Weekly Articles: 3/28/2021

Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021;325(12):1185–1195. doi:10.1001/jama.2021.2747

This is a meta-analysis consisting of all RCTs published in peer-reviewed journals as well as pre-prints evaluating convalescent plasma in confirmed or suspected COVID patients. Primary outcomes were all-cause mortality at any point, length of hospital stay, number of patients with clinical improvement or deterioration, number of patients requiring mechanical ventilation. Primary analysis included RCTs in published journals while a second analysis included all RCTs that included those in pre-print websites.  10 RCTs were included (4 in journals, 5 in pre-print, and one press release). 5 trials evaluated only one dose, while in the other a total of 2 doses were administered. There was no difference in mortality when evaluating the peer-reviewed journals, the pre-prints, or all studies pooled together:

The same was the case with length of hospital stay:

Or mechanical ventilation use:

While there was no significant heterogeneity between trials (see above), the certainty of evidence for morality was low due to imprecision concerns regarding the wide 95% CI for summary RR. I have not been a fan of convalescent plasma to begin with so these studies are not surprising to me. I suspect we are nearing the end of this plasma experiment. 

Voysey et al. (Feb 19, 2021). Single-Dose Administration and the Influence of the Timing of the Booster Dose on Immunogenicity and Efficacy of ChAdOx1 NCoV-19 (AZD1222) Vaccine: A Pooled Analysis of Four Randomised Trials. The Lancet. https://doi.org/10.1016/S0140-6736(21)00432-3

This one was a difficult one to tease through. This is an analysis of 4 randomized trials evaluating the ChAdOx1 vaccine (AZD1222), which is a chimp adenoviral vectored vaccine with the full-length SARS-CoV2 spike insert. The original trials had sought to evaluate a single dose, but after review of phase 1 data, a second dose was planned. Despite this, many patients did not choose to undergo the second dose and those that did had a delay due to manufacturing. As such, these trials were pooled together. Primary outcome was confirmed symptomatic COVID-19, with primary analysis consisting of cases occurring more than 14 days after the second dose. Patients were randomized in a 1:1 fashion to either vaccine or placebo. One trial evaluated a low first dose followed by a full, second dose. Over 17 thousand patients were included. Overall,  the vaccine proved to be 66.7% effective in preventing primary symptomatic infection:

It was less efficacious for non-symptomatic infections, though across all groups, the low dose plus standard dose had  higher efficacy. Furthermore, vaccine efficacy against cases requiring hospitalization was 100%. One notable thing here is that vaccine efficacy was not terribly impacted by the delay between the first and the (booster) second dose in all who got the vaccine:

Moreover, the amount of anti-SARS-CoV2 spike IgG response was not affected by the interval, up to 12 weeks in those aged <56:

And over the first 3 months, there was a minimal decrease in antibody levels (GMR 0.66, 95% CI 0.59 to 0.74) and up to 6 months (GMR 0.36, 95% CI 0.27 to 0.47).

This is reassuring in terms of being able to space out doses of vaccine beyond 14-21 days. I am curious as to how much would the titers drop if we extend the vaccine interval by 3 months and if only a single booster vaccine would be needed down the line, once this virus settles into circulation amongst all other respiratory viruses. I suspect this will be a vaccine we get every year along with the flu shot.

Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, Kottkamp A, Neuzil KM, Laufer MK, Deming M, Paasche-Orlow MK, Kissinger PJ, Luk A, Paolino K, Landovitz RJ, Hoffman R, Schaafsma TT, Krows ML, Thomas KK, Morrison S, Haugen HS, Kidoguchi L, Wener M, Greninger AL, Huang ML, Jerome KR, Wald A, Celum C, Chu HY, Baeten JM. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med. 2021 Mar;174(3):344-352. doi: 10.7326/M20-6519. Epub 2020 Dec 8. Erratum in: Ann Intern Med. 2021 Mar;174(3):435. PMID: 33284679; PMCID: PMC7732017.

The last nail in the coffin for HCQ? This was a mulit-center, double blind, controlled, household-randomized trial of HCQ as post-exposure prophylaxis (PEP) among close contacts of patients with COVID-19. Patients have to had close contact with an index case within 96hrs of enrollment. Exclusion criteria includedL symptoms of COVID, positive testing, hospitalization, or HCQ being contraindicated. Patients were randomized in a 1:1 ratio to HCQ (400mg/d for 3 day followed by 200mg/d for 11 days) or vitamin C. Meds were delivered within 48hrs of enrollment, which included a kit for RT-PCR testing. Primary endpoint was RT-PCR positivity, assessed daily, through day 14. 829 participants were enrolled, though after exclusion, the mITT population included 689 patients. A total of 98 cases were reported (incidence of 14.3%), 53 in the HCQ group, and 45 in the control group (aHR 1.10, 95% CI 0.73 to 1.66). The aHR for symptomatic COVID cases was 1.38 (95% CI 0.82 to 2.33):

I am not surprised, though it could be argued the delay in recruitment, enrollment, and delivery of medications may have affected the efficacy of HCQ, however the patients in the mITT analysis did not test positive prior to starting meds, so this may be a moot point. Notably, this study was funded by the Bill & Melinda Gates foundation, if that is a concern. 

