67, and LUX-Lung 78 trials. In this study, the TTF in the afatinib group was significantly longer than that calculated for the gefitinib group in most subgroup analyses after adjustments for all covariates. This finding is consistent with the findings of the LUX-Lung 7 trial, indicating the superiority of afatinib over gefitinib8.The LUX-Lung 7 trial15 involving 448 patients with advanced NSCLC and EGFR-activating mutations who received EGFR-TKIs as first-line therapy showed that afatinib and erlotinib exerted significant benefits in PFS compared to gefitinib. As expected, in this study, the administration of afatinib and erlotinib was associated with prolonged TTF and OS compared with those observed following the administration of gefitinib. However, there was no difference observed in BM-free survival between the three EGFR-TKI groups.Erlotinib has not been compared with afatinib in randomized controlled trials. To the best of our knowledge, this was the first study showing that use of afatinib was associated with prolonged TTF compared with that observed following the use of erlotinib. After adjustment, afatinib showed lower risk of treatment failure compared with erlotinib  in most subgroup analyses. A Taiwanese retrospective cohort study16 and statins17 in decreasing the risk of cancer occurrence in humans. Observational data suggest that the use of metformin18 and statins9 may decrease the incidence of lung cancer and mortality. Mevalonate is the product of HMG-CoA via HMG-CoA reductase. Mevalonate metabolites have been shown to play a role in EGFR signaling pathway. There is some suggestion that HMG-CoA reductase inhibitors (statins) and EGFR-TKIs may act cooperatively to target EGFR-mediated signaling19. Metformin use may overcome the acquired resistance to EGFR-TKI in NSCLC. Metformin is able to synergize with other treatment in NSCLC including targeted therapy, chemotherapy and radiotherapy20.Emerging evidence indicates the potential role of metformin21, involving 90 patients with advanced NSCLC and EGFR-activating mutations, found that patients who received EGFR-TKI plus metformin were linked to prolonged PFS and OS than those treated with EGFR-TKI monotherapy. However, that study was limited by a small sample size and the retrospective design. In the present study, the combination of metformin with EGFR-TKIs did not prolong PFS and OS after adjusting for all covariates.Several studies have been conducted to evaluate the effect of metformin or statins in combination with EGFR-TKIs on the prognosis of NSCLC patients. A small Chinese retrospective cohort study22. In another study, EGFR-TKIs (erlotinib or gefitinib) plus statins (atorvastatin or simvastatin) prolonged PFS in patients with advanced NSCLC harboring KRAS mutations23. However, the effect of a regimen combining statins plus EGFR-TKIs in patients with advanced NSCLC and activating EGFR mutations remains unclear. In a retrospective, nationwide, longitudinal cohort study24, administration of statin was associated with prolonged PFS and OS in patients with lung cancer receiving treatment with EGFR-TKIs. However, data on the pathology, AJCC TNM stage of lung cancer, BM, EGFR mutation status, and PS were not available in that study. In contrast, in the present study, these data were available. After adjustment for all factors, use of statins was not associated with prolonged TTF and OS in advanced NSCLC patients with EGFR-activating mutations who received first-line therapy with EGFR-TKIs. However, only 4.7% and 4.5% of the enrolled patients used metformin and statins, respectively. The detection power of this study may not be sufficient to detect the beneficial effects of metformin and statins.The combination of gefitinib with statins was shown to improve the response rate and PFS in previously treated patients with wild-type EGFR nonadenocarcinomas25. A retrospective population-based study26 demonstrated a possible negative clinical effect stemming from the co-administration of erlotinib and antacids. Of note, in that study26, patients were unselected for activating EGFR mutations. Two retrospective cohort studies27, involving 157 and 130 patients treated with erlotinib or gefitinib, respectively, for the treatment of EGFR mutation-positive advanced NSCLC have been conducted. These studies showed that the combination of EGFR-TKIs with antacid did not affect the efficacy of erlotinib and gefitinib. Our study corroborated this finding i.e., treatment with antacids did not alter the effectiveness of EGFR-TKIs on PFS and OS.EGFR-TKIs show physiological pH-dependent solubility, which may be susceptible to drug–drug interactions in the presence of antacids12. A systematic review of randomized controlled trials involving glucocorticoid therapy indicated that patients with lung cancer receiving concomitant use of chemotherapy and glucocorticoids had worse outcomes than those who received chemotherapy alone28. However, the effect of glucocorticoids on the efficacy of EGFR-TKIs in patients with advanced lung cancer and EGFR-activating mutations remains unclear. In this study, we found that the concomitant use of glucocorticoids may reduce the efficacy of EGFR-TKIs in such patients. The results of the subgroup analyses were consistent with this finding. Other possible explanations for the higher risk of treatment failure and mortality associated with the use of glucocorticoids may be related to disease severity. In addition, excessive use of glucocorticoids has been associated with poor control of obstructive pneumonitis and BM, which may be the cause of this increased risk. Regardless