Publications by authors named "Jonathan R Honegger"

14 Publications

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Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant.

J Allergy Clin Immunol 2021 Feb 30;147(2):532-544.e1. Epub 2020 Sep 30.

Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, Ohio; Center for Vaccines and Immunity, The Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio; Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, Ohio.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others.

Objective: Although several risk factors have been identified as related to complications from and severity of COVID-19, much about the virus remains unknown. The host immune response appears to affect the outcome of disease. It is not surprising that patients with intrinsic or secondary immune compromise might be particularly susceptible to complications from SARS-CoV-2 infection. Pathogenic loss-of-function or gain-of-function heterozygous variants in nuclear factor-κB2 have been reported to be associated with either a combined immunodeficiency or common variable immunodeficiency phenotype.

Methods: We evaluated the functional consequence and immunologic phenotype of a novel NFKB2 loss of function variant in a 17-year-old male patient and describe the clinical management of SARS-CoV-2 infection in this context.

Results: This patient required a 2-week hospitalization for SARS-CoV-2 infection, including 7 days of mechanical ventilation. We used biologic therapies to avert potentially fatal acute respiratory distress syndrome and treat hyperinflammatory responses. The patient had an immunologic phenotype of B-cell dysregulation with decreased switched memory B cells. Despite the underlying immune dysfunction, he recovered from the infection with intense management.

Conclusions: This clinical case exemplifies some of the practical challenges in management of patients with SARS-CoV-2 infection, especially in the context of underlying immune dysregulation.
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http://dx.doi.org/10.1016/j.jaci.2020.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525247PMC
February 2021

Nucleic Acid Testing for Diagnosis of Perinatally-Acquired Hepatitis C Virus Infection in Early Infancy.

Clin Infect Dis 2020 Jul 8. Epub 2020 Jul 8.

Division of Pediatric Infectious Disease, Department of Pediatrics, Nationwide Children's Hospital - The Ohio State University College of Medicine, Columbus, OH, USA.

Background: Most U.S. children with perinatal hepatitis C virus (HCV) exposure fail to receive the recommended anti-HCV antibody test at age ≥18 months. Earlier testing for viral RNA might facilitate increased screening, but sensitivity of this approach has not been established. We hypothesized that modern HCV-RNA RT-PCR platforms would adequately detect infected infants.

Methods: Nationwide Children's Hospital electronic health records from 1/1/2008 to 6/30/2018 were reviewed to identify perinatally-exposed infants tested by HCV-RNA RT-PCR at age 2-6 months. Diagnostic performance was determined using a composite case definition: 1) infected children had positive repeat HCV-RNA testing or positive anti-HCV at age ≥24 months; 2) uninfected children lacked these criteria and had negative anti-HCV at age ≥18 months.

Results: During the study period, 770 perinatally-exposed infants underwent HCV-RNA testing at age 2-6 months. Of these, 28 (3.6%) tested positive, and viremia was confirmed in all who underwent repeat testing (n=27). Among 742 infants with negative HCV-RNA results, 226 received follow-up anti-HCV testing at age ≥18 months, of whom 223 tested negative. Three children had low-positive anti-HCV results at age 18-24 months that were negative upon re-testing after age 24 months, possibly indicating waning maternal antibodies. Using the composite case definitions, early HCV-RNA screening demonstrated sensitivity of 100% (87.5%-100%, Wilson-Brown 95% confidence interval) and specificity of 100% (98.3-100%).

Conclusion: Modern HCV-RNA RT-PCR assays have excellent sensitivity for diagnosis of perinatally-acquired infection at age 2-6 months and could aid HCV surveillance given the substantial loss to follow-up at ≥18 months of age.
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http://dx.doi.org/10.1093/cid/ciaa949DOI Listing
July 2020

T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy.

Cold Spring Harb Perspect Med 2021 Jan 4;11(1). Epub 2021 Jan 4.

The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA.

Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4 and CD8 T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an era of highly effective antiviral therapy for chronic hepatitis C. First, the characteristics of successful T-cell responses that promote resolution of HCV infection are considered, as they will underpin development of vaccines that prevent HCV persistence. Second, defects in T-cell immunity that facilitate HCV persistence and whether they are reversed after antiviral cure to provide protection from reinfection are also addressed.
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http://dx.doi.org/10.1101/cshperspect.a036954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778213PMC
January 2021

CD4+ T cell restoration and control of hepatitis C virus replication after childbirth.

