Weekly Articles – 1/10/2021

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Happy new year, it feels like 2021 is trying to give 2020 a run for its money. Oh boy!

Anyways, some COVID stuff since we’re over 4000 deaths a week here in the states.

Oussalah A, Gleye S, Clerc Urmes I, Laugel E, Callet J, Barbé F, Orlowski S, Malaplate C, Aimone-Gastin I, Caillierez BM, Merten M, Jeannesson E, Kormann R, Olivier JL, Rodriguez-Guéant RM, Namour F, Bevilacqua S, Losser MR, Levy B, Kimmoun A, Gibot S, Thilly N, Frimat L, Schvoerer E, Guéant JL. Long-term ACE Inhibitor/ARB Use Is Associated With Severe Renal Dysfunction and Acute Kidney Injury in Patients With Severe COVID-19: Results From a Referral Center Cohort in the Northeast of France. Clin Infect Dis. 2020 Dec 3;71(9):2447-2456. doi: 10.1093/cid/ciaa677. PMID: 32623470; PMCID: PMC7454376.

One interesting question that has been asked has been the risk of infection in those who take ACE-i. Recall that SARS-CoV2 binds to ACE receptors, so if you inhibit ACE then you would, reasonably, upregulate the amount of ACE-r in your body and have a higher risk of infection. This was a retrospective cohort study that evaluated the association of chronic ACE/ARB use with occurrence of kidney, lung, heart, and liver dysfunction in one center. Multivariate logistic regression analysis and bias-corrected and accelerated bootstrap interval was used to analyse the data. 162 patients were evaluated, of which 149 had data for ACEi/ARGB use. 19 were treated with ACEi (13%) compared to 25 (17%) treated with ARB. Patients treated with ACEi/ARB were associated with higher phosphorus, higher creatinine and BUN, lower bilirubin, and independently associated with AKI stage >1:

The low numbers are not terribly impressive here, so I do not know what to make of it. For now, I would keep the ACEi if someone is admitted with COVID unless I have a compelling reason to stop it. 

Timothy M Rawson, Luke S P Moore, Nina Zhu, Nishanthy Ranganathan, Keira Skolimowska, Mark Gilchrist, Giovanni Satta, Graham Cooke, Alison Holmes, Bacterial and Fungal Coinfection in Individuals With Coronavirus: A Rapid Review To Support COVID-19 Antimicrobial Prescribing, Clinical Infectious Diseases, Volume 71, Issue 9, 1 November 2020, Pages 2459–2468, https://doi.org/10.1093/cid/ciaa530

This was a review that evaluated 18 studies, 9 of which were SARS-CoV2 specific while the others were a mix of SARS and MERS. The goal was to evaluate the incidence of bacterial/fungal co-infection in those who were admitted. Overall, the incidence of bacterial/fungal coinfection was 8% (62/806), with 6% having reported bacteremia. The types of organisms ranged from Enterobacter spp, acinetobacter spp, legionella, Staph, E. coli, strep pneumo, Klebsiella pneumoniae, pseudomonas aeruginosa, Candida, and Aspergillus. So not a high percentage.Despite this, around 72% of patients across all studies received empiric antibiotic therapy. 

Couturaud F, Bertoletti L, Pastre J, Roy PM, Le Mao R, Gagnadoux F, Paleiron N, Schmidt J, Sanchez O, De Magalhaes E, Kamara M, Hoffmann C, Bressollette L, Nonent M, Tromeur C, Salaun PY, Barillot S, Gatineau F, Mismetti P, Girard P, Lacut K, Lemarié CA, Meyer G, Leroyer C; PEP Investigators. Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms. JAMA. 2021 Jan 5;325(1):59-68. doi: 10.1001/jama.2020.23567. PMID: 33399840. 