of the causal nature of this association, chronic use of glucocorticoids is a powerful marker of high mortality risk in patients with lung cancer. Therefore, such patients warrant special attention.The use of glucocorticoids in the treatment of NSCLC remains controversial. The concomitant administration of glucocorticoids may reduce the efficacy of chemotherapy in patients with lung cancerThe present study had several limitations. Firstly, we were unable to ascertain information on adverse events, which were not consistently recorded in administrative claims data. Secondly, our study used a retrospective design from the claims database of a tertiary referral hospital in Taiwan. Prospective studies are necessary to validate the present findings. Thirdly, we must acknowledge the lack of information on certain confounders . The reasons for co-medication prescriptions are usually not explicitly documented in the patient record. Additionally, patients who expired or switched to other treatment due to disease progression within 3 months were excluded in this study. The results of our study might not reflect the real-world efficacy of three EGFR-TKIs as first-line treatment in patients with advanced NSCLC harboring EGFR mutations. Finally, the generalizability of our findings may be questionable, considering that almost all patients included in this study were Taiwanese. Future studies are warranted to verify these findings in non-Asian populations.This study demonstrated that administration of afatinib was associated with a lower risk of treatment failure compared to that observed following the administration of erlotinib and gefitinib in patients with advanced NSCLC harboring EGFR mutations. Moreover, the use of afatinib and erlotinib was associated with a lower risk of all-cause mortality compared to that observed following the use of gefitinib. The concurrent use of systemic glucocorticoids with EGFR-TKIs was associated with a higher risk of treatment failure and mortality. Further well-designed prospective studies, focusing on distinguishing the effects of different EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations, are warranted.Supplementary Information.


BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality worldwide. Knowledge about the pathophysiology of the disease and its effect on multiple systems is growing. Kidney injury has been a topic of focus, and rhabdomyolysis is suspected to be one of the contributing mechanisms. However, information on rhabdomyolysis in patients affected by COVID-19 is limited. We aim to describe the incidence, clinical characteristics, and outcomes of patients hospitalized with COVID-19 who developed rhabdomyolysis.Materials and methodsA retrospective observational cohort consisted of patients who were admitted and had an outcome between March 16 to May 27, 2020, inclusive of those dates at a single center in the Bronx, New York City. All consecutive inpatients with lab-confirmed COVID-19 were identified. Patients with peak total creatine kinase (CK) over 1,000 U/L were reviewed; 140 patients were included in the study. The main outcomes during hospitalization were new-onset renal replacement therapy and in-hospital mortality.ResultsThe median age was 68 years (range: 21-93); 64% were males. The most common comorbidities were hypertension (73%), diabetes mellitus (47%), and chronic kidney disease (24%). Median CK on admission was 1,323 U/L . Median CK on discharge among survivors was 852 . Median creatinine on admission was 1.78 mg/dL (IQR: 1.23 - 3.06). During hospitalization, 49 patients (35%) received invasive mechanical ventilation, 24 patients (17.1%) were treated with renal replacement therapy (RRT), and 66 (47.1%) died.ConclusionsRhabdomyolysis was a common finding among hospitalized patients with COVID-19 in our hospital in the Bronx. The incidence of new-onset renal replacement therapy and in-hospital mortality is higher in patients who develop rhabdomyolysis. McMahon score, rather than isolated creatine kinase levels, was a statistically significant predictor of new-onset RRT. Clinicians should maintain a high level of suspicion for rhabdomyolysis in COVID-19 patients throughout their admission and use validated scores like McMahon score to devise their treatment plan accordingly. Rhabdomyolysis is a syndrome characterized by skeletal muscle breakdown with the resultant release of intracellular contents into the bloodstream leading to systemic complications, most commonly acute kidney injury (AKI). Creatine kinase (CK) is the most sensitive indicator of muscle damage and has been used for laboratory confirmation of rhabdomyolysis . It has There are multiple causes of rhabdomyolysis. Viral infections causing rhabdomyolysis are more common in the pediatric population but have been reported frequently also in adults. Many viral, bacterial, fungal, and protozoal infections have been associated with rhabdomyolysis, of which influenza A is the most commonly implicated . More reThe world is currently facing a global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding of the full spectrum of coronavirus disease 2019 (COVID-19), the disease caused by the new virus, is evolving. Since the beginning of the pandemic, it was noted that CK elevation above the upper limit of normal >185 U/L) correlated with severe disease and increased mortality . In one  U/L corrKidney involvement is common in COVID-19. The spectrum ranges from mild proteinuria to progressive AKI requiring renal replacement therapy (RRT) . The patA better understanding of the incidence of rhabdomyolysis in COVID-19 patients