J Clin Invest 2020 02;130(2):748-753

The Ohio State University College of Medicine, Columbus, Ohio, USA.

Chronic hepatitis C virus (HCV) infection is characterized by persistent high-level viremia and defective cellular immunity, including a lack of functional HCV-specific CD4+ T cells. We previously described an exceptional period of viral control that occurs in some chronically infected women after childbirth. Here, we investigated whether reduced HCV replication after pregnancy is associated with recovery of CD4+ T cell immunity. Class II tetramer analysis revealed significantly greater frequencies of circulating HCV-specific CD4+ T cells at 3 months postpartum in women with concurrent declines in viremia compared with those with stable viremia. These HCV-specific CD4+ T cells had an effector-memory phenotype. Inhibitory coreceptor expression on these cells corresponded to the degree of viral control. Circulating CD4+ T cells produced IL-2 and IFN-γ after HCV antigen stimulation, demonstrating Th1 functionality. These data provide direct evidence that the profound loss of HCV-specific CD4+ T cell help that results in chronic infection is reversible following pregnancy, and this recovery of CD4+ T cells is associated with at least transient control of persistent viral replication.
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http://dx.doi.org/10.1172/JCI123623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994162PMC
February 2020

Ledipasvir-Sofosbuvir for 12 Weeks in Children 3 to <6 Years Old With Chronic Hepatitis C.

Hepatology 2020 02 19;71(2):422-430. Epub 2019 Aug 19.

Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH.

For children under 12 years of age who have chronic hepatitis C virus (HCV) infection, there are currently no approved treatments with direct-acting antiviral agents. We therefore evaluated the safety and efficacy of ledipasvir-sofosbuvir in HCV-infected children aged 3 to <6 years. In an open-label study, patients 3 to <6 years old chronically infected with HCV genotype 1 (n = 33) or 4 (n = 1) received weight-based doses of combined ledipasvir-sofosbuvir as granules (33.75 mg/150 mg for weights <17 kg or 45 mg/200 mg for weights ≥17 kg) for 12 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). For the first 14 patients, intensive pharmacokinetic sampling was done on day 10 of treatment. All patients had been infected through perinatal transmission and were treatment naïve. No patients had known cirrhosis. Ten patients (29%) weighed <17 kg. SVR12 was achieved in 97% of patients (33 of 34); the patient who did not achieve SVR12 was 3 years old and discontinued treatment after 5 days because of an adverse event "abnormal drug taste." The most common adverse events were vomiting (24% of patients), cough (21%), and pyrexia (21%). No patients experienced a serious adverse event. Intensive pharmacokinetic analysis of 13 patients for whom data were evaluable confirmed that the doses selected were appropriate. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 3 to <6 years old with chronic HCV infection.
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http://dx.doi.org/10.1002/hep.30830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028138PMC
February 2020

Clinical and Radiologic Manifestations of Bone Infection in Children with Cat Scratch Disease.

J Pediatr 2018 10 2;201:274-280.e12. Epub 2018 Jul 2.

Pediatrics, Nationwide Children's Hospital, Columbus, OH; The Ohio State University College of Medicine, Columbus, OH.

We identified 13 patients with cat scratch (Bartonella henselae) bone infection among those admitted to a large tertiary care children's hospital over a 12-year period. The median age was 7 years and the median time from onset of illness to diagnosis was 10 days. Multifocal osteomyelitis involving spine and pelvis was common; no patient had a lytic bone lesion. Median treatment duration was 28 days (IQR, 24.5 days). Despite significant variations in treatment duration and antimicrobial therapy choices, all patients showed improvement.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.033DOI Listing
October 2018

Enhanced identification of maternal hepatitis C virus infection using existing public health surveillance systems.

Paediatr Perinat Epidemiol 2018 07 4;32(4):401-410. Epub 2018 Jul 4.

Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.

Background: Hepatitis C virus (HCV) infection is under-recognized among US adults and children. Prenatal HCV screening may help close the diagnosis gap among women while also identifying at-risk infants. Current surveillance efforts for maternal HCV rely primarily on birth certificate data. We sought a more accurate assessment of HCV prevalence among pregnant women in Ohio by combining existing public health surveillance data.

Methods: Vital Statistics (VS) birth certificate data and Ohio Disease Reporting System (ODRS) HCV case data, both available through the Ohio Department of Health, were linked to determine rates of past or present HCV infection among women giving birth from 2012 to 2015 in Ohio, overall and by county. Among women with available test results, the proportion with present HCV infection indicated by detectable viraemia during pregnancy was calculated.

Results: Birth certificate data identified 4695 deliveries to women with past/present HCV infection during the study period. Linkage to ODRS revealed an additional 1778 deliveries to women with past/present infection, including 355 with confirmed viraemia during pregnancy. The prevalence of past/present HCV among pregnant women in Ohio rose from 0.82% in 2012 to 1.54% in 2015.

Conclusions: Maternal HCV infection is under-recognized and increasing in prevalence. Current case identification processes are inadequate in pregnancy, even among women with prior positive HCV testing. Alternative approaches, including enhanced risk factor-based screening or universal prenatal screening in high prevalence settings, are needed to improve rates of HCV recognition among reproductive-aged women and newborns at risk of vertical transmission.
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http://dx.doi.org/10.1111/ppe.12481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512319PMC
July 2018

Prolonged activation of innate antiviral gene signature after childbirth is determined by IFNL3 genotype.

Proc Natl Acad Sci U S A 2016 09 6;113(38):10678-83. Epub 2016 Sep 6.

Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30329; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329

Maternal innate and adaptive immune responses are modulated during pregnancy to concurrently defend against infection and tolerate the semiallogeneic fetus. The restoration of these systems after childbirth is poorly understood. We reasoned that enhanced innate immune activation may extend beyond gestation while adaptive immunity recovers. To test this hypothesis, the transcriptional profiles of total peripheral blood mononuclear cells following delivery in healthy women were compared with those of nonpregnant control subjects. Interestingly, interferon-stimulated genes (ISGs) encoding proteins such as IFIT1, IFIT2, and IFIT3, as well as signaling proteins such as STAT1, STAT2, and MAVS, were enriched postpartum. Antiviral genes were primarily expressed in CD14(+) cells and could be stratified according to genetic variation at the interferon-λ3 gene (IFNL3, also named IL28B) SNP rs12979860. Antiviral gene expression was sustained beyond 6 mo following delivery in mothers with a CT or TT genotype, but resembled baseline nonpregnant control levels following delivery in mothers with a CC genotype. CT and TT IFNL3 genotypes have been associated with persistent elevated ISG expression in individuals chronically infected with hepatitis C virus. Together, these data suggest that postpartum, the normalization of the physiological rheostat controlling IFN signaling depends on IFNL3 genotype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035891PMC
http://dx.doi.org/10.1073/pnas.1602319113DOI Listing
September 2016

Influence of IFNL3 and HLA-DPB1 genotype on postpartum control of hepatitis C virus replication and T-cell recovery.

Proc Natl Acad Sci U S A 2016 09 6;113(38):10684-9. Epub 2016 Sep 6.

The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205;

Chronic hepatitis C virus (HCV) infection is characterized by exhaustion of virus-specific T-cells and stable viremia. Pregnancy is an exception. Viremia gradually climbs during gestation but sometimes declines sharply in the months following delivery. Here, we demonstrated that postpartum HCV control was associated with enhanced virus-specific T-cell immunity. Women with viral load declines of at least 1 log10 between the third trimester and 3-mo postpartum exhibited HCV-specific T-cell responses of greater breadth (P = 0.0052) and magnitude (P = 0.026) at 3-mo postpartum than women who failed to control viremia. Moreover, viral dynamics were consistent in women after consecutive pregnancies, suggesting genetic underpinnings. We therefore searched for genetic associations with human leukocyte antigen (HLA) alleles and IFN-λ3 gene (IFNL3) polymorphisms that influence HCV infection outcome. Postpartum viral control was associated with the IFNL3 rs12979860 genotype CC (P = 0.045 at 6 mo) that predicts a positive response to IFN-based therapy. Suppression of virus replication after pregnancy was also strongly influenced by the HLA class II DPB1 locus. HLA-DPB1 alleles are classified by high and low patterns of expression. Carriage of at least one high-expression HLA-DPB1 allele predicted resurgent virus-specific T-cell immunity and viral control at 3-mo postpartum (P = 0.0002). When considered together in multivariable analysis, IFNL3 and HLA-DPB1 independently affected viral control at 3- and 6-mo postpartum. Together, these findings support a model where spontaneous control of HCV such as sometimes follows pregnancy is governed by genetic polymorphisms that affect type III IFN signaling and virus-specific cellular immune responses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035892PMC
http://dx.doi.org/10.1073/pnas.1602337113DOI Listing
September 2016

HCV adaptations to altered CD8 T-cell immunity during pregnancy.

Future Virol 2014 Apr;9(4):333-336

Center for Vaccines & Immunity, Nationwide Children's Hospital, Columbus, OH, USA ; Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH, USA.

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http://dx.doi.org/10.2217/fvl.14.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145594PMC
April 2014

Will there be a vaccine to prevent HCV infection?

Semin Liver Dis 2014 Feb 29;34(1):79-88. Epub 2014 Apr 29.

The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio.

Prevention of hepatitis C virus (HCV) infection by vaccination has been a priority since discovery of the virus and the need has not diminished over the past 25 years. Infection rates are increasing in developed countries because of intravenous drug use. Reducing transmission will be difficult without a vaccine to prevent persistence of primary infections, and also secondary infections that may occur after cure of chronic hepatitis C with increasingly effective direct-acting antiviral (DAA) regimens. Vaccine need is also acute in resource poor countries where most new infections occur and DAAs may be unaffordable. Spontaneous resolution of HCV infection confers durable protection, but mechanisms of immunity remain obscure and contested in the context of vaccine design. A vaccine must elicit a CD4+ helper T cell response that does not fail during acute infection. The need for neutralizing antibodies versus cytotoxic CD8+ T cells is unsettled and reflected in the design of two very different vaccines evaluated in humans for safety and immunogenicity. Here we review the status of vaccine development and the scientific and practical challenges that must be met if the burden of liver disease caused by HCV is to be reduced or eliminated.
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http://dx.doi.org/10.1055/s-0034-1371081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278371PMC
February 2014

Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses.

Nat Med 2013 Nov 27;19(11):1529-33. Epub 2013 Oct 27.

1] The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio, USA. [2] Department of Pediatrics, The Ohio State University School of Medicine, Columbus, Ohio, USA.

Globally, about 1% of pregnant women are persistently infected with the hepatitis C virus (HCV). Mother-to-child transmission of HCV occurs in 3-5% of pregnancies and accounts for most new childhood infections. HCV-specific CD8(+) cytotoxic T lymphocytes (CTLs) are vital in the clearance of acute HCV infections, but in the 60-80% of infections that persist, these cells become functionally exhausted or select for mutant viruses that escape T cell recognition. Increased HCV replication during pregnancy suggests that maternofetal immune tolerance mechanisms may further impair HCV-specific CTLs, limiting their selective pressure on persistent viruses. To assess this possibility, we characterized circulating viral quasispecies during and after consecutive pregnancies in two women. This revealed a loss of some escape mutations in HLA class I epitopes during pregnancy that was associated with emergence of more fit viruses. CTL selective pressure was reimposed after childbirth, at which point escape mutations in these epitopes again predominated in the quasispecies and viral load dropped sharply. Importantly, the viruses transmitted perinatally were those with enhanced fitness due to reversion of escape mutations. Our findings indicate that the immunoregulatory changes of pregnancy reduce CTL selective pressure on HCV class I epitopes, thereby facilitating vertical transmission of viruses with optimized replicative fitness.
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http://dx.doi.org/10.1038/nm.3351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823809PMC
November 2013

Hepatitis C virus in pregnancy.

Am J Perinatol 2013 Feb 6;30(2):149-59. Epub 2013 Feb 6.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Wexner Medical Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA.

Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.
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http://dx.doi.org/10.1055/s-0033-1334459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862252PMC
February 2013

Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with antitumor necrosis factor alpha therapy: a case series.

Inflamm Bowel Dis 2011 Jan;17(1):56-61

Nationwide Children's Hospital, Columbus, Ohio 43205, USA.

Background: Antitumor necrosis factor alpha (aTNF) therapies are commonly used in the treatment of pediatric inflammatory bowel disease (IBD). However, inhibition of the TNF-alpha pathway predisposes to serious infections, including histoