Weekly Articles 8/29/2021

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ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators, Lawler PR, Goligher EC, Berger JS, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4. PMID: 34351721; PMCID: PMC8362594.

A pair of articles on anticoagulation. The first one is on non-critically ill patients admitted to non-ICU settings. This was an international, adaptive, ultiplatform, RCT that compared therapeutic anticoagulation with prophylactic anticoagulation with either LMWH or UFH. Patients with moderate COVID-19 who were admitted within 48 hours were enrolled. Patients were stratified according to their baseline D-dimer (>2 times ULN, <2 times ULN, or unknown). Primary outcome was organ support- free days, evaluated on an ordinal scale that combined in-hospital death and the number of days free of CV or respiratory organ support up to day 21. Primary analysis using a Bayesian cumulative logistic model that calculated the posterior probability distribution for the proportional OR for therapeutic-dose anticoagulation. 2219 patients were enrolled, with both groups being fairly well balanced. Adherence was better in the prophylactic group (98%) compared to the therapeutic cohort (88%). Primary outcome was achieved in 76% of the prophylactic group compared to 80.2% of the therapeutic-dose group, for an adjusted OR of 1.27 (95% CI 1.03-1.58), yielding a probability of superiority of therapeutic dose anticoagulation:

This comes out to 40 additional patients surviving for every 1000 hospitalizations with a therapeutic dose anticoagulation strategy at the expense of 7 additional major bleeding events. 

REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators, Goligher EC, Bradbury CA, McVerry BJ, Lawler PR, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):777-789. doi: 10.1056/NEJMoa2103417. Epub 2021 Aug 4. PMID: 34351722; PMCID: PMC8362592.

The second part of this study, published in the same issue, evaluated the critically ill cohort of patients that require any type of ICU support, either NIPPV, mechanical ventilation, or cardiovascular support. Primary outcome was the same as the other study, with similar statistical analysis being carried out. 1207 patients with severe COVID were enrolled, with both  groups being fairly well balanced with regards to baseline characteristics. 63% of patients in the therapeutic cohort and 65% of the prophylactic cohort survived to hospital discharge, with organ support free days according to the ordinal scale being 1 in the therapeutic dose cohort and 4 in the usual care cohort (aOR 0.83, 95% CI 0.67 to 1.03). 

This yielded a posterior probability of futility lf 99.9% and posterior probability of inferiority of 95%. There was also no significant difference in terms of major thrombotic events, death, or major bleeding between groups. In sensitivity analysis, there was no interaction between anticoagulation or IL-6 use or corticosteroid use. 

I think it has been a difficult ride in terms of what to do with anticoagulation. In fact, I think most of the initial post-mortem studies likely reflected disseminated intravascular coagulation in context of a very severe case of COVID and anticoagulation wouldn’t have done much in that context (i.e. the cytokine storm). Either way, I think thus far, it seems like a reasonable choice to do therapeutic anticoagulation in those who are not critically ill or if there is another indication for it, provided there is no high risk of bleeding. 

Jeremy Ratcliff, Dung Nguyen, Matthew Fish, Jennifer Rynne, Aislinn Jennings, Sarah Williams, Farah Al-Beidh, David Bonsall, Amy Evans, Tanya Golubchik, Anthony C Gordon, Abigail Lamikanra, Pat Tsang, Nick A Ciccone, Ullrich Leuscher, Wendy Slack, Emma Laing, Paul R Mouncey, Sheba Ziyenge, Marta Oliveira, Rutger Ploeg, Kathryn M Rowan, Manu Shankar-Hari, David J Roberts, David K Menon, Lise Estcourt, Peter Simmonds, Heli Harvala, REMAP-CAP Immunoglobulin Domain UK Investigators, Virological Characterization of Critically Ill Patients With COVID-19 in the United Kingdom: Interactions of Viral Load, Antibody Status, and B.1.1.7 Infection, The Journal of Infectious Diseases, Volume 224, Issue 4, 15 August 2021, Pages 595–605, https://doi.org/10.1093/infdis/jiab283

This was a study evaluating serological status and detection of B.1.1.7 during the enrollment of the REMAP-CAP trial. Patients who were admitted to the ICU with severe COVID within 48 hours were enrolled, and had RT-PCR and serology performed. A total of 1192 patients were enrolled, of which 251 had B.1.1.7 infection. Of the cohort, 804 were seropositive. Overall, the median viral load in seronegative patients was 36 time higher than in seropositive patients:

Negative serology, increasing age, and higher disease severity were associated with higher viral loads. Further, those who required invasive mechanical ventilation were found to have raised viral loads:

There was also a difference in terms of viral loads when looking at wild-type and B.1.1.7 infections, however this was only when those infected with WT strains had antibodies. In the cohort that did not have antibodies, the viral loads were fairly equal:

Looking at this table, its easier to see that immunosuppression, diabetes, and mechanical ventilation were associated with higher viral loads:

As we have seen in other article summaries, both mRNA vaccines as well as the adenovirus vector vaccine seem to induce some sort of antibody response that may be protective even against other variants. As a result of lower viral loads, there may be a protective benefit to them in terms of outcomes such as mechanical ventilation (which was associated with higher viral loads here). 

Yao L, Wang GL, Shen Y, Wang ZY, Zhan BD, Duan LJ, Lu B, Shi C, Gao YM, Peng HH, Wang GQ, Wang DM, Jiang MD, Cao GP, Ma MJ. Persistence of Antibody and Cellular Immune Responses in COVID-19 patients over Nine Months after Infection. J Infect Dis. 2021 May 12:jiab255. doi: 10.1093/infdis/jiab255. Epub ahead of print. PMID: 33978754; PMCID: PMC8243600.

This cross-sectional study evaluated 59 patients who were originally infected in China around 9-11 months back and evaluated their virus-specific antibody level as well as T cell and B cells. For each patient, 30 age and sex-matched health controls were used. Of the 59 COVID patients, 38 had moderate COVID, 16 had mild, and 5 were asymptomatic. 67% of those who had asymptomatic/mild disease and 50% with moderate disease had positive anti-IgG antibody at the time of testing:

Overall, 94% of patients had a positive anti-S IgG antibody detected:

Neutralization antibody activity was seen indirectly via sVNT in 63% of moderate patients and 71% of asymptomatic/mild patients, which was higher when directly evaluated by pVNT:

Geometric mean titer of neutralizing antibody seen was still higher in asymptomatic/mild patients compared to the moderate patients:

IgG memory B cell activity was similar between groups, as was IFN release, with levels being significantly higher in both COVID groups, though here, responses seemed to favor the moderate cohort:

I think this is reassuring in terms of immunity, at least when it comes to the concern for waning immunity with vaccination. Though it is difficult to make this assertion given this data comes from those who were infected, and the impact on waning immunity on variants remains to be seen. Nevertheless, the immune response seems to be fairly adequate even up to 11 months out. One concern in the future would be if the idea of “antigenic sin” would apply, meaning would subsequent exposures to different variants of COVID would boost the initial response rather than the subsequent exposures. Questions for later, I think. 

Steensels D, Pierlet N, Penders J, Mesotten D, Heylen L. Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273. JAMA. Published online August 30, 2021. doi:10.1001/jama.2021.15125

This cohort evaluated health care workers in a tertiary center who received either the Pfizer or Moderna vaccine in terms of antibodies against the nucleocapsid protein. Overall, 1647 people were enrolled. The mean titer following 2 doses of the moderna vaccine was 3863 U/mL vs 1444 U/mL in the Pfizer vaccine. Previously infected individuals also had a higher antibody titer (GMT 9461 U/mL) compared to those who were not previously infected (1613 U/mL). In both groups, the moderna vaccine elicited higher antibody response, however:

Regression coefficient found that vaccination with the moderna shot and prior infection were correlated with antibody response:

The authors postulate this could have been due to the longer interval of priming between the primer and booster vaccines, but both seem to provide similar protection in clinical trials.

Omland LH, Vestergaard HT, Dessau RB, Bodilsen J, Andersen NS, Christiansen CB, Ellermann-Eriksen S, Nielsen L, Andersen CØ, Lebech AM, Obel N. Characteristics and long-term prognosis of Danish patients with varicella zoster virus detected in the cerebrospinal fluid, compared with the background population. J Infect Dis. 2021 Jan 8:jiab013. doi: 10.1093/infdis/jiab013. Epub ahead of print. PMID: 33417703.

