Article Summaries: 10/31/2021

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It’s been quite a while since I’ve actually written any post and I have quite a bit of Articles to talk about this time around.  blame it  on moving and a new job. 

Connors JM, Brooks MM, Sciurba FC, Krishnan JA, Bledsoe JR, Kindzelski A, Baucom AL, Kirwan BA, Eng H, Martin D, Zaharris E, Everett B, Castro L, Shapiro NL, Lin JY, Hou PC, Pepine CJ, Handberg E, Haight DO, Wilson JW, Majercik S, Fu Z, Zhong Y, Venugopal V, Beach S, Wisniewski S, Ridker PM; ACTIV-4B Investigators. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19: The ACTIV-4B Randomized Clinical Trial. JAMA. 2021 Nov 2;326(17):1703-1712. doi: 10.1001/jama.2021.17272. PMID: 34633405; PMCID: PMC8506296.

Let’s get the covid articles out of the way. This was a randomized, double-blind, placebo-controlled trial of aspirin and two doses of apixaban in patients with COVID that did not require hospitalization. People who were between the ages of 40 and 80 with newly diagnosed symptomatic COVID were randomized in a 1:1:1:1 ratio to receive either 81 mg of aspirin, prophylactic dose of apixiban (2.5 mg twice a day), apixiban at therapeutic dose, or placebo for 45 days. The primary endpoint was a composite of symptomatic DVT, pulmonary embolism, arterial thrombosis, myocardial infarction, ischemic stroke, hospitalization for cardiovascular and pulmonary events, and all cause mortality for up to 45 days after treatment. A total of 558 patients were randomized, There were no significant differences in the baseline characteristics between groups, although the prophylactic Apixaban group had higher CRP & D dimer levels. 

Overall, there was no difference in the primary outcome between any groups:

This also held true when looking at those who actually started treatment and those in the intention-to-treat analysis. While a higher percentage of patients in the therapeutic apixaban group were more likely to have any bleeding, the vast majority of cases were minor bleeding.

Given what we know about anticoagulation in critically ill patients, I am not surprised about the results of this trial. I think it’s a bit discouraging that we still do not have a good way to prevent clotting complications in patients with covid, So it seems that just relaxing in the acute setting seems to be the way to go. 

Writing Committee for the REMAP-CAP Investigators, Estcourt LJ, Turgeon AF, McQuilten ZK, McVerry BJ, Al-Beidh F, Annane D, Arabi YM, Arnold DM, Beane A, Bégin P, van Bentum-Puijk W, Berry LR, Bhimani Z, Birchall JE, Bonten MJM, Bradbury CA, Brunkhorst FM, Buxton M, Callum JL, Chassé M, Cheng AC, Cove ME, Daly J, Derde L, Detry MA, De Jong M, Evans A, Fergusson DA, Fish M, Fitzgerald M, Foley C, Goossens H, Gordon AC, Gosbell IB, Green C, Haniffa R, Harvala H, Higgins AM, Hills TE, Hoad VC, Horvat C, Huang DT, Hudson CL, Ichihara N, Laing E, Lamikanra AA, Lamontagne F, Lawler PR, Linstrum K, Litton E, Lorenzi E, MacLennan S, Marshall J, McAuley DF, McDyer JF, McGlothlin A, McGuinness S, Miflin G, Montgomery S, Mouncey PR, Murthy S, Nichol A, Parke R, Parker JC, Priddee N, Purcell DFJ, Reyes LF, Richardson P, Robitaille N, Rowan KM, Rynne J, Saito H, Santos M, Saunders CT, Serpa Neto A, Seymour CW, Silversides JA, Tinmouth AA, Triulzi DJ, Turner AM, van de Veerdonk F, Walsh TS, Wood EM, Berry S, Lewis RJ, Menon DK, McArthur C, Zarychanski R, Angus DC, Webb SA, Roberts DJ, Shankar-Hari M. Effect of Convalescent Plasma on Organ Support-Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2021 Nov 2;326(17):1690-1702. doi: 10.1001/jama.2021.18178. PMID: 34606578; PMCID: PMC8491132.