and its clinical implications is important to fully appreciate the spectrum of damage caused by the virus and guide decision making regarding fluid management and prognostication. Our study aims to shed light on the burden of rhabdomyolysis in COVID-19 patients and to describe the demographic and clinical characteristics, laboratory findings, and outcomes among patients who presented with or developed this condition during their admission in a hospital at one of the hardest hit boroughs of New York City.This is a retrospective observational cohort study. We obtained data from a teaching hospital  in the Bronx borough of New York City on hospitalized patients and had an outcome between March 16 and May 27, 2020. Patients were found by applying search criteria to the hospital’s electronic medical records (EMR) registry. We then obtained information by manual chart review on patient demographics , presenting symptoms, vital status at hospital discharge, electronic discharge summaries, and inpatient laboratory values. Approval for this study was granted by the institutional review board at Albert Einstein College of Medicine; the need for informed consent was waived because of the retrospective nature of the study.Inclusion criteria were age older than 18 years, lab-confirmed COVID-19 , and peak total CK level more than 1,000 U/L during hospitalization. We excluded patients with end-stage renal disease (ESRD) and those who had evidence of a secondary cause of rhabdomyolysis, including seizures, acute coronary syndrome or crush injuries prior to admission. Primary outcomes were in-hospital mortality and new-onset RRT. The only RRT modality offered in our campus was intermittent hemodialysis.AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria . BaselinEight-hundred twenty-five patients were admitted to MMC Wakefield hospital during the study period with laboratory-confirmed COVID-19. One-hundred sixty-five patients (17%) met the criteria for rhabdomyolysis diagnosis  during their admission. Twenty-five patients were excluded based on exclusion criteria mentioned prior; 140 patients were included in the study.This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient-relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.Descriptive statistics were used to summarize the data; results are reported as medians and interquartile ranges (IQR) or means and standard deviations, as appropriate. Categorical variables were summarized as counts and percentages. Univariate logistic regression was used to assess the effect of demographics, comorbidities, laboratory data, and invasive mechanical ventilation on mortality and new-onset RRT; multivariate models were created including all variables with univariate p-values <0.2. All statistical analyses were performed using SPSS statistics software . No imputation was made for missing data.Demographic and clinical characteristicsDemographics and clinical characteristics of our patients are shown in Table Laboratory resultsLaboratory data during hospitalization are summarized in Table OutcomesOut of the 140 patients who were included in this study, 74 (52.9%) were discharged, and 66 (47.1%) died in the hospital. One-hundred-and-twelve patients (80%) developed AKI, twenty-four (17.1%) of which required RRT. Five patients were planned for RRT but expired prior to RRT initiation or family refused RRT. All patients planned for RRT were included in the final analysis. Results of our univariate and multivariable logistic regression model for mortality and new-onset RRT are summarized in Tables Outcomes as compared to MMC Wakefield COVID-19 admissions who had peak CK less than 1,000 U/L during the same period are summarized in Table Most patients  in our cohort met the definition of rhabdomyolysis  within the first week of admission, while seven patients developed rhabdomyolysis during their second week of admission. Notably, all seven patients were intubated. In total, 49 patients (35%) were intubated and mechanically ventilated. The mortality rate among intubated patients was 79.2%.This study represents the first observational study providing a snapshot of the burden of rhabdomyolysis among COVID-19 patients admitted to one hospital in one of the most affected boroughs at the pandemic epicenter.Patients who developed rhabdomyolysis had higher rates of mortality and new-onset RRT as compared to COVID-19 patients with peak CK less than 1,000 U/L. However, based on our logistic regression models, CK levels on admission and peak CK levels were not found to be statistically significant predictors of either new-onset RRT or mortality in our study group. McMahon’s score on admission had the strongest correlation with new-onset RRT, highlighting its prognostic value in COVID-19 patients with rhabdomyolysis as well as its role in guiding the initiation of renal protective therapies. Other statistically significant predictors of new-onset RRT were young age, diabetes mellitus, hypertension, and admission creatinine. We suspect a young age was a significant predictor because younger patients were more likely to receive more aggressive treatment modalities, including RRT.In our multivariate model for mortality, age, dementia, peak C-reactive protein (CRP) levels, and mechanical ventilation were found to be statistically significant predictors of mortality. These findings support recent reports correlating age, CRP levels, and dementia with mortality -17. CRP The mechanism of muscle damage in viral infections, particularly COVID-19, is not fully understood. Proposed hypotheses include direct and indirect mechanisms. The