Weekly Articles 12/26/21

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COVID, man. You miss a little, you miss a lot. Here is a backlog of several articles I have not had the time to write about.

Lu L, Mok BW, Chen LL, Chan JM, Tsang OT, Lam BH, Chuang VW, Chu AW, Chan WM, Ip JD, Chan BP, Zhang R, Yip CC, Cheng VC, Chan KH, Jin DY, Hung IF, Yuen KY, Chen H, To KK. Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients. Clin Infect Dis. 2021 Dec 16:ciab1041. doi: 10.1093/cid/ciab1041. Epub ahead of print. PMID: 34915551.

This study evaluated the ability of serum from recipients from either the Coronavac or BNT16b2 to neutralize the Omicron variant. 50 recipients, 25 of each, were evaluated with 2 strains of Omicron cultures being compared. When compared to the wild-type strain, the geometric mean microneutralization titer was up to 35-lower when looking at the Omicron titers:

It was also lower when compared to both beta and delta variants. This would suggest that the protection conferred against the newest variants are significantly reduced, although how these translate clinically remains to be seen (i.e. do you still get infected but not critically ill?). Either way, I suspect that booster shots will be a thing from now on.

Desai AP, Dirajlal-Fargo S, Durieux JC, Tribout H, Labbato D, McComsey GA. Vitamin K & D Deficiencies Are Independently Associated With COVID-19 Disease Severity. Open Forum Infect Dis. 2021 Jul 29;8(10):ofab408. doi: 10.1093/ofid/ofab408. PMID: 34642636; PMCID: PMC8344499.

This prospective, observational cohort study evaluated the vitamin D and vitamin K status on the ability to predict COVID-19 outcomes. 100 COVID-19 infected patients were matched with 50 controls. After adjustment, an increase in dp-ucMGP (which quantifies extrahepatic vitamin K status i.e. the higher it is, the worse it is) was associated with higher odds of acute critical illness or death from COVID-19 as was lower vitamin D status:

Bager P, Wohlfahrt J, Fonager J, Rasmussen M, Albertsen M, Michaelsen TY, Møller CH, Ethelberg S, Legarth R, Button MSF, Gubbels S, Voldstedlund M, Mølbak K, Skov RL, Fomsgaard A, Krause TG; Danish Covid-19 Genome Consortium. Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study. Lancet Infect Dis. 2021 Nov;21(11):1507-1517. doi: 10.1016/S1473-3099(21)00290-5. Epub 2021 Jun 23. Erratum in: Lancet Infect Dis. 2021 Nov;21(11):e341. PMID: 34171231; PMCID: PMC8219488.

This was an observational cohort study that evaluated the risk of hospitalization with the B.1.1.7 strain of SARS-CoV2 (the alpha strain) compared with others using the Danish Heath Registry. Over 50,000 patients were included, of which 571 were infected with the alpha variant. The overall proportion of individuals that were infected with this variant increased from 3.5% in the first week of the study to nearly 93% of all cases at week 10. Further, there was a lower proportion of infections with this variant in those aged 60 or older. After adjustment for sex, age, period, region, and co-morbidities, infection with B.1.1.7 was associated with a higher likelihood of hospitalization related to COVID-19:

Ermias D Belay, Shana Godfred Cato, Agam K Rao, Joseph Abrams, W Wyatt Wilson, Sarah Lim, Christopher Newton-Cheh, Michael Melgar, Jennifer DeCuir, Brandon Webb, Paige Marquez, John R Su, Lu Meng, Heather N Grome, Elizabeth Schlaudecker, Kawsar Talaat, Kathryn Edwards, Elizabeth Barnett, Angela P Campbell, Karen R Broder, Sapna Bamrah Morris, Multisystem Inflammatory Syndrome in Adults After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and Coronavirus Disease 2019 (COVID-19) Vaccination, Clinical Infectious Diseases, 2021;, ciab936, https://doi.org/10.1093/cid/ciab936

This one was interesting. Multisystem inflammatory syndrome is an entity that was initially described in children who were infected with COVID-19 and was similar to that of Kawasaki’s disease. This cohort of 26 patients evaluated the findings of MIS-A (MIS in adults) following both infection with COVID or vaccination. This was the criteria used to define this entity:

20 of the patients evaluated fit the above definition. 16 had a COVID-19 like illness while 4 did not have any prior symptoms. 7 had received a vaccine prior to this, four with Pfizer and 3 with moderna. Almost all developed GI and CV manifestations, usually diarrhea, abdominal pain, vomiting, rash, headache, and shortness of breath. These usually occurred around 26 or 28 days after COVID-19. 