From one intervention that does not seem to work to another one that may not work either. This was a multicenter randomized clinical trial  evaluating the use of convalescent plasma in patients who were critically ill with covid-19. Patients who were aged 18 years or older with COVID infection classified as either moderately or severely ill were eligible for enrollment. Patients were randomized to either convalescent plasma at randomization, convalescent plasma if clinical deterioration occurred, or no convalescent plasma. The primary outcome was respiratory and cardiovascular organs support free days through day 21. Statistical analysis was performed from a Bayesian cumulative logistic model. A total of 4763 patients were enrolled In the parent trial, with 2087 patients being enrolled in the convalescent plasma arm. There were no significant differences in baseline characteristics between groups. The median number of orgasms for free days with 0 in the convalescent plasma group and 3 in the no convalescent plasma group. That mean adjusted odds ratio for the primary model with 0.97 (95%CrI 0.83-1.15) yielding a posterior probability of futility of 99.4%. 

The mortality rate was 37.3% in the convalescent plasma group compared to 38.4% in the new convalescent plasma group. The mean adjusted OR for in hospital survival was 1.04 (95%CrI  0.85 to 1.27) Building a posterior probability of utility of 91.8%.

Given the prior data on convalescent plasma, I cannot say I am surprised. Better luck for the next intervention, I guess.

Essy Mozaffari, Aastha Chandak, Zhiji Zhang, Shuting Liang, Mark Thrun, Robert L Gottlieb, Daniel R Kuritzkes, Paul E Sax, David A Wohl, Roman Casciano, Paul Hodgkins, Richard Haubrich, Remdesivir treatment in hospitalized patients with COVID-19: a comparative analysis of in-hospital all-cause mortality in a large multi-center observational cohort, Clinical Infectious Diseases, 2021;, ciab875, https://doi.org/10.1093/cid/ciab875

Speaking of which, I think the next intervention has surprised me the most in terms of its efficacy compared to other antivirals. I am talking about remdesivir. This was a retrospective study evaluating the efficacy of remdesivir in terms of 14- and 28-day mortality among patients hospitalized with covid-19. Logistic regression models were used for high-flow oxygen, local option, and no supplemental oxygen groups as well as those who we’re on mechanical ventilation and ECMO And matching was performed based on baseline characteristics in 2-month blocks of admissions, as well as between hospitals for the same bed size. This was done to account for differences in hospital practices. Over 34,000 patients in the remdesevir cohort and over 41,000 patients in the non-remdesivir cohort were evaluated, of which 28,855 remdesevir patients were matched with 16687 not receiving the therapy. Overall, there was a significant reduction in 14 day mortality (aHR 0.76, 95% CI 0.69-0.83) and 28 day mortality (aHR 0.88, 95% CI 0.81-0.96):

This held true for those who were not in oxygen or who received low-flow oxygen, and when controlling for baseline and clinical covariates, the pattern also held true for 14 day mortality but not 28 day mortality. Interestingly, even those who required mechanical ventilation and ECMO seem to have benefitted from therapy. I am still quite surprised about the efficacy of remdesevir and while this is a retrospective study and the results should be considered a hypothesis generating, the large number of patients suggests this is not just a statistical fluke. 

Here is an interesting review article on the RAAS system, ACEi/ARB, and COVID. 

Ventura D, Carr AL, Davis RD, Silvestry S, Bogar L, Raval N, Gries C, Hayes JE, Oliveira E, Sniffen J, Allison SL, Herrera V, Jennings DL, Page RL 2nd, McDyer JF, Ensor CR. Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury. Open Forum Infect Dis. 2021 Apr 4;8(10):ofab170. doi: 10.1093/ofid/ofab170. PMID: 34642634; PMCID: PMC8083494.

Erlandson KM, Carter CC, Melbourne K, Brown TT, Cohen C, Das M, Esser S, Huang H, Koethe JR, Martin H, McComsey GA, Orkin C, Post FA, Rockstroh JK, Sax PE, Stellbrink HJ, Waters L, Wei X, Lake JE. Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials. Clin Infect Dis. 2021 Oct 20;73(8):1440-1451. doi: 10.1093/cid/ciab444. PMID: 33987636.