first theory is via direct viral muscle invasion. Angiotensin-converting enzyme 2 (ACE2), which was identified as the functional receptor for SARS-CoV and SARS-CoV-2, is present in skeletal muscles -19. SARSSerum CK usually begins to rise approximately two to 12 hours after onset of muscle injury, peaks within 24 to 72 hours, and then declines gradually over 7-10 days unless there is continuing muscle injury or development of compartment syndrome -9. Most Our study had several limitations. First, all data were retrospectively obtained from electronic medical records, so some demographic and clinical data were missing. Second, we were unable to retrieve data pertaining to treatments given to the patients, especially the rate and timing of intravenous hydration. Obtaining accurate fluids data retrospectively would be challenging. Third, the only RRT modality offered in our campus was intermittent hemodialysis, limiting access for hemodynamically unstable patients. Fourth, resource allocation during a time of crisis like this pandemic might have resulted in a lack of hemodialysis treatment or shortened hemodialysis time, which could have impacted mortality rates. Fifth, for some predictors of outcomes in our models, the confidence interval was very wide, likely secondary to small sample size. Larger studies are warranted.In conclusion, rhabdomyolysis is an important aspect of the multifaceted nature of COVID-19 and is likely underreported. CK levels in isolation might not correlate with outcomes, so clinicians are encouraged to use validated scores like McMahon score to better predict outcomes and guide treatment decisions for patients who develop rhabdomyolysis, most importantly their fluid management, which can be challenging in patients with impending respiratory failure and should be decided on a case-by-case basis.


To the Editor—Italy has been hard hit by coronavirus disease 2019 (COVID-19), mostly in the northern regions,1 while the Lazio region was partially spared. Although no evidence thus far has shown vertical transmission,3 neonatologists are concerned about preventing the spread of infection-related disease (COVID-19) in infants and healthcare workers (HCWs) of neonatal intensive care units (NICUs).4 Here, we report our NICU’s reorganization during the COVID-19 pandemic.5This observational study focused on infants admitted to our tertiary-care–level NICU during the COVID-19 outbreak in Italy from March 15 to May 15, 2020. Severe acute respiratory coronavirus virus 2 (SARS-CoV-2) was ruled out by nasopharyngeal swab in all infants before NICU admission. Detection of SARS-CoV-2 was performed using the Allplex 2019-nCoV assay  as previously described.Nasopharyngeal swabbing was performed at referring center in stable neonates. SARS-CoV-2–positive neonates were managed in a dedicated pediatric COVID-19 unit. If the swab test was negative, the newborn was referred to our non–COVID-19 NICU as usual by neonatal emergency transport service (NETS) staff. For untested babies, accurate telephone contacts between spoke and hub centers were crucial to assuring the safest pathway for admission. Newborns were managed by HCWs wearing surgical masks (when COVID-19 was not suspected and/or mothers were negative within 24 hours of life) or N95 masks (in case of suspected or confirmed SARS-CoV-2–positive newborns), gloves, eye protection, and gowns. Upon arrival at our hospital, newborns were isolated and temporarily managed by an NETS dedicated neonatologist and nurse in a separate pavilion. The staff were equipped with personal protective equipment until the negative result of the nasopharyngeal swab for SARS-CoV-2 arrived. Thereafter, the neonate could be hospitalized in our NICU in a room with other infants.Infants admitted to the emergency department (ED) were tested for SARS-CoV-2 on arrival and remained there until the negative result was available prior to NICU admission.6 Kangaroo-mother care has always been performed in our NICU. Through the institutional database, we identified all subjects hospitalized during this period and retrospectively analyzed medical records. As nasopharyngeal swab was requested by the health directorate of our institution, and no approval from our institution’s ethical committee was required for this study.In the NICU, disposable surgical masks were always required for HCWs; body temperature was measured every day for all HCWs. Parental visits are still restricted to 6 hours each day, and only 1 parent is allowed for each baby, after signing a self-certification regarding fever, symptoms, and contacts. All parents are required to wear masks, gloves, and disposable clothing. If they have fever or respiratory symptoms the visit to the baby is forbidden, as reported in Veneto.During the study period, 101 newborns required NICU admission; of these, 71 newborns were referred from other institutions and 30 infants who were firstly discharged from other institutions and then required rehospitalization were admitted from the ED , who required hospitalization because of urinary tract infection, tested positive via nasopharyngeal swab test for SARS-CoV-2. Considering his stable conditions, the infant was hospitalized in the dedicated pediatric COVID-19 unit and not in NICU; a neonatologist gave requested advices for the appropriate management. No COVID-19 cases were registered in infants hospitalized in the NICU under the adopted procedures and avoiding any contact with COVID-19 cases. No HCWs acquired COVID-19.1 Although concern about COVID-19 severity is less in children,7 the amount of SARS-CoV-2 viral material that could