Research Spotlight

Terrault, N.A., Burton, J., Ghobrial, M., Verna, E., Bayer, J., Klein, C., Victor, D., Mohan, S., Trotter, J., Dodge, J., Niemann, C.U. and Rubin, R.A. (2020). “Prospective Multicenter Study of Early Antiviral Therapy in Liver and Kidney Transplant Recipients of HCV-Viremic Donors.” Hepatology Sep 14. [Epub ahead of print.].

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Organs from HCV-viremic donors have been used in HCV-uninfected recipients (D+/R-) but the optimal treatment approach has not been defined. We evaluated the kinetics of HCV infection post-transplant in D+/R- kidney (KT) and liver transplant (LT) recipients when a preemptive antiviral strategy was used. Six U.S. transplant programs prospectively treated D+/R- primary LT and KT recipients with sofosbuvir-velpastasvir for 12 weeks starting once viremia was confirmed post-transplant and the patient judged to be clinically stable including eGFR >30 ml/min. Primary endpoints were sustained virologic response at 12 weeks post-transplant (SVR12) and safety (assessed by proportion of treatment-related adverse and serious adverse events). Of 24 patients transplanted (13 liver of whom 2 had prior treated HCV infection, 11 kidney), 23 became viremic post-transplant. The median (IQR) time from transplant to start of antiviral therapy was 7.0 (6.0,12.0) vs. 16.5 (9.8,24.5) days and the median (IQR) HCV RNA level 3 days after transplant was 6.5 (3.9,7.1) vs. 3.6 (2.9,4.0) log(10) IU/mL in LT vs. KT recipients, respectively. By week four of treatment, 10/13 (77%) LT, but only 2/10 (20%) KT had undetectable HCV RNA (p=0.01). At the end of treatment, all LT recipients were HCV RNA undetectable, while three (30%) of the kidney recipients still had detectable, but not quantifiable, viremia. All achieved SVR12 (lower 95% CI bound 85%). Serious adverse events considered possibly related to treatment were antibody-mediated rejection, biliary sclerosis, cardiomyopathy and graft-versus-host-disease, with the latter associated with multiorgan failure, premature treatment discontinuation and death. We conclude that despite differing kinetics of early HCV infection in liver versus non-liver recipients, a preemptive antiviral strategy is effective. Vigilance for adverse immunologic events is warranted.

Palazzuoli, A., Ruberto, F., De Ferrari, G.M., Forleo, G., Secco, G.G., Ruocco, G.M., D’Ascenzo, F., Mojoli, F., Monticone, S., Paggi, A., Vicenzi, M., Corcione, S., Palazzo, A.G., Landolina, M., Taravelli, E., Tavazzi, G., Blasi, F., Mancone, M., Birtolo, L.I., Alessandri, F., Infusino, F., Pugliese, F., Fedele, F., De Rosa, F.G., Emmett, M., Schussler, J.M., McCullough, P.A. and Tecson, K.M. (2020). “Inpatient Mortality According to Level of Respiratory Support Received for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019) Infection: A Prospective Multicenter Study.” Crit Care Explor 2(9): e0220.

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OBJECTIVES: To describe patients according to the maximum degree of respiratory support received and report their inpatient mortality due to coronavirus disease 2019. DESIGN: Analysis of patients in the Coracle registry from February 22, 2020, to April 1, 2020. SETTING: Hospitals in the Piedmont, Lombardy, Tuscany, and Lazio regions of Italy. PATIENTS: Nine-hundred forty-eight patients hospitalized for coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 948 patients, 122 (12.87%) received invasive ventilation, 637 (67.19%) received supplemental oxygen only, and 189 (19.94%) received no respiratory support. The median (quartile 1-quartile 3) age was 65 years (54-76.59 yr), and there was evidence of differential respiratory treatment by decade of life (p = 0.0046); patients greater than 80 years old were generally not intubated. There were 606 men (63.9%) in this study, and they were more likely to receive respiratory support than women (p < 0.0001). The rate of in-hospital death for invasive ventilation recipients was 22.95%, 12.87% for supplemental oxygen recipients, and 7.41% for those who received neither (p = 0.0004). A sensitivity analysis of the 770 patients less than 80 years old revealed a lower, but similar mortality trend (18.02%, 8.10%, 5.23%; p = 0.0008) among the 14.42%, 65.71%, and 19.87% of patients treated with mechanical ventilation, supplemental oxygen only, or neither. Overall, invasive ventilation recipients who died were significantly older than those who survived (median age: 68.5 yr [60-81.36 yr] vs 62.5 yr [55.52-71 yr]; p = 0.0145). CONCLUSIONS: Among patients hospitalized for coronavirus disease 2019, 13% received mechanical ventilation, which was associated with a mortality rate of 23%.