I have spoken a lot about the effects of certain antiretrovirals on weight gain and metabolic syndrome, with the suggestion that the newer integrase to promote more weight gain compared to the older medications in the class. Furthermore, there seems to be a signal that TAF rather than TDF may also be associated with weight gain. This is a prospective pooled analysis of 12 randomized, active control double blind or open label studies on patients with HIV who received a minimum of three months of therapy with either their stable regimen or who underwent a switch. In this analysis, 4166 patients were randomized to switch ART while 3150 were randomized to continue this stable regimen. Weight gain was achieved in most switch and SBR categories, reaching a plateau between weeks 24 and 36. Switching from efavirenz to either rilpivirine or elvitegravir and switching TDF to TAF were associated with >10% weight gain at week 48:

As seen above, only baseline underweight/normal BMI and age <35 were strongly associated with >10% weight gain. I think the jury is still out on the impact of different components of ART on weight gain although there wasn’t much comparison between dolutegravir and efavirenz, the former of which is the one that gets labeled as causing a lot of weight gain (along with bictegravir). The finding of TAF being associated with weight gain may confound those initial findings, and it is confirmed here that it is associated with weight gain. It may be that in the future, we will find that it was TAF all along causing all the issues (since it is usually in BIC or DTG containing regimens). 

Justin J Choi, Lars F Westblade, Lee S Gottesdiener, Kyle Liang, Han A Li, Graham T Wehmeyer, Marshall J Glesby, Matthew S Simon, Impact of a Multiplex Polymerase Chain Reaction Panel on Duration of Empiric Antibiotic Therapy in Suspected Bacterial Meningitis, Open Forum Infectious Diseases, Volume 8, Issue 10, October 2021, ofab467, https://doi.org/10.1093/ofid/ofab467

This is a retrospective pre and post intervention study that evaluated the clinical impact of the multiplex PCR meningitis panel. The primary outcome was the duration of antibiotic therapy measured in hours. 137 patients in the pre-multiplex cohort and 69 in the post-multiplex cohort were evaluated. The duration of antibiotic therapy was significantly shorter after implementation of the PCR assay (34.7 hours vs 12.3 hours, p=0.01). Other outcomes of interest included shorter duration of antibiotic therapy in the multiplex cohort, and a shorter time to targeted therapy:

I would like to see a mortality-powered study down the line, but I think that PCR is the way of the future and hopefully we will see more data regarding this modality in the future. 

Amoah J, Klein EY, Chiotos K, Cosgrove SE, Tamma PD; CDC Prevention Epicenters Program. Administration of a β-lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients with Bloodstream Infections. Clin Infect Dis. 2021 Oct 4:ciab865. doi: 10.1093/cid/ciab865. Epub ahead of print. PMID: 34606585.

A study for all critical-care folks out there. This was a retrospective, observational cohort study that evaluated the administration of a broad-spectrum beta-lactam prior to vancomycin as protective against mortality in the first 7 days of hospitalization in those who have bloodstream infections. The beta-lactams included piperacillin-tazobactam, cefepime, and carbapenems. Propensity score matching was used, with 3376 meeting eligibility criteria. 2685 patients received a beta-lactam as the first agent while 691 got vancomycin first. While there were some differences at baseline between cohorts (namely, higher lactate in the beta-lactam group, lower Pitt bacteremia scores, and lower co-morbidity index) these disappeared after propensity score matching. The administration of beta-lactam prior to vancomycin was protective against 7 day mortality (OR 0.68, 95% CI 0.5 to 0.92) which persisted in the adjusted model (aOR 0.48, 95%  CI 0.22 to 0.69). 

Notably, in the subset of patients who had MRSA bacteremia, the administration of beta-lactam prior to vancomycin was not protective (0.93, 95% CI 0.33 to 2.63), although there was no benefit in these patients in giving vancomycin first. So get to using that beta-lactam first! Beta-lactams FTW?

Heil EL, Harris AD, Brown C, Seung H, Thom KA, von Rosenvinge E, Sorongon S, Pineles L, Goodman KE, Leekha S. A Multicenter Evaluation of Probiotic Use for the Primary Prevention of Clostridioides difficile Infection. Clin Infect Dis. 2021 Oct 20;73(8):1330-1337. doi: 10.1093/cid/ciab417. PMID: 33972996.