While this one is not an ID specific article, I nevertheless found it interesting, since COPD exacerbations are generally brought on by infections. This was a multicenter, cross-sectional study in 7 French groups. Primary endpoint was PE diagnosis within 48 hours of admission, patients were included if they were admitted within 48hrs and had some suspicion of pulmonary embolism based on the modified Geneva score. 740 patients were evaluated, of which 44 had pulmonary embolism confirmed during the admission (5.9%, 95% CI 4.5-7.9). PE was diagnosed in an additional 5 patients at 3 month follow up. Notably all-cause mortality rate was 6.8% (95 CI 5.2-8.8), with those with venous thromboembolism at admission having a mortality risk of 25.9% vs 5.2% without it (risk difference 20.7%, 95% CI 10.7 to 33.8%).

So overall, the risk of PE is low in COPD patients. I am not surprised those with clots have higher mortality, as risk of clots include immobility, which would stand to reason this means they’re so sick they cannot move. I still think this was an interesting article, nonetheless.

Now, a few interesting articles on CMV in the transplant population. Prior to this, let’s go over the IGRA (a full post is forthcoming in its role in tuberculosis, at some point…). Interferon-gamma release assays essentially allow you to measure the amount of interferon-gamma when your plasma is exposed to an antigen of a certain organism that you have been infected with in the past. So if you have been exposed to tuberculosis and your blood is exposed to these antigens, then your cells will release interferon-gamma. This is cellular immunity. In other words, if you have been exposed to TB at any point, when your blood is exposed to TB antigens, your cells should release interferon-gamma. This is what the assay measures. This can be used for other infections. 

When we talk about CMV and transplant, we talk about risk of CMV reactivation. Usually, this comes in the form of recipient IgG status and donor IgG status (R/D). So if you’re +/+, then you’re low risk of reactivation etc. Of course, even if you’re at low risk, you may still have reactivation of CMV. As such, certain strategies have emerged, with 2 of them usually seen depending on your transplant center. One of them is the  pre-emptive strategy, where you measure for CMV viremia at certain points prior to starting treatment. The other is prophylaxis where you just give therapy for a certain period of time. Again, this depends on your transplant center.  For CMV IGRA, interferon can be released in vitro when exposed to phosphoprotein 65 (pp65) and immediately-early 1 (IE-1). Usually IE-1 tends to have higher IFN-gamma levels when compared to pp65. 

Roy F Chemaly, Lynn El Haddad, Drew J Winston, Scott D Rowley, Kathleen M Mulane, Pranatharthi Chandrasekar, Robin K Avery, Parameswaran Hari, Karl S Peggs, Deepali Kumar, Rajneesh Nath, Per Ljungman, Sherif B Mossad, Sanjeet S Dadwal, Ted Blanchard, Dimpy P Shah, Ying Jiang, Ella Ariza-Heredia, Cytomegalovirus (CMV) Cell-Mediated Immunity and CMV Infection After Allogeneic Hematopoietic Cell Transplantation: The REACT Study, Clinical Infectious Diseases, Volume 71, Issue 9, 1 November 2020, Pages 2365–2374, https://doi.org/10.1093/cid/ciz1210

This is a multicenter study that evaluated CMV-ELISPOT assay in CMV-seropositive allo-HCT recipients to evaluate the relationship of the strength of T-cell response and CMV-reactivation. 241 CMV-seropositive patients were enrolled, with primary endpoint being clinically significant CMV infection (CMV reactivation or CMV disease requiring CMV therapy). IE-1 levels >100 per 250000 cells (cutoff 1) or IE-1 and pp65 levels both >100 per 250000 cells (cutoff 2) were the targets evaluated. These patients were evaluated over 6 months, notably those who had CMV-disease were more likely to have unrelated transplant, more likely to have received ATG and received steroid during the study period. 70 patients (29%) had CMV infection, of which 66 (94%) of patients had low CMV-cell mediated immunity (lower than the aforementioned threshold) according to cutoff 1. Notably, patients with low CMV-CMI were more likely to have CS-CMVi than patients with high CMV-CMI (RR 5.3, 95%CI 2.0-14) with IE-1 being higher in those who did not have CS-CMVi). 

Risk factors for CMV-disease included low CMV-CMI in univariate analysis as well as in the multivariate analysis, along with steroid use, sex, type of transplant, and acute GVHD:

Despite this, CMV-CMI levels was not associated with decreased mortality. 