be potentially harmful in neonates remains unknown, especially in preterm infants.2 Therefore, strict preventive measures should be adopted in all NICUs. The relative ease of horizontal transmission, even within a controlled NICU, has been highlighted.8One of the lessons learned from the COVID-19 pandemic in Italy is that hospital overcrowding was a serious mistake that led hospitals to become the first places to spread the infection.9 which is especially important in an outborn NICU such as ours. However, none of the infants referred from other institutions tested positive for SARS-CoV-2 during the study period. On the contrary, infants admitted from the ED, including the sole neonate who screened positive for SARS-CoV-2, had a higher age at admission and thus they had potentially been more exposed to the community. Differences between the 2 groups were not calculated because of the small sample size and a sole neonate who tested positive. The main limitation of our study was the single center site in a medium-risk region, and 70% of these cases were registered in northern Italy. However, the procedures outlined here allowed us to ensure continuity of care in the NICU, with limited risks of infection for newborns and HCWs. Although no newborns screened positive among NICU patients in the higher-risk Veneto region,6 by testing all newborns before admission, we could have separated a positive neonate from other fragile infants, avoiding life-threatening risks for them and the incalculable costs of spreading the virus to the unit. The fight against the COVID-19 pandemic should not affect the quality of the assistance to high-risk infants. Therefore, we conclude that all newborns should be tested for SARS-CoV-2 before being admitted to NICUs, especially if admitted from an ED.Our NICU is a referral care center for severely ill neonates, with a delivery room only for highly selected patients. Therefore, almost all babies are referred from Rome and Lazio, and other regions either as a planned or an emergency admission because of a variety of high-risk conditions: surgical emergencies, congenital heart defects, perinatal asphyxia, prematurity, genetic syndromes, infections, metabolic disorders, etc. NETS play a key role in minimizing the risk of contamination from one institution to another,


Chronic liver diseases are common worldwide, especially in developing countries. The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/(COVID-19) leads to the infection of many patients with underlying chronic liver diseases. As a relatively new disease, management of COVID-19, in the context of chronic liver disease, is mainly based on the experience of the treating physician and the available data. In this review, we summarize the available evidence about the management of liver disease patients, in the context of COVID-19 infection, which can increase the severity of viral hepatitis B. Also, its clearance in HBV patients is delayed. A sixfold increased severity of COVID-19 was reported in obese patients with metabolic associated fatty liver disease (MAFDL). In patients with autoimmune liver disease (AILD), it is not recommended to change their immunosuppressive therapy (as long as they are not infected with COVID-19), in order to avoid a flare of liver disease. However, immunosuppressant drugs should be modified, in the case of infection with COVID-19. To date, no data suggest an increased risk or severity in metabolic liver diseases, such as hemochromatosis, Wilson’s disease, or alpha-1 antitrypsin deficiency. Patients with liver cirrhosis should be carefully managed with minimum exposure to healthcare facilities. Basic investigations for follow-up can be scheduled at wider intervals; if patients need admission, this should be in COVID-19-clean areas. Patients with hepatocellular carcinomas may have a poor prognosis according to preliminary reports from China. The course of COVID-19 in liver transplant recipients on immunosuppression seems to have a benign course, based on few reports in children and adults. The hepatotoxicity of COVID-19 drugs ranges from mild liver enzyme elevation to a flare of underlying liver diseases. Therefore, the decision should be customized. Telemedicine can minimize the exposure of healthcare workers and patients to infection with COVID-19 and decrease the consumption of personal protective equipment. The recently discovered coronavirus COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has proven its pathogenicity to different organs including (but not limited to) respiratory, gastrointestinal, hematopoietic, renal, and cardiovascular systems 9 caused . Liver dThere are relatively low screening rates for the most common viral hepatitis, HBV, and HCV in most diagnosed COVID-19 cases, especially in low and middle socioeconomic countries. Active screening is crucial for studying the clinical and epidemiological manifestations that could negatively affect public health efforts . A 3% prMoreover, a Chinese single-center retrospective study observed that 12.2% of 123 COVID-19 patients had HBV infection, and they developed a more severe course relative to HBV-negative patients and had higher total bilirubin levels (46.7% versus 24.1%); the mortality rate is 13.3% versus 2.8%, respectively . MoreoveKarimi-Sari and Rezaee-Zavareh noticed that hepatitis-related research articles published in PubMed, for example, during the COVID-19 era, are markedly decreased; this may clarify our idea about the impact of COVID-19 on the elimination programs of viral hepatitis . Some reA recent study reported that non-alcoholic fatty liver