Corey L, Gilbert PB, Juraska M, Montefiori DC, Morris L, Karuna ST, Edupuganti S, Mgodi NM, deCamp AC, Rudnicki E, Huang Y, Gonzales P, Cabello R, Orrell C, Lama JR, Laher F, Lazarus EM, Sanchez J, Frank I, Hinojosa J, Sobieszczyk ME, Marshall KE, Mukwekwerere PG, Makhema J, Baden LR, Mullins JI, Williamson C, Hural J, McElrath MJ, Bentley C, Takuva S, Gomez Lorenzo MM, Burns DN, Espy N, Randhawa AK, Kochar N, Piwowar-Manning E, Donnell DJ, Sista N, Andrew P, Kublin JG, Gray G, Ledgerwood JE, Mascola JR, Cohen MS; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 Study Teams. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N Engl J Med. 2021 Mar 18;384(11):1003-1014. doi: 10.1056/NEJMoa2031738. PMID: 33730454.

This was an analysis of two phase 2b, multicenter, randomized, double-blind, placebo-controlled trials of the broadly neutralizing antibody against HIV type 1 (VRC01). One trial enrolled males, transgendered patients while the other enrolled heterosexual women. Patients were randomized in a 1:1:1 fashion to a low dose of antibody (10mg/kg), high dose (30mg/kg) or placebo at a 8 week interval for 10 infusions (20mo total). Primary endpoint was documented HIV infection at week 80). PrEP was also provided to patients who wanted it. 4611 patients were enrolled across the two studies. VRC01 was not associated with lower incidence of HIV acquisition in either trial:

Viruses that were sensitive to the antibody (IC80 <1ug/mL) and pooled data noted lower incidence of infection here (0.20 per 100 person years in the VRC01 recipients vs 0.86 per 100 person years in placebo) when compared to intermediate or resistant antibodies:

Those in the study group had overall lower VL (9800 copies/mL vs 176k copies/mL) when compared to placebo group, suggesting some sort of inhibition even when there is some sort of breakthrough. This is unfortunate as I was hoping this would be a good alternative to PrEP for certain patient populations, but we will have to wait and see. 

Sarah Stabler, Jonathan Giovannelli, David Launay, Angélique Cotteau-Leroy, Marion Heusele, Guillaume Lefèvre, Louis Terriou, Marc Lambert, Sylvain Dubucquoi, Eric Hachulla, Vincent Sobanski, Serious Infectious Events and Immunoglobulin Replacement Therapy in Patients With Autoimmune Disease Receiving Rituximab: A Retrospective Cohort Study, Clinical Infectious Diseases, Volume 72, Issue 5, 1 March 2021, Pages 727–737, https://doi.org/10.1093/cid/ciaa127

This is a retrospective study evaluating the risk of serious infections following the use of rituximab in patients getting the drug for autoimmune disease. RTX was administered weekly for 4 weeks followed by maintenance of one dose every 6 months for up to 24 months. 247 patients were evaluated, of which 221 were analyzed corresponding to 276 courses of RTX. Most had some sort of connective tissue disease, SLE, Sjogren, RA, or systemic vasculitis, among other diseases. 78% were receiving some sort of steroid therapy and 48% were getting other immunosuppressive therapy (cyclophosphamide, azathioprine, cyclosporine, MTX, MMF, etc). There were a total of 47 episodes of infectious complications in 42 patients (19%), corresponding to a 1- and 2-year incidence of 17.3 (95% CI 12-22.5) and 11.3 (95% CI 8.1 to 14.5) per 100 person years, with a prevalence of 7.2%, 15.5%, and 17.8% at 3, 12, and 24 months, respectively.  45% were pneumonias while 21% were bacteremias. Univariate analysis found that diagnoses other than CTD/systemic vasculitis, and autoimmune cytopenia (HR 4.81, 95% CI 1.8 to 12.85), age (HR 1.02, 95% CI 1-1.04), diabetes (HR 2.35, 95% CI 1.21-4.56), history of cancer (HR 2.88, 95% CI 1.58-5.28), and steroid therapy >10mg daily (HR 2.99, 95% CI 1.06-8.43) were associated with higher likelihood of serious infectious complications. This is overall an interesting study to look at, even if single center. In the table looking at all infections, there are only 3 cases of PJP and no reactivation of viruses (only one case of JC virus). 