Chapagain, M., Gumbo, T., Heysell, S.K. and Srivastava, S. (2020). “Comparison of a Novel Regimen of Rifapentine, Tedizolid, and Minocycline with Standard Regimens for Treatment of Pulmonary Mycobacterium kansasii.” Antimicrob Agents Chemother 64(10).

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The combination of isoniazid, rifampin, and ethambutol is recommended by the American Thoracic Society (ATS) for treatment of pulmonary Mycobacterium kansasii, while the British Thoracic Society (BTS) recommends clarithromycin, rifampin and ethambutol. Unfortunately, therapy duration for both regimens lasts for years. In this study, we administered tedizolid, minocycline, clarithromycin, and rifapentine as monotherapy as well as novel combinations in the intracellular hollow-fiber model system of M. kansasii (HFS-Mkn) in a 28-day study. The ATS and BTS regimens were used as comparators. Repetitive sampling was used to validate the intended intrapulmonary pharmacokinetics of each drug and to monitor changes in M. kansasii burden. As monotherapy, tedizolid at an observed area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC of 5.85 and minocycline at an AUC(0-24)/MIC of 5.77 failed to kill the bacteria below day 0 (stasis), clarithromycin at an AUC(0-24)/MIC of 2.4 held the bacterial burden at stasis, but rifapentine at an AUC(0-24)/MIC of 140 killed 2 log(10) CFU/ml below stasis. The BTS regimen kill slope was -0.083 ± 0.035 CFU/ml/day, which was significantly superior to the ATS regimen slope of -0.038 ± 0.038 CFU/ml/day. The rifapentine-tedizolid-minocycline combination kill slope was -0.119 ± 0.031 CFU/ml/day, superior to that of the ATS regimen and comparable to that of the BTS regimen. In conclusion, the BTS regimen and the novel rifapentine-tedizolid-minocycline regimen showed better kill of intracellular bacteria in the HFS-Mkn However, the efficacy of the new combination regimen remains to be tested in clinical settings.

Shih, E., Squiers, J.J., Turner, J., DiMaio, M., Brinkman, W.T. and Smith, R.L. (2020). “Differential gene expression in patients with primary mitral valve disease: identifying potential therapeutic targets in the era of precision medicine.” J Investig Med 68(7): 1289-1291.

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Primary (degenerative) mitral valve (MV) disease is a result of structural remodeling due to degenerative and adaptive changes of MV tissue. We hypothesized that in patients with primary MV disease undergoing surgery for severe mitral regurgitation (MR), a distinct genetic expression profile within the MV leaflet tissue could be identified as compared with patients without MV disease. Tissue samples from the MV leaflets of 65 patients undergoing MV surgery for MR due to primary MV disease and 4 control cadavers without MV disease were collected and analyzed. MicroRNA transcripts were hybridized to Illumina HumanHT-12 v4 Beadchips. Ingenuity pathway analyses (IPAs) were conducted to provide biological interpretation. Of the approximately 20 000 genes examined, 4092 (20%) were differentially expressed between patients with primary MV disease and normal controls (false discovery rate<0.05). The differentially expressed genes could be clustered into five regulator effect networks from the Ingenuity Knowledge IPA database with a consistency score of >6. These five networks have been previously implicated in pathophysiological cardiac abnormalities, including inhibited contractility of the heart and fatty acid oxidation as well as activation of apoptosis of smooth muscle cells, cardiac degeneration, and hypertrophy of cardiac cells. MV tissue in patients with primary MV disease demonstrated distinct genetic expression patterns as compared with normal controls. Further studies are necessary to determine whether the molecular pathways identified in this experiment may represent potential therapeutic targets to prevent degeneration of MV tissue leading to severe MR.

Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., van Spaendonk, R.M.L., Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sebire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., de Grauw, T., Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Gonzalez Moron, D., Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A.M., Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., La Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Pineda Marfa, M., Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Rodriguez Espinosa, N., Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Sønderberg Roos, L.K., Stevens, C.A., Synofzik, M., Sztriha, L., Tibussek, D., Timmann, D., Tonduti, D., van de Warrenburg, B.P., Vázquez-López, M., Venkateswaran, S., Wasling, P., Wassmer, E., Webster, R.I., Wiegand, G., Yoon, G., Rotteveel, J., Schiffmann, R., van der Knaap, M., Vanderver, A., Martos-Moreno, G., Polychronakos, C., Wolf, N.I. and Bernard, G. (2020). “Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.” J Clin Endocrinol Metab Oct 1;dgaa700. [Epub ahead of print.].

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CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015-2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from three predominant centers. PATIENTS: 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-1, prolactin, ACTH, cortisol, TSH, and T4), height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically under-investigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.