Weekly Articles of 12/13/2020

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COVID-19 Articles

Its been a while since I’ve talked about COVID. Anyways.

Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(22):2292–2300. doi:10.1001/jama.2020.22760

Fluvoxamine is an SSRI which has an affinity towards S1R which regulates cytokine production. This was a double-blind, placebo controlled, single-center RCT that compared fluvoxamine and a placebo in outpatients with COVID-19 who were symptomatic within 7d of trial enrollment. Patients who were hospitalized or had SpO2 <92% were excluded. Primary end point was clinical deterioration, defined by both (1) presence of dyspnea or hospitalization for SOB or pneumonia and (2) decrease O2 sat <92% in room air. 181 patients were randomized, while 152 were included in the analysis. Both groups were well balanced at baseline. Deterioration occurred in 0/80 patients in the study group vs 6/72 (8.3%) in the placebo group, absolute difference 8.7% (95% CI 1.8-16.4). 

Of course, it is difficult to say if these are clinically relevant effects given the overall small size of the trial as well as its single-center nature. There is some hope for a PO option that is not remdesivir, but I would not pursue this until more robust data comes out. 

National SARS-CoV-2 Serology Assay Evaluation Group. Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison. Lancet Infect Dis. 2020 Dec;20(12):1390-1400. doi: 10.1016/S1473-3099(20)30634-4. Epub 2020 Sep 23. Erratum in: Lancet Infect Dis. 2020 Dec;20(12):e298. PMID: 32979318; PMCID: PMC7511171.

This was a study evaluating a total of 4 commercial SARS-CoV2 antibody immunoassays as well as one ELISA assay that targeted trimeric spike proteins. Blood was collected from patients about 6 months prior to the known appearance of SARS-CoV2 for specificity analysis. Two assays evaluated IgG while 2 others evaluated total antibodies. In general, 2 assays targeted the nucleocapsid protein and 2 target spike protein. 1000 pre-pandemic samples and 769 COVID samples were analysed. The overall sensitivity and specificity for all assay taken >20 days after symptom onset was higher than 92%:

Adjusting the threshold could achieve a sensitivity/specificity of 98% at around 30 days after symptoms. PPV and NPV were also evaluated for each assay, with the Abbott assay having the highest rate of false negatives:

Looks like these will be good antibody tests going forwards, with the highest performance being roughly about a month out of the illness. 

Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PEH, Taiwo B, Paules CI, Arguinchona H, Goepfert P, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2020 Dec 11. doi: 10.1056/NEJMoa2031994. Epub ahead of print. PMID: 33306283.

This is the continuation of the ACTT-1 trial, which evaluated the combination of remdesivir and baricitinib. The latter is a JAK 1 and 2 inhibitor that inhibits intracellular signaling of cytokines (including IL-2, 6, 10, IFN-gamma). This was a multi-center, double-blind, placebo controlled trial. Patients were randomized in a 1:1 fashion to either remdesivir + baricitinib or remdesivir + placebo. Primary outcome was time to recovery at day 28 on an eight-point ordinal scale. 1033 patients were randomized with both groups being fairly well balanced at baseline. Around 10% of patients in both groups were on invasive mechanical ventilation or ECMO, while over 50% in each group were requiring some sort of supplemental oxygen. Overall patients in the combination group recovered one day faster than patients in the placebo group (median 7 days vs 8 days, RR 1.16, 95% CI 1.01 to 1.32). 

The highest rate of recovery was seen in patients who were on non-invasive ventilation or high-flow oxygen, with a median time to recovery in the combination group of 10 days vs 18 days (RR 1.51, 95% CI 1.10 to 2.08). 

There was no statistical difference in mortality, though notably the highest difference in survival was seen in those with a baseline score of 5 or higher. There was no difference in outcomes when stratified by duration of symptoms:

Sounds promising, though given the prior findings with other immunomodulators such as Anakinra, then color me skeptic. I still am surprised remdesivir still works somewhat even up to 10 days after symptom onset. 

Wilson AM, Clark AB, Cahn T, et al. Effect of Co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Moderate and Severe Idiopathic Pulmonary Fibrosis: The EME-TIPAC Randomized Clinical Trial. JAMA. 2020;324(22):2282–2291. doi:10.1001/jama.2020.22960

This is a phase 3, double-blind, placebo-controlled trial that evaluated TMP-SMX vs standard of care in patients with IPF in terms of hospital admission, time to death and lung-transplant. Patients were excluded if they had a recent infection within 4 weeks, were on immunosuppression, or had FVC >75%.  342 patients were randomized across 39 sites. There were 0.45 (84/186) events per person years in the TMP-SMX Group vs 0.38 (80/209) in the standard of care group (HR 1.2, 95% CI 0.9-1.6).:

In terms of secondary outcomes, there were no statistical differences in lung function, or other questionnaire findings:

The idea behind this is that IPF patients tend to have higher bacterial loads and change in their lung microbiome. It has been found that those with high bacterial loads was associated with reduced progression-free survival. When compared to other trials, this one did not show any difference in antibiotic use for the composite primary outcome. One suggestion as to this difference may be that previous trials included patients with immunosuppression. Another one is the wide use of anti-fibrotics in this trial (pirfenidone and nintedanib) compared to prior trials (where this wasn’t the case). 