Ospina-Tascón GA, Calderón-Tapia LE, García AF, Zarama V, Gómez-Álvarez F, Álvarez-Saa T, Pardo-Otálvaro S, Bautista-Rincón DF, Vargas MP, Aldana-Díaz JL, Marulanda Á, Gutiérrez A, Varón J, Gómez M, Ochoa ME, Escobar E, Umaña M, Díez J, Tobón GJ, Albornoz LL, Celemín Flórez CA, Ruiz GO, Cáceres EL, Reyes LF, Damiani LP, Cavalcanti AB; HiFLo-Covid Investigators. Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Dec 7;326(21):2161-2171. doi: 10.1001/jama.2021.20714. PMID: 34874419; PMCID: PMC8652598.

To more clinical stuff, I guess. THis was an open-label, randomized clinical trial evaluating high flow nasal canula vs conventional oxygen therapy on the need for intubation and mechanical ventilation in COVID-19 patients. Adult patients with minimal co-morbidities who had a P/F ratio <200 along with signs of respiratory distress were enrolled and randomized in a 1:1 fashion to conventional respiratory support with high-flow nasal cannula (the large bore nasal prongs starting at 60L/min)  or conventional oxygen therapy. Primary outcome was needed for intubation and time to clinical recovery within 28 days of randomization. 200 patients were randomized, with 199 being included in the analysis. While both cohorts were overall similar in baseline characteristics, more patients in the HFNC group had symptoms for longer prior to randomization (10d vs 8d). By day 28, more patients in the conventional oxygen group had achieved the primary outcome compared to those in HFNC group:

Patients <60yo tended to benefit more from HFNC, as well as those with IL-6 <100:

I suspect the PEEP HFNC provides may attenuate the need for mechanical ventilation in a subpopulation of patients in respiratory distress hence, the benefit. I do wonder if similar benefits would be seen with other types of non-invasive ventilation such as BiPAP or CPAP, but we will have to see. I guess this would suggest that HFNC should be used in these patients (i.e. those with severe ARDS) upfront rather than using pure oxygenation techniques. 

Benfield T, Bodilsen J, Brieghel C, Harboe ZB, Helleberg M, Holm C, Israelsen SB, Jensen J, Jensen TØ, Johansen IS, Johnsen S, Lindegaard B, Lundgren J, Meyer CN, Mohey R, Pedersen LM, Nielsen H, Nielsen SL, Obel N, Omland LH, Podlekareva D, Poulsen BK, Ravn P, Sandholdt H, Starling J, Storgaard M, Søborg C, Søgaard OS, Tranborg T, Wiese L, Christensen HR. Improved Survival Among Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) Treated With Remdesivir and Dexamethasone. A Nationwide Population-Based Cohort Study. Clin Infect Dis. 2021 Dec 6;73(11):2031-2036. doi: 10.1093/cid/ciab536. PMID: 34111274; PMCID: PMC8344480.

This was a retrospective study evaluating the use of both dexamethasone and remdesivir in a Danish cohort who were hospitalized with COVID-19. Those who had evidence of multiorgan failure were not included. Remdesivir was given for 5 days. 1053 patients received standard of care while 1695 received SOC + remdesivir and dexamethasone. Those who got therapy with dexamethasone and remdesivir were more likely to have pulmonary infiltrates on radiography and require supplemental oxygen. IPTW was used to determine 30 day mortality as well as probability of mechanical ventilation. OR for mortality at 30 days was 0.47 (95% CI 0.38-0.57) while for mechanical ventilation, it was 0.36 (95% CI 0.29-0.46) suggesting a benefit of the combination.:

While not a randomized trial, this data supports the use of dexamethasone and steroids in severe COVID.

Choksi T, Agrawal A, Date P, Rathod D, Gharat A, Ingole A, Chaudhari B, Pawar N. Cumulative Mortality and Factors Associated With Outcomes of Mucormycosis After COVID-19 at a Multispecialty Tertiary Care Center in India. JAMA Ophthalmol. 2021 Dec 9:e215201. doi: 10.1001/jamaophthalmol.2021.5201. Epub ahead of print. PMID: 34882192; PMCID: PMC8662533.

This case-control study evaluated 73 cases of rhino-cerebral mucormycosis in COVID-19. 98% had received corticosteroids, 74% had diabetes, and mucormycosis developed within a median of 31 days after COVID recovery. 21 day mortality was high, roughly 43% using survival estimates:

Mechanical ventilation or NIV as associated with higher risk of death, meanwhile receipt of IV amphotericin was associated with lower mortality:

Goyal R, Hotchkiss J, Schooley RT, De Gruttola V, Martin NK. Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 Transmission Mitigation Strategies on a University Campus Using an Agent-Based Network Model. Clin Infect Dis. 2021 Nov 2;73(9):1735-1741. doi: 10.1093/cid/ciab037. PMID: 33462589; PMCID: PMC7929036.