This was a quasi experimental before-and after study evaluating the impact of a computerized clinical decision support tool (i.e those “best practice” pop up alerts that you get in the EMR) alerting you to use probiotics for the prevention of C. diff infection. This intervention was performed in 4 hospitals in Canada, with the alert prompting people to write for a capsule that contained 100 billion CFUs of probiotics. Patients who were >50yo, had systemic antibiotic therapy with anticipated need for >48hrs and being able to take things by mouth were eligible to be enrolled. Primary endpoint was the primary exposure and hospital-based C. diff infection between the two study periods while a secondary analysis was performed in those who got probiotics and those who didn’t in the post-implementation period. In the pre-intervention period, 0.75% of patients had CDI compared to 1.02% of patients in the post-intervention group (p=0.01). After controlling for several variables, including length of stay, co-morbidity index, and PPI use, the OR of CDI was higher in the post-intervention group (OR 1.4, 95% CI 1.13-1.84):

Similarly, in the post-intervention cohort, those who got probiotics had a higher odds of CDI (RR 1.46, 95% CI 0.87 to 2.45). It should be noted that only around 17% of patients in the post-intervention cohort received probiotics, so perhaps a higher adherence rate would have demonstrated a protective benefit, though this study seems to suggest the opposite. 

Sassine J, Khawaja F, Shigle TL, Handy V, Foolad F, Aitken SL, Jiang Y, Champlin R, Shpall E, Rezvani K, Ariza-Heredia EJ, Chemaly RF. Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era. Clin Infect Dis. 2021 Oct 20;73(8):1346-1354. doi: 10.1093/cid/ciab298. PMID: 33830182; PMCID: PMC8528390.

Letermovir is a novel antiviral drug that has been approved for primary prophylaxis in CMV-seropositive patients after allo-HCT. This single-center retrospective study evaluated the effect of primary letermovir prophylaxis in the development of refractory or resistant CMV infections in allo-HCT recipients. Patients were given 480mg of letermovir daily starting day 5 after transplant through day 100. 123 patients received letermovir while 414 did not. Patients wo got letermovir were more likely to get peripheral stem cell transplant, less likely to receive ATG and more likely to receive post-transplant cyclophosphamide. Overall, letermovir was associated with lower incidence of refractory or resistant CMV infection (2% vs 11%, p=0.001). Multivariate analysis found that letermovir prophylaxis was an independent protective factor against refractory/resistant CMV:

Furthermore, there was a lower rate of clinically significant CMV-infection in the letermovir group (17% vs 53%) as well as lower incidence of end-organ disease (6% vs 20%). Logistic regression analysis identified primary letermovir prophylaxis as a protective factor against CMV disease (aOR 0.23, 95% CI 0.1 to 0.52)

Wilson GM, Suda KJ, Fitzpatrick MA, Bartle B, Pfeiffer CD, Jones M, Rubin MA, Perencevich E, Evans M, Evans CT; QUERI CARRIAGE Program. Risk Factors Associated With Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Positive Cultures in a Cohort of US Veterans. Clin Infect Dis. 2021 Oct 20;73(8):1370-1378. doi: 10.1093/cid/ciab415. PMID: 33973631.

This was a retrospective cohort study of the VA system that sought to evaluate risk factors for carbapenamase-producing CRE. 5778 isolates were identified in 3096 patients, of which 1603 were carbapenamase producing CRE. Multivariate analysis found that culture year of 2017 (3.11, 95% CI 2.13-4.54) or 2018 (3.93, 95% CI 2.64-5.84), being African American (OR 1.44, 95% CI 1.15-1.80), having GERD (OR 1.39, 95% CI 1.03-1.87), and having CHF (OR 1.35, 95% CI 1.11-1.64) were independently associated with increased odds of having carbapenamase-producing CRE. Interestingly, there was no difference in terms of antibiotic exposure between CP-positive and CP-negative individuals (26.5% vs 27.9%). 

Buijs SB, Bleeker-Rovers CP, van Roeden SE, Kampschreur LM, Hoepelman AIM, Wever PC, Oosterheert JJ. Still New Chronic Q Fever Cases Diagnosed 8 Years After a Large Q Fever Outbreak. Clin Infect Dis. 2021 Oct 20;73(8):1476-1483. doi: 10.1093/cid/ciab476. PMID: 34028546.

This retrospective study evaluated a cohort of patients who were diagnosed with Q fever following a large outbreak. In this cohort, 45 patients were ultimately diagnosed with chronic Q fever, with multivariate regression analysis finding that those with serological follow up being less likely to have chronic Q fever. 216 patients out of 394 had some sort of complications, including abscess formation, osteomyelitis, heart failure, a d acute aneurysm formation:

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