Now for some non-COVID articles. This study evaluated risk factors for detection of VZV DNA in CSF as well as prognosis in those who have it in comparison to negative controls in terms of mortality, neurologic, and psychiatric co-morbidities. Patients who had VZV DNA in their CSF were matched with 19 patients with the same sex and date of birth. 517 patients with positive PCR were identified, of which 43% had encephalitis, 20% had meningitis. Of these, 149 VZV cohort were matched with 447 controls. Comparing both cohorts, those who had VZV were more likely to be admitted to the hospital, be on immunosuppressive therapy leading up to the study, had a co-morbidity or immunosuppressive conditions:

Mortality was increased in the VZV cohort (HR 5.42, 95% CI 3.59-8.19 in first year; HR 1.54, 95% CI 1.21-1.95 second year). I encourage you to look at table 3, but to summarize, those who had VZV had higher risk of epilepsy even within one year of admission, as well as increased risk of dementia which held true up to 12 years out.

Interestingly, this was not seen for psychiatric conditions. Further, those in the VZV cohort were more likely to be prescribed CNS medications and social function was lower as well in the same cohort. This shouldn’t be surprising, as meningitis/encephalitis tend to be seen more in older populations and can be a devastating disease in terms of social functioning. 

McMahon DK, Zheng L, Cyktor JC, Aga E, Macatangay BJ, Godfrey C, Para M, Mitsuyasu RT, Hesselgesser J, Dragavon J, Dobrowolski C, Karn J, Acosta EP, Gandhi RT, Mellors JW. A Phase 1/2 Randomized, Placebo-Controlled Trial of Romidespin in Persons With HIV-1 on Suppressive Antiretroviral Therapy. J Infect Dis. 2021 Aug 16;224(4):648-656. doi: 10.1093/infdis/jiaa777. PMID: 34398236; PMCID: PMC8366434.

This study was a phase 1 and 2, double-blind, randomized, placebo controlled trial that evaluated the drug Romidepsin, which is a histone deacetylase inhibitor in patients with HIV who were virally suppressed and on a regimen that was not PI-based (due to drug-drug interactions). The idea here was to induce HIV-1 expression from latent areas, essentially a “kick and kill” strategy to get rid of any area of the body which may harbor some sort of latent HIV copies that are not high to allow for viremia. This was more of a safety trial, with different doses being evaluated (single dose in the following doses: 0.5mg/m2, 2mg/mg2, or 5mg/m2 OR a total of 20mg/m2 over 4 doses at day 0, 14, 28, and 42). Primary safety outcome was occurrence of grade 3+ adverse events with primary outcomes being conducted between the pooled romidepsin cohort and the placebo in the first 3 doses, and pooled cohort 4 (the 20mg/m2 dose) vs placebo. 59 patients were enrolled, with minimal differences seen (for instance, CD4 count in the placebo that was compared with the 20mg/m2 total dose was significantly higher) though this is likely due to the small number of patients. There were no virologic failures. For the first 3 cohorts (overall dose <5mg/m2), no grade 3 adverse events were reported, with the most common being neutropenia in 1, prolonged QTc in 2, and fatigue in 3. The multi dose cohort did have one grade 3 adverse event with neutropenia down to 744 cells/mm3, however this improved after cessation of drug:

There was no difference in single-copy assay HIV-RNA at any point when comparing the first 3 cohorts with the placebo cohort:

This pattern held true in the cumulative cohort, though there was a difference at hour 72 post infusion with a blip in SCA for the placebo cohort:

This was a fairly interesting subject, in an attempt to see if HIV-1 therapy can be better than “lifelong” by stimulating those copies that are hiding in the body, but we’ll see if better results come from a larger trial. 

Hearps AC, Angelovich TA, Trevillyan JM, Wong ME, Calmy A, Hoy JF, Jaworowski A. Effect of Rosuvastatin Therapy on Biomarkers of Inflammation and Immune Activation in People With Human Immunodeficiency Virus at Intermediate Cardiovascular Risk. J Infect Dis. 2021 Aug 16;224(4):667-672. doi: 10.1093/infdis/jiaa775. PMID: 34398237.

What about rosuvastatin and HIV? This was a subanalysis of a randomized, placebo-controlled trial evaluating rosuvastatin in patients with HIV with moderate cardiovascular risk. Here, they took a look at markers of inflammation (CXCL10, endothelial activation molecule sVCAM-1, soluble TNF-2 receptor, and LPS-induced monocyte activation, sCD14), as well as standard lipid panel. Patients were randomized in a 1:1 fashion to receive 20mg rosuvastatin or placebo, with primary outcome being the change from baseline to week 96 in carotid intima-media thickness. 99 patients were enrolled, with those in the placebo cohort having overall lower CD4 count on enrollment and a shorter time since diagnosis, however both groups were fairly similar. In this cohort, the median cIMT was 0.7mm, suggesting minimal atherosclerosis. Rosuvastatin decreased LDL, total cholesterol, and triglyceride levels after 48 weeks:

Looking at the inflammatory biomarkers, however, there was no difference between groups as seen above, suggesting minimal impact of statin on these. How statin will impact the overall CVD risk in this population remains to be seen, pending the results of the parent trial, though it is early to jump the gun at the moment.  

Barbee LA, Soge OO, Khosropour CM, Haglund M, Yeung W, Hughes J, Golden MR. The Duration of Pharyngeal Gonorrhea: A Natural History Study. Clin Infect Dis. 2021 Jan 30;73(4):575–82. doi: 10.1093/cid/ciab071. Epub ahead of print. PMID: 33513222; PMCID: PMC8366826.

How long does it take for pharyngeal gonorrhea to go away? In this longitudinal cohort study, 140 men who have sex with men were enrolled in this cohort study and they were asked to self-collect both rectal and pharyngeal specimens weekly along with completing a survey. Infections were classified when they had 2 consecutive positive tests and clearance as 2 consecutive negative tests. Notably, the authors also included patients who used methamphetamines or poppers as well as those who had >2 sexual partners in the past 2 months or >5 within <12 months. The STI test were not delivered in real time. Of the 140 men, 28 did not complete any study. 21 pharyngeal gonorrhea infections developed in 19 men, corresponding to an incidence of 31/7/100 person-years. The median duration of untreated pharyngeal gonorrhea was 16.3 weeks:

This did not vary based on HIV status, concurrent pharyngea. Chlamydia, smoking status, or history of gonorrhea. In addition, there were 25 single-positive specimens which decreased the median duration to 10 weeks. Risk factors here included kissing, oral-penal, oral-anal sex or any combination. 

Saman Nematollahi, Nitipong Permpalung, Sean X Zhang, Megan Morales, Kieren A Marr, Aspergillus lentulus: An Under-recognized Cause of Antifungal Drug-Resistant Aspergillosis, Open Forum Infectious Diseases, Volume 8, Issue 8, August 2021, ofab392, https://doi.org/10.1093/ofid/ofab392

This case-series describes 4 patients who were diagnosed with Aspergillus lentulus of pulmonary specimens (BAL). All had some degree of immunosuppression (alcoholic cirrhosis s/p liver transplant, untreated pulmonary sarcoidosis, metastatic pancreatic cancer with pulmonary sarcoidosis, and OHT). The main table is as follows:

As noted, the MIC to voriconazole was high in 3 out of 4 specimens (most cut-offs are at around 2), while MIC For ampB was as high as 8. The main point is that A. lentulus, which can be misidentified as A. fumigatus, has high MICs to several antifungals.

Hofmann D, Sayasone S, Sengngam K, Chongvilay B, Hattendorf J, Keiser J. Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial. Lancet Infect Dis. 2021 Aug;21(8):1151-1160. doi: 10.1016/S1473-3099(20)30691-5. Epub 2021 Mar 30. PMID: 33798487.

THis was a randomized, parallel-group, single-blind, placebo controlled trial evaluating the efficacy and safety of moxidectin for the treatment of strongyloidiasis. Patients were randomized into seven groups, one placebo and 6 experimental groups with increasing doses of moxidectin: 2mg, 4mg, 6mg, 8mg, 10mg, and 12mg. All patients were given a single dose of the drug or placebo. Primary endpoint was cure rate against S. stercoralis assess based on the difference between baseline stool samples and 28 day stool samples. A total of 223 patients were enrolled. Cure rates increased with increasing doses, plateauing at 8mg:

Further all experimental groups had a reduction in larvae of at least 98%. There were also minimal adverse events, with most being headaches, diarrhea, itching, mostly occurring around 3-24hrs after therapy. Of note, there were minimal cure rates against other worms, such as A. lumbricoides or T. trichuria.

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