Mitochondrial DNA (MT-DNA) levels assessed within a day of patients’ hospitalization for COVID-19 were highly elevated in those who ultimately died, required intensive care, intubation, or vasopressor or renal replacement therapy in comparison to those without these complications (JCI Insight 2021;jci.me/143299/pdf). After further validation, this testing, performed in about an hour using standard reverse transcription-polymerase chain reaction (rt-PCR) but without a DNA purification step, could give doctors a tool to know better when to implement treatments such as monoclonal antibodies, according to co-senior author Andrew Gelman, PhD.
Viral infections can trigger cellular necrosis, which releases MT-DNA and other MT-damage associated molecular patterns known to cause acute lung injury and systemic inflammation. With these pathologies found in COVID-19, the authors questioned whether elevated levels of circulating MT-DNA might be a risk factor for severe disease.
The blood samples of 97 patients with laboratory-confirmed SARS-CoV-2 infection admitted to Barnes-Jewish Hospital in St. Louis underwent two rounds of centrifugation to generate platelet poor plasma. The investigators then performed rt-PCR using a BioRad CFX-Connect instrument to measure MT-DNA levels.
The researchers found that MT-DNA levels were about 10-times higher in those who developed acute respiratory failure or eventually died. After multivariate analysis adjusting for age, sex, and comorbidities, MT-DNA remained an independent risk factor for mortality (2.24 adjusted odds ratio (OR); 1.28–4.16 95% confidence interval (CI); p value 0.015), intensive care admission (3.97 adjusted OR; 1.83–10.34 CI; p value 0.002), and intubation (8.48 adjusted OR; 3.48–27.33 CI; <0.0001 p value).
In comparison to other markers of inflammation typically measured in COVID-19 patients, including C-reactive protein, ferritin, lactase dehydrogenase, and D-dimer, MT-DNA levels yielded similar or improved area under the receiver operator characteristic (AUROC) for key outcomes (mortality and intensive care, similar AUROC of 0.68 and 0.75, respectively; intubation, superior AUROC at 0.86%).
The authors intend to continue assessing MT-DNA in a larger multicenter trial of patients hospitalized with COVID-19.
2021 ADA Standards of Care Highlight Glucose Meter Analytics
In the American Diabetes Association Standards of Medical Care in Diabetes–2021, the association (ADA) clarified its guidance about using point-of-care tests (POCT) to diagnose diabetes, expanded descriptions of glycemic measures beyond A1c, and emphasized analytical considerations with glucose meters (Diab Care 2021;44:S1).
In the section on diagnosing diabetes, ADA underscored that while POCT might have NGSP-certification and Food and Drug Administration (FDA) clearance for monitoring glycemic control in patients with diabetes, in both CLIA-regulated and CLIA-waived settings, only POCT cleared by FDA for diagnosing the disease should be deployed for that purpose, and only in the settings for which they have clearance.
In addition, the A1C testing subsection has been renamed to “Glycemic Assessment” and the recommendations for assessing A1C changed to “Assess glycemic status (A1C or other glycemic measurement).” The 2021 document also removed the prior 6.3 recommendation, “Point-of-care testing for A1C provides the opportunity for more timely treatment changes.”
ADA strengthened the recommendation on assessing hypoglycemia (6.9) to state that patients should not only be asked about any hypoglycemic episodes, but also that these episodes should be investigated as indicated. The prior recommendation did not stress the need for investigating these incidents.
In the section on diabetes technology, ADA made more prominent the recommendation that providers should be aware of differences in glucose meter accuracy, moving it to 7.3 from 7.7. The document also placed comments on meter standards earlier in the discussion. In addition, the authors changed a prior subsection labeled “Glucose Meter Accuracy” to “Glucose Meter Inaccuracy.”
The technology section also reflects changes to recommendation 27, which previously noted patients might be using glucose monitoring systems not approved by FDA to stating that “patients using diabetes devices should be allowed to use them in an inpatient setting when proper supervision is available.” The discussion around this recommendation notes FDA’s recent policy change in light of the COVID-19 pandemic to support hospitalized patients’ using their continuous glucose monitors.
Percentage Donor-derived Cell-free DNA Bests Endomyocardial Biopsy in Detecting Early Heart Transplant Rejection
Levels of donor-derived cell-free DNA (ddcfDNA) detect acute rejection (AR) after heart transplant and avert about 80% of invasive tissue biopsies used to detect rejection (Circulation 2021; 10.1161/CIRCULATIONAHA.120.049098).
The Genomic Research Alliance for Transplantation study involved 171 patients who underwent heart allografts at five hospitals in the metropolitan Washington, D.C. area. These individuals had surveillance monitoring at pre-specified times after their transplants, including endomyocardial biopsy (EMBx) and donor specific antibody and cytomegalovirus testing, along with assessment of immunosuppression trough levels. Before the transplants, the researchers also genotyped DNA from whole blood samples via shotgun sequencing of both transplant donors and recipients to identify single nucleotide polymorphisms for each donor-recipient pair.
The subjects, followed for a median of 17.7 months, had 1,392 EMBx and 1,834 ddcfDNA measurements. Median %ddcfDNA levels declined after surgery to 0.13% by 28 days. In patients with AR, %ddcfDNA rose again compared to those without rejection, 0.38 versus 0.03, and was detected 2 weeks to 3.2 months before a histopathology diagnosis from EMBx. The maximum %ddcfDNA area under the receiver operator characteristics curve (AUROC) for detecting AR (0.92) occurred at day 28 after transplant. %ddcfDNA ≥0.25% had a sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 81%, 85%, 19.6%, and 99.2%, respectively. In contrast, the sensitivity of EMBx to detect AR when %ddcfDNA ≥25 was 19.6%, with a specificity of 99.2% and NPV of 85%.
The researchers also found several notable differences in %ddcfDNA levels in patients who experienced antibody-mediated rejection (AMR) versus acute cellular rejection (ACR). %ddcfDNA levels were significantly higher in AMR than ACR, overall and at all grades of rejection. %ddcfDNA elevations also occurred earlier in AMR than in ACR, and the AUROC for AMR was higher than for ACR. Discerning AMR from ACR matters because the initial treatment strategies and long-term implications of rejection are quite different, according to the researchers.