This was a simulation of SARS-CoV2 transmission in UC San Diego that evaluated several mitigation methods among university campus populations. Specifically, the authors used the following strategies in combination or in isolation: campus housing de-densification, classroom caps and hybrid instruction, asymptomatic testing, and masking and social distancing. The authors simulated 38798 students and 8000 faculty members and found replication number decreased as more intense methods of mitigation were employed:

Notably, with the higher intensity of mitigation strategies, the impact of testing either monthly or twice per week diminished:

Cohen MS, Wohl DA, Fischer WA, Smith DM, Eron JJ. Outpatient Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 Infection to Prevent Coronavirus Disease 2019 Progression. Clin Infect Dis. 2021 Nov 2;73(9):1717-1721. doi: 10.1093/cid/ciab494. PMID: 34048568; PMCID: PMC8194682.

This was a fairly neat review on the outpatient therapies for COVID, mainly the two monoclonal antibody combinations that are available, as well as a brief word on monupiravir. I put this as I find it a bit interesting overall.

Brust JCM, Gandhi NR, Wasserman S, Maartens G, Omar SV, Ismail NA, Campbell A, Joseph L, Hahn A, Allana S, Hernandez-Romieu AC, Zhang C, Mlisana K, Viljoen CA, Zalta B, Ebrahim I, Franczek M, Master I, Ramangoaela L, Te Riele J, Meintjes G. Effectiveness and Cardiac Safety of Bedaquiline-Based Therapy for Drug-Resistant Tuberculosis: A Prospective Cohort Study. Clin Infect Dis. 2021 Dec 6;73(11):2083-2092. doi: 10.1093/cid/ciab335. PMID: 33882121; PMCID: PMC8664482.

This was a prospective observational cohort study evaluating the impact of bedaquiline in QTc prolongation in a setting with high HIV prevalence. Specifically, the authors were looking at the impact of bedaquiline on lopinavir-ritonavir as there is a significant drug interaction between these medications. 195 patients were eligible, with 26 of these recieving ART with lopinavir-ritonavir during the study. Primary effectiveness outcome was cure or treatment completion, with 89% achieving sputum conversion during the trial, with 66% achieving cure. During this study, 66% received moxifloxacin, and 10.4% of patients overall had a change in QTc >60ms at any time. Only four had QTc >500, of which 2 had received lopinavir-ritonavir. After adjustment, only age was the factor associated with significant QTc prolongation:

The numbers for each drug are small to draw a conclusion, but the lack of any VT is reassuring. 

Sankar A, Swanson KM, Zhou J, Jena AB, Ross JS, Shah ND, Karaca-Mandic P. Association of Fluoroquinolone Prescribing Rates With Black Box Warnings from the US Food and Drug Administration. JAMA Netw Open. 2021 Dec 1;4(12):e2136662. doi: 10.1001/jamanetworkopen.2021.36662. PMID: 34851398; PMCID: PMC8637256.

This was a cross sectional study evaluating the changes in prescribing of FQs after the 2013 and 2016 FDA black box warnings. Three periods were analyzed; before 2013, which served as the baseline, post-warning 1 which was after the first warning and post-warning 2, after 2016. Using a 20% random fee-for-service beneficiaries, the outcome of interest was the number of FQ prescriptions written within 7 days of an index visit. Over 2.7 million visits were evaluated, with FQ prescription increasing by 3.42 percentage points after period 1 but declining by 0.77 percentage points after period 2. 

Notably, when compared to sinusitis or bronchitis, prescriptions for uncomplicated UTIs increased slightly after the first period but declined overall after period 2.

This is a fairly reassuring trend, as there are several adverse events FQs are associated with such as tendonitis or QTc prolongation and I hope the trend continues forward.

Swaminathan L, Flanders S, Horowitz J, Zhang Q, O’Malley M, Chopra V. Safety and Outcomes of Midline Catheters vs Peripherally Inserted Central Catheters for Patients With Short-term Indications: A Multicenter Study. JAMA Intern Med. 2021 Nov 29:e216844. doi: 10.1001/jamainternmed.2021.6844. Epub ahead of print. PMID: 34842905; PMCID: PMC8630646.

This study evaluated the outcomes in patients who received a PICC line vs a midline place for either difficult vascular access or antibiotic therapy for 30 days or less. Complications were defined as a compsoit of symptomatic upper extremity DVT or PE, CLABSI or CRSBI, and catheter occlusion. 5758 PICCs were placed compared to 5105 midlines, with single lumen devices making the bulk in both cohorts (63% for PICCs, 85% for midlines). Difficult IV access was the most common indication for midlines (72% Vs 40% for PICCs). Unadjusted risk was higher for PICC compared to midlines (9.9% vs 3.9%), with more patients in the PICC group having bloodstream infections (1.6% for PICC vs 0.4% for midlines). After adjustments, OR for PICC complications were 1.99 (95% CI 1.61-2.47), with infections being significantly more common in PICC patients:

Seems that if you have a choice, midlines tend to be safer than PICCs but I do not know how long they can stay on for. 