disease (NAFLD) was more prevalent in patients with severe compared with those with non-severeCOVID-19 illness . MAFLD  scores were older and more obese and have a higher prevalence of diabetes, a higher level of liver enzymes, a higher level of C-reactive protein (CRP), and a lower level of lymphocyte count compared to patients without MAFLD or with low FIB-4 scores. Moreover, patients with MAFLD and increased scores of fibrosis were more likely to have severe COVID-19 illness, irrespective of the presence of metabolic abnormalities. In the same context, the presence of severe fibrosis in patients with MAFLD may exacerbate the virus-induced cytokine storm . In anotThe dysregulated hepatic innate immunity in patients with MAFLD may contribute to the pathogenesis of COVID-19. Abundant expression of ACE2 receptors was found in the enterocytes of the small intestine. This could be another portal of entry to COVID-19. In this context, one quarter of the COVID-19 patients are complaining of gastrointestinal manifestations, such as diarrhea and abdominal pain, without cough with positive COVID-19 RNA in fecal and respiratory specimens concomitantly . ObesityMinimizing the dosage of high-dose prednisone but maintaining a sufficient dosage to avoid adrenal insufficiency.Reducing azathioprine or mycophenolate dosages, especially in the setting of lymphopenia, fever, or worsening pneumonia attributed to COVID-19.Reducing, but not stopping, daily calcineurin inhibitor dosage, especially in the setting of lymphopenia, fever, or worsening pulmonary status attributed to COVID-19 .Autoimmune liver disease (AILD) is a group of diseases that include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and overlap syndrome. Although the diagnosis of AIH is based on histological abnormalities (interface hepatitis), characteristic of clinical and laboratory findings (elevated AST and ALT levels and increased serum IgG concentration), and the presence of one or more characteristic autoantibodies –36, the No need to adjust the dose of immunosuppressive drugs in patients without COVID-19.For patients with mild to moderate COVID-19, keep current immunosuppressant dosage and closely monitor the patient’s condition. Avoid prescription of medications that cause significant fluctuations in tacrolimus plasma concentrations.For patients with severe or rapidly progressing COVID-19, reduce the amount of calcineurin inhibitor and consider stopping anti-metabolic drugs as mycophenolate and azathioprine.If decided to reduce the dose of steroids, keep at least a daily dose of 10 mg prednisone or equivalence to avoid adrenal insufficiency.Corticosteroids or other immunosuppressive therapies can be re-initiated with caution when the potential benefits outweigh their discontinuation .A more detailed recommendation report about the management of patients on immunosuppressive medication was published by the Beijing Working Team for liver transplantation. Although it is targeting liver-transplanted patients, it can be applicable to AILD patients on immunosuppressive therapy. The recommendations were as follows:Patients with AILD, who have cirrhosis or one of it is complications, should be treated according to the recommendation of treatment of complications of cirrhosis during the COVID-19 epidemic .https://www.haemochromatosis.org.uk/cornonavirus-update-march-2020).In light of previous evidence, people with genetic hemochromatosis are not at increased risk of contracting COVID-19 infection. So, the only risk of infection depends on the patient’s behavior with the best protective measures being to stay home and practice social distancing. However, the most critical question is whether this particular category of patients will be at high risk of complications, if they contract COVID-19 infection , , [Venesection must be delayed if the patient contracts coronavirus infection or is self-isolated; in this case, the patient has to avoid attending to his general practitioner or the hospital or even to blood donation centers to avoid transmission of infection to others, including the medical teams. If the patient is in good health, he can attend his session of venesection unless he has been instructed by the local health authority not to attend (h-2020), .Wilson’s disease does not appear to increase the risk of contracting COVID-19. There is a common belief between scientists, with insufficient evidence, that patients with well-controlled Wilson disease are not highly susceptible to COVID-19 than the general population. As COVID-19 is a novel virus, its interactions with people with Wilson disease have not been specifically studied; however, people at increased risk of complications are those with advanced age, severe liver, heart disease, and renal failure or comorbid disease. Therefore, theoretically speaking, this special category of patients, if they have liver cirrhosis or severe comorbid disease, is at increased risk of complications , 51–53.Patients with Wilson disease are strictly advised not to stop their medications to avoid exacerbation of the disease. Dose adjustment may be considered, if copper control is excellent and low copper status causes a decrease of white blood cells after consultation with the treating physician , 53.Since COVID-19 primarily causes fever and respiratory symptoms and often leads to pneumonia in exposed people, people with alpha-1 are more likely to be particularly vulnerable to coronavirus infection. Alpha-1 deficiency affected lung disease, or those who have had a lung transplant are among the groups that are most at risk of severe complications, if they become infected . This paThe following guidelines were recommended for the management of patients with liver cirrhosis, during the COVID-19 pandemic, by the latest European Association for the Study of the Liver (EASL) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) position paper .Visits to specialized liver centers can be postponed, and these centers should provide accessible contact information for local healthcare providers to facilitate good co-operation in the management of patients with liver cirrhosis.Use telemedicine consultations, by phone, wherever possible.Routine follow-up laboratory testing can be performed locally, e.g., through primary care physicians; its frequency needs careful individual risk-benefit considerations.Hepatocellular carcinoma (HCC) surveillance: abdominal ultrasound examination can be deferred based on available resources (including the availability of therapeutic options in case of HCC diagnosis), at the center and the individual risk assessment. Patients with increased risk, such as patients with elevated alpha-fetoprotein levels and advanced cirrhosis with chronic hepatitis B virus infection, may be prioritized if resources are limited .Screening for varices: depending on available resources, screening for varices by esophagogastroduodenoscopy (EGD) should be reserved for patients at risk of variceal bleeding, such as patients with a history of variceal bleeding or signs of significant portal hypertension . Non-invasive risk assessment for the presence of varices can be used to stratify the portal hypertensive status of the patients .Guidelines on prophylaxis of spontaneous bacterial peritonitis and hepatic encephalopathy, in patients with decompensated cirrhosis, should be carefully followed to prevent decompensation and avoid hospital admission during this pandemic.Include testing for SARS-CoV-2 in any patients with acute decompensation of their liver status or patients with acute on top of chronic liver cell failure.Emphasis on the importance of vaccination of the patients for streptococcus pneumonia and influenza.Outpatient care:Many patients will require inpatient care during the COVID-19 pandemic for decompensation or other complications like variceal bleeding, spontaneous bacterial peritonitis, and hepatic encephalopathy. General measures to prevent SARS-CoV-2 exposure and infection will be of utmost importance for these patients. Depending on the local infrastructure, the implementation of COVID-19-clean wards or hospitals is warranted. Wherever possible, patients with liver cirrhosis requiring inpatient care for non-COVID-19 causes should be admitted to COVID-19-clean wards or hospitals .Inpatient care:Consider early admission according to the presence of additional risk factors and inclusion in clinical trials and  antiviral therapy of COVID-19 following local guidelines.Treatment for cirrhosis-associated complications, such as portal hypertension, ascites, hepatic encephalopathy, and spontaneous bacterial peritonitis, should be continued.Avoid acetaminophen overdosing  and avoid the use of non-steroidalanti-inflammatory drugs in patients with cirrhosis and portal hypertension .Anticoagulants can be used in patients with liver cirrhosis in the absence of absolute contraindications, keeping in mind the status of varices in this group of patients before starting anticoagulants .Endoscopic procedures in patients with COVID-19 should be limited to emergencies, such as gastrointestinal variceal bleeding.HCC surveillance should be deferred until after recovery from COVID-19.General considerations:Specific treatment considerations:Chloroquine/hydroxychloroquine: these drugs are not usually associated with hepatotoxicity and an infrequent cause of clinically significant acute liver injury .Lopinavir/ritonavir: not recommended to be used in patients with decompensated liver cirrhosis .Favipiravir/favilavir: no data available on their use in patients with liver cirrhosis.Remdesivir: no data available on its use in patients with liver cirrhosis. Reportedly, it can cause raised liver enzymes .Tocilizumab: reportedly, it could cause raised liver enzymes, rarely linked to severe liver injury, and better not to be used in patients with decompensated cirrhosis .Convalescent plasma: no data available on its use in patients with liver cirrhosis.Although there are currently no drugs approved for COVID-19, several repurposed drugs have been tested in recent weeks, and many are still under investigation . HoweverHCC represents the sixth most common cancer worldwide . HCC sur➢ Surveillance should be continued for those at risk  as scheduled, although a 2-month delay may be reasonable .➢ The multidisciplinary meetings are conducted by conference calls to reduce the risk for healthcare operators without delaying decisions .➢ Proceed with liver cancer treatments or surgical resection, whenever possible, rather than delaying them due to the pandemic .➢ Locoregional treatment (LRT) is preferred when applicable, and surgery should be left only as a salvage option for those who fail to complete radiological response or are not appropriate for LRTs .➢ LT should be reserved for patients with a high risk of dropout, due to the shortage of intensive care unit bed availability and the dramatic reduction in the donor pool; LRT, whenever possible, may be used as a bridge treatment to reduce the risk of disease progression, during the waiting period .➢ Palliative treatments, such as trans-arterial chemo (radio) embolization , are maintained; however, in old ages (>80 years) or patients with comorbidities, palliative should be delayed, weighing the oncological benefit versus the risk of exposure to SARS-CoV-2 .