Marta Jarque, Elena Crespo, Edoardo Melilli, Alex Gutiérrez, Francesc Moreso, Lluís Guirado, Ignacio Revuelta, Nuria Montero, Joan Torras, Lluís Riera, Maria Meneghini, Omar Taco, Anna Manonelles, Javier Paul, Daniel Seron, Carme Facundo, Josep M Cruzado, Salvador Gil Vernet, Josep M Grinyó, Oriol Bestard, Cellular Immunity to Predict the Risk of Cytomegalovirus Infection in Kidney Transplantation: A Prospective, Interventional, Multicenter Clinical Trial, Clinical Infectious Diseases, Volume 71, Issue 9, 1 November 2020, Pages 2375–2385, https://doi.org/10.1093/cid/ciz1209

Another study was performed in renal transplant patients. This was a 12-month prospective, multicenter, observational study evaluating pre-emptive or prophylactic therapy for CMV IgG positive recipients. These groups were then stratified according to risk of CMV based on CMV IE-1 positivity. These were put in a low risk category or a high risk category. Within these 2 categories, the groups were then randomized into 2 further groups, to either go into prophylactic or preemptive therapy. Super confusing, I know, so here’s the diagram:

The above is not really important, as that was part of another study and the authors just got the data to evaluate the incidence of CMV infection in the high risk pre-emptive group with comparison to the low-risk pre-emptive group. A cutoff of 20 IFN-gamma spots/ 3 x 103 was used. A total of 160 patients were enrolled and found that patients in the high risk CMI group had a higher incidence of CMV infection compared to the low-risk CMI group (73% vs 44%, OR 3.44, 95% CI 1.3 to 9.08), which was also seen in the prophylaxis cohort (OR 11.75, 95% CI 2.31-59.71). 

Notably, from the above table, it seems that basiliximab induction was associated with higher incidence of CMV infection when compared to rATG. Late onset CMV disease was also higher in the high risk group:

The accompanying editorial mentions that the application of IGRA-CMV is going to be difficult, as the optimal cutoffs are not known for each specific scenario, and what antigen is going to be best is still on the table. Further, you may actually need more than one IGRA and in fact, may have to track it post-transplant. Still, I think it is an interesting way of risk stratifying these patients. 

R R Kempker, L Mikiashvili, Y Zhao, D Benkeser, K Barbakadze, N Bablishvili, Z Avaliani, C A Peloquin, H M Blumberg, M Kipiani, Clinical Outcomes Among Patients With Drug-resistant Tuberculosis Receiving Bedaquiline- or Delamanid-Containing Regimens, Clinical Infectious Diseases, Volume 71, Issue 9, 1 November 2020, Pages 2336–2344, https://doi.org/10.1093/cid/ciz1107

This one is interesting. Delamanid, a new tuberculosis drug that works by inhibiting the synthesis of the mycobacterial cell wall. It is used to treat MDR-TB (resistant to rifampin, INH) and XDR-TB (resistant to rifampin, INH, a fluoroquinolone, and an injectable drug). Along with bedaquiline, it has been used as salvage therapy. This was a prospective observational study in patients with both MDR and XDR TB comparing outcomes in those getting bedaquiline vs delamanid. Patients were also started on linezolid and clofazamine. Primary endpoint was sputum culture conversion by 2 and 6 months and clinical treatment outcomes. Notably, those who got delamanid were those with albumin less than 3 grams/dL and those with HIV, HCV, and T2DM. 64 patients got bedaquiline and 31 got delamanid. Those in the bedaquiline group were more likely to be male, have multilobar involvement, and lower creatinine than those getting delamanid. The proportion of patients achieving sputum culture conversion were higher in patients getting bedaquiline-based regimen compared to delamanid-based regimen at 2 months (67% vs 47%, p-value 0.10) and at 6 months (95% vs 74%, p-value <0.01). There were 2 deaths and 7 treatment failures; all of these with the exception of one treatment failure were in patients getting delamanid-based regimens. 

Looking at this, it may be that bedaquiline may be superior to delamanid, however this is a small, observational study that is subject to bias. Either way, more data is forthcoming in regards to delamanid, and it is exciting to know there are more options for treatment of XDR-TB, as delamanid actually has less drug-drug interactions. 

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