Lisette A P Krassenburg, Wayel R Zanjir, Firas Georgie, Emily Stotland, Harry L A Janssen, Bettina E Hansen, Jordan J Feld, Evaluation of Sustained Virologic Response as a Relevant Surrogate Endpoint for Long-term Outcomes of Hepatitis C Virus Infection, Clinical Infectious Diseases, Volume 72, Issue 5, 1 March 2021, Pages 780–786, https://doi.org/10.1093/cid/ciaa144

This one is a tricky one to talk about, but to start off with, it deals with SVR following therapy for HCV. Back in the days of IFN-based therapy, SVR was a surrogate marker for good outcomes. Now with the direct-acting antivirals (DAAs), everyone is getting SVR, meaning this will not be a good surrogate outcome anymore (in other words, whatever SVR meant when no one was getting it may not mean much now that everyone is able to achieve it. To quote the greatest second greatest villain of all “if everyone is a super, then no one is.”) This is a single center study taking place from June 2006 to December 2016 in those patients that were treated with either IFN or DAA, though the major analysis was between IFN-eligible patients who got DAA and IFN-treated patients. Primary outcome was liver-related event-free survival (decompensated liver disease and HCC). One interesting thing they did in the statistical analysis was use inverse probability of treatment weighting (IPTW) to figure out if SVR lead to a change in prognosis in those who got DAA by applying risk factors associated with disease progression in those who got IFN-treatment and did not achieve SVR. They also excluded patients who did not meet lab criteria for the IDEAL study. 1306 patients were evaluated, with 242 IFN-treated patients and 239 DAA treated patient who were IDEAL ineligible being evaluated as well for comparison. Most of hte patients who got DAA had cirrhosis at  baseline and were less likely to have NAFLD. A higher percentage of those who got DAA achieved SVR:

Event-free survival at 10 yeast was 93% in all SVR patients compared to 74% of patients who did not achieve SVR:

Furthermore, those who got IFN therapy had a higher incidence of events (63/10000 PY) compared to those who got DAA (29.5/10000 PY). Univariate and multivariate analysis found that achievement of SVR was associated with event-free survival at 24 months, while DAA therapy was not:

This suggests that SVR continues to maintain a prognostic value. Further, comparing patients who got IFN-therapy but did not get SVR to those with similar characteristics but got DAA, the event rate in IFN was 3.4% compared to 1.3% in the DAA group (p=0.02). While this is reassuring, the short duration and the fact that IPTW may likely not account for all confounders may limit its applicability and not necessarily remove doubts about the value of SVR in the age of DAA. 

Paula Debroy, Jordan E Lake, Carlee Moser, Maxine Olefsky, Kristine M Erlandson, Ann Scherzinger, James H Stein, Judith S Currier, Todd T Brown, Grace A McComsey, Antiretroviral Therapy Initiation Is Associated With Decreased Visceral and Subcutaneous Adipose Tissue Density in People Living With Human Immunodeficiency Virus, Clinical Infectious Diseases, Volume 72, Issue 6, 15 March 2021, Pages 979–986, https://doi.org/10.1093/cid/ciaa196

More HIV and weight gain! This was part of the AIDS Clinical Trial group that evaluated treatment-naive patients who were randomized to open-lael TDF/FTC + RAL OR TDF/FTC + ATV/r OR TDF/FTC + DRV/r for 96 weeks. A subset of these patients underwent CT for interpretation of body composition. Here, they quantified visceral abdominal fat and subcutaneous abdominal fat (VAT and SAT). These were interpreted based on area (cm2) and density (HU). Patients also had several lab values. A total of 334 patients were evaluated. In all treatment arms, the SAT and VAT density decreased over 96 weeks:

One surprising bit was the fact Raltegravir had a higher decrease in visceral fat compared to the ritonavir-boosted regimens. Readers will recall several summaries highlighting the weight-gain associated with integrase inhibitors. Women had a higher decrease in VAT as well:

Though 89% of the patients enrolled were male. The most interesting (or shocking, I should say) part of the study was that changes in VAT were associated with higher levels of hs-CRP/IL-6, as well as lower HDL and higher triglycerides, suggesting significant metabolic disturbances with reduction in VAT:

The authors note several hypothesis, including lower adipose tissue density being an indicator of larger adipocytes with larger lipid droplets, reflecting impaired adipogenesis, but I do not know what to make of this, in other words are these higher lab values reflective of underlying disorders of metabolism in these patients or are ART contributing to such things (as in the case with integrase inhibitors). Stay tuned, I guess. 