➢ Imaging techniques carried out for diagnosis, staging, or follow-up should be revised via telemedicine. Radiological follow-up is scheduled as usual, but postponed up to 3 months, in elderly patients and those with comorbidities .➢ The COVID-19 test is carried out in all patients 1 day before admission; only negative patients are admitted to dedicated rooms in the ward  .The following are the recommendations regarding HCC management during the COVID-19 pandemic;2), with hyperlipidemia and diabetes (median HbA1c of 6.9%), and their immunosuppressive regimen had been gradually tapered off, with deficient concentrations of calcineurin inhibitors. By contrast, three of 40 recently transplanted  patients have tested COVID-19-positive, and although quarantined, all are experiencing an uneventful course of disease [LT remains the only curative treatment for selected patients with end-stage liver diseases and acute liver failure. Survival rates have improved significantly in the last 25 years . Advance disease . It was  disease . Other c disease .A-➢ All donors (deceased and living donors) and recipients must be tested for COVID-19 at the time of urgent transplant using nasopharyngeal swab in approved laboratories . Moreove➢ A detailed history regarding exposure history, fever, and respiratory symptoms should be reviewed. Additional data including chest imaging and inflammatory markers  should be considered to minimize the significant false-negative testing rate .➢ COVID-19-positive transplant candidates may be considered for transplantation at least 14–21 days after symptom resolution and 1 or 2 negative COVID-19 diagnostic tests .➢ Preventing transmission from an infected patient to a healthcare worker and vice versa is of great importance. Current recommendations are for both droplet and airborne precautions for infection control, in the hospital setting. Social distancing by widening the patients’ waiting areas, frequent hand washing, cleaning frequently touched surfaces, following cough etiquettes, and strict infection control precautions are critical , 70.➢ Consider evaluating only patients with HCC or those patients with high Model for End-Stage Liver Disease (MELD) scores, who are likely to benefit from immediate liver transplant listing. Telemedicine can be used for evaluation, whenever applicable .➢ Consider resource utilization, including intensive care unit (ICU) beds, ventilators, personal protective equipment (PPE), and supply of blood products in the decision to proceed with liver transplantation , 75.➢ Moratorium on all non-urgent transplants. Liver transplantation should be restricted only to those with high MELD scores and HCC patients . LRT, wh➢ Pre-procedure consent should include the potential hazard for the acquisition of nosocomial COVID-19 infection .Before liver transplantationB-➢ Strict infection control precautions and the use of (PPE) for all surgical teams are essential .During the procedureC-➢ Liver transplant recipients should be admitted to separate wards, with strict implementation of prevention measures .➢ Limit or even prohibit non-essential team members in the hospital  to minimize exposure risk and prioritize the use of PPE .➢ Minimize in-person visits for post-transplant patients, by maximizing the use of telemedicine. However, those patients with post-transplant emergencies should attend hospital, as usual, and should be provided with necessary standard care by the transplant team .➢ Limit the number of visitors who may see inpatients. Ideally, no visitors should be permitted in patient rooms, except in specific circumstances  , 71.Post-operative care for liver transplant patients.There is no evidence, until now, for the need to modify the immunosuppression protocol. Standard immunosuppression should be followed in the post-transplant period, until further data is available .In post-transplant patients without COVID-19:The National Institute of Health (NIH) recommends against the routine use of systemic corticosteroids for the treatment of COVID-19 in hospitalized patients, unless they are in the intensive care unit . MinimizConsider reducing azathioprine or mycophenolate dosages, especially in the setting of lymphopenia, fever, or worsening pneumonia attributed to COVID-19 .Consider reducing, but not stopping daily calcineurin inhibitor dosage, especially in the setting of lymphopenia, fever, or worsening pulmonary status attributed to COVID-19 .In post-transplant patients with COVID-19:Telehealth (or telemedicine) service implies providing medical care at a distance where both the patient and his healthcare worker are in geographically distant places. Providing regular face-to-face medical services in clinics and hospitals has been significantly replaced by telehealth services during the pandemic of COVID-19 . In the In patients with chronic liver disease, possible adverse events have to be considered with the use of COVID-19 treatment regimens . RemdesiManagement of chronic liver disease during the COVID-19 pandemic is challenging. Several patients with underlying chronic liver disease are prone to the rapidly spreading SARS-CoV-2 infection, which can affect their underlying liver disease. Patients with hepatitis B, MAFLD, autoimmune liver disease, and HCC and liver transplant recipients need special attention for follow-up and treatment management. Hepatotoxicity of COVID-19 medications, if managed properly, can be overcome. Telemedicine can help in decreasing contact between patients and potential sources of infection.