Petersiel N, Sherman A, Paul M. The Impact of Nosocomial Bloodstream Infections on Mortality: A Retrospective Propensity-Matched Cohort Study. Open Forum Infect Dis. 2021 Nov 6;8(12):ofab552. doi: 10.1093/ofid/ofab552. PMID: 34888398; PMCID: PMC8651175.

This retrospective, propensity cohort study evaluated the impact of nosocomial bacteremias over 10 years on 30-day, 90-day, and one year mortality. Patients were matched in a 1:1 fashion, resulting in 1361 cases and corresponding controls. Controls tended to have slightly higher hemoglobin and albumin, but had no other differences. 30-day mortality from index day was higher in the nosocomial bacteremia group when compared to the control group, and using the Norton score to assess functional changes, those with nosocomial bacteremia had lower functional scores:

Nosocomial bacteremia was also found to be associated with higher mortality at one year:

Samura M, Hirose N, Kurata T, Takada K, Nagumo F, Koshioka S, Ishii J, Uchida M, Inoue J, Enoki Y, Taguchi K, Higashita R, Kunika N, Tanikawa K, Matsumoto K. Identification of Risk Factors for Daptomycin-Associated Creatine Phosphokinase Elevation and Development of a Risk Prediction Model for Incidence Probability. Open Forum Infect Dis. 2021 Nov 10;8(12):ofab568. doi: 10.1093/ofid/ofab568. PMID: 34888403; PMCID: PMC8651170.

What risk factors are associated with Daptomycin-induced CK elevation? This single-center retrospective study evaluated patients who received at least 5 days of daptomycin and a logistic regression analysis was performed to evaluate the factors associated with this. 198 patients were included, and multivariate analysis found that the use of statins and antihistamines were associated with higher rates of CK elevation:

Furthermore, rising troughs were also associated with CK elevation. Scores of 0-4 indicated low incidence of CK elevation (<10%), while 5-6 indicated intermediate risk (10-25%), and anything above 8 was high risk (>25%). While this is kind of helpful, we do not generally measure daptomycin troughs though it stands to reason that if you give someone who is on rosuvastatin 10mg/kg while on allergy season, you need to be hypervigilant about a rise in CK. 

Padmapriydarsini C, Mamulwar M, Mohan A, Shanmugam P, Gomathy NS, Mane A, Singh UB, Pavankumar N, Kadam A, Kumar H, Suresh C, Reddy D, Devi P, Ramesh PM, Sekar L, Jawahar S, Shandil RK, Singh M, Menon J, Guleria R; METRIF Team. Randomized trial of Metformin with Anti-tuberculosis drugs For Early Sputum Conversion in Adults with Pulmonary Tuberculosis. Clin Infect Dis. 2021 Nov 26:ciab964. doi: 10.1093/cid/ciab964. Epub ahead of print. PMID: 34849651.

This one was kind of funny. The idea was that metformin inhibits intracellular growth of M. tuberculosis in infected mice, so this phase IIB trial evaluated the addition of metformin to a daily anti-TB regimen in adults with pulmonary TB and evaluate the time and proportion of sputum culture conversion. HIV- or HepB/C positive patients were excluded. Patients were randomized in a 1:1 fashion to either RIPE or RIPE + metformin (500mg daily for one week and then 1000mg daily for the remaining 7 weeks). Primary endpoint was time to sputum culture conversion in MGIT taken at least 8 days apart. 320 patients were enrolled, with median time to sputum conversion by MGIT being 42 days in the control and 41 days in the metformin arm:

There was a significant difference in the time to culture conversion in the LJ medium (35 days in the metformin arm vs 29 in the  control arm, p=0.05) as well as difference in the proportion of culture negativity by MGIT by the end of week 8 (72% in metformin arm vs 86% in the control arm, p=0.004), suggesting slower time to culture conversion with metformin addition. After adjustment, time to stable culture conversion after 8 weeks revealed a HR of 0.8 (95% CI 0.62-1.03) in the metformin arm, with alcohol consumption and higher sputum smear grading benign associated with longer time to sputum conversion. There was some improvement in radiography, with cavitary lesions being noticed only in 5.3% of those in the metformin arm compared to 13% in the control arm (RR 0.42, 95% CI 0.18=0.96). Those in the metformin arm also had lower inflammatory markers, suggestion an immunomodulatory effect here. So add metformin to azithromycin and statins as possibly having immunomodulatory effects. 

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