Kuehl R, Morata L, Boeing C, Subirana I, Seifert H, Rieg S, Kern WV, Kim HB, Kim ES, Liao CH, Tilley R, Lopez-Cortés LE, Llewelyn MJ, Fowler VG, Thwaites G, Cisneros JM, Scarborough M, Nsutebu E, Gurgui Ferrer M, Pérez JL, Barlow G, Hopkins S, Ternavasio-de la Vega HG, Török ME, Wilson P, Kaasch AJ, Soriano A; International Staphylococcus aureus collaboration study group and the ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis. Defining persistent Staphylococcus aureus bacteraemia: secondary analysis of a prospective cohort study. Lancet Infect Dis. 2020 Dec;20(12):1409-1417. doi: 10.1016/S1473-3099(20)30447-3. Epub 2020 Aug 4. PMID: 32763194.

This is a prospective study of multiple European centers which aimed to defined sustained Staphylococcus aureus bacteremia in a clinically relevant cut-off value. Duration of bacteremia was calculated in 2 different ways, one since the first day of positive blood cultures and another one from the first day of active antibiotic therapy after antibiotic therapy. Primary outcome was 90d mortality. A total of 987 patients were included in the analysis. Compared to patients with one day of bacteremia, those with more than 1 day had higher Charlson co-morbidity scores, higher SOFA scores, higher CRP< and longer interval from start of symptoms until first blood culture, Further, 90 day mortality increased from 22% on those with 1 day of bacteremia to 39% in those with 2-4 days of bacteremia. Using a cut-off of 2 days gave the investigators the earliest cut-off associated with increased hazard for mortality. Indeed, this cut-off gave them the most pronounced differentiator for 90-day mortality (aHR 1.93, 95% CI 1.51 to 2.46)

It shouldn’t be surprising that patients who . had longer bacteremia were more likely to have a deep focus of infection. For instance 7% of patients with a one day of bacteremia had IE compared to 29% of those with >7 days. I think this is a reasonable cut-off for staph aureus bacteremia, especially since after this I would start looking for a deep focus of infection. Either way, most ID people would give at least 4 weeks of antibiotics to anyone who has more than 2 days of bacteremia without endocarditis, as this would likely be a complicated case of SAB. 

Edison J Cano, Zachary A Yetmar, Raymund R Razonable, Cryptococcus Species Other Than Cryptococcus neoformans and Cryptococcus gattii: Are They Clinically Significant?, Open Forum Infectious Diseases, Volume 7, Issue 12, December 2020, ofaa527, https://doi.org/10.1093/ofid/ofaa527

This one is more of an interesting read. This was a retrospective study evaluating cases of isolated cryptococcus that were not neoformans or gatii. They found 54 cultures, of which 8 isolates were deemed pathogenic. These included C. laurentii, C. liquifaciens, C magnus, and C albidosimilis. 6 of these were part of a polymicrobial infection, and only one was a primary infection (peritonitis). Susceptibility of 2 isolates are as follows:

While interesting, I doubt we will be encountering any non-neoformains/gatii cryptococcus anytime soon, though it should be noted that if you do find them, there is a chance they will be resistant to either fluconazole or flucytosine. 

Supavit Chesdachai, Nicole W Engen, Joshua Rhein, Lillian Tugume, Tadeo Kiiza Kandole, Mahsa Abassi, Kenneth Ssebambulidde, John Kasibante, Darlisha A Williams, Caleb P Skipper, Kathy H Hullsiek, Abdu K Musubire, Radha Rajasingham, David B Meya, David R Boulware, Baseline Serum C-Reactive Protein Level Predicts Mortality in Cryptococcal Meningitis, Open Forum Infectious Diseases, Volume 7, Issue 12, December 2020, ofaa530, https://doi.org/10.1093/ofid/ofaa530

And staying on topic of cryptococcal meningitis, elevated CRP at baseline (or at least drawn within 5 days of diagnosis) was associated with higher mortality. In this cohort of 168 HIV-positive patients, CRP levels and their utility to predict mortality were evaluated. There were not difference between CRP levels and any CSF parameter, though CRP was higher in the ART group (56.3) when compared to the non-ART groups (45). Notably, those who were on ART for less than 30 days had higher CRP (77) compared to those who were on it for >30 days (48.8). 18-week mortality increased with increasing CRP quartiles: 14% in the <29 quartile, 41% in the 29-49.5 quartile, 56% in the 49.6-83.6 quartile, and 54% in the >83.6 quartile:

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