Laura A S Quilter, Alex de Voux, Rachel M Amiya, Erin Davies, Robin R Hennessy, Roxanne P Kerani, Robbie Madera, James Matthias, Victoria M Pearson, Jaime K Walters, Craig Wilson, Sarah Kidd, Elizabeth Torrone, Prevalence of Self-reported Neurologic and Ocular Symptoms in Early Syphilis Cases, Clinical Infectious Diseases, Volume 72, Issue 6, 15 March 2021, Pages 961–967, https://doi.org/10.1093/cid/ciaa180

This was a surveillance network study that evaluated the prevalence of self-reported neurological and/or ocular symptoms in patients with early syphilis (primary, secondary, or early latent). This network spans 5 states (Oregon, New York, Pennsylvania, Washington, and Florida). Providers were given a tool that included questions to be asked with regards to neurologi and/or ocular symptoms. Those who had symptoms and had tested positive for early syphilis then underwent enhanced neurosyphilis screening and then underwent a lumbar puncture. Over 13,000 cases of early syphilis were reported, of which 9123 were screened for neurologic symptoms. Of these, 151 reported at least one symptom (incidence of 1.7%, 95% CI 1.4-1.9). 35% of the 151 patients (n=51) underwent an LP, of which 42% had abnormal CSF. 12/98 patients without CSF were treated empirically for neurosyphilis. 

This study highlights two things: 1) neurosyphilis is quite rare and 2) being unable to get an LP in someone who does have CNS or ocular symptoms would make me treat for neurosyphilis, as nearly ½ of those who had CNS symptoms had abnormal CSF. This is an issue when it comes to altered patients (of which only 7 had AMS as their neurological symptom). The vast majority (39%) had headaches, followed by tinnitus:

Shelton W Wright, Taniya Kaewarpai, Lara Lovelace-Macon, Deirdre Ducken, Viriya Hantrakun, Kristina E Rudd, Prapit Teparrukkul, Rungnapa Phunpang, Peeraya Ekchariyawat, Adul Dulsuk, Boonhthanom Moonmueangsan, Chumpol Morakot, Ekkachai Thiansukhon, Direk Limmathurotsakul, Narisara Chantratita, T Eoin West, A 2-Biomarker Model Augments Clinical Prediction of Mortality in Melioidosis, Clinical Infectious Diseases, Volume 72, Issue 5, 1 March 2021, Pages 821–828, https://doi.org/10.1093/cid/ciaa126

Meliodosis is an infection caused by Burkholderia pseudomallei (I thought it was a skin condition) found in Southeast Asia and northern Australia. It causes severe septic shock. This study evaluated a biomarker model to predict mortality in these patients. Patients admitted to a single-center Thai hopsital were evaluated within 24hrs of admission. 191 patients were used in the derivation and internal validation sets, while an external validation set of 161 patients from another hospital was used. 8 biomarkers were subjected to a logistic regression analysis by least absolute shrinkage and selection operator (LASSO) to evaluate predictors of 28-day mortality and these, along with clinical variables, were used a logistic regression model. All 8 biomarkers were significantly higher in the non-survivors:

Of these, IL-6 and IL-8 were selected. A baseline risk model (age, sex, CCI was assesed with mSOFA and IL-6 and IL-8 and the addition of the biomarkers increased the mortality discrimination:

As seen above, this held true for the derivation and the internal and external cohorts. A model consisting of just IL-6 and IL-8 had a good AUC (0.83, 95% CI 0.75-0.91). In models that included the baseline risk model and mSOFA, both IL-6 and IL-8 had higher OR for mortality:

I think the study in and of itself is interesting, but kind of useless. It was difficult to follow as to the threshold of cytokines (most of them just note higher levels = badness). Plus there is no real score they report (unless I am missing something here). It goes on the way of, more inflammation = higher risk of mortality, which is not really surprising. I only mention this because B. psuedomallei is not something I read much on. 

Roman Kuchta, Marta Kołodziej-Sobocińska, Jan Brabec, Daniel Młocicki, Rusłan Sałamatin, Tomáš Scholz, Sparganosis (Spirometra) in Europe in the Molecular Era, Clinical Infectious Diseases, Volume 72, Issue 5, 1 March 2021, Pages 882–890, https://doi.org/10.1093/cid/ciaa1036

This is an interesting one to read. It talks about Sparganosis, which is a zoonosis caused by broad tapeworms of the genus Spirometra. This usually comes about when eating or using raw flesh of frogs, snakes or other tetrapods. It is similar to another larvae in that it causes subcutaneous manifestations (migrating larvae) where it is a mild disease, but it can reach the human intestine and cause disseminated infection. I would read on it, though it dables mostly into molecular phylogeny which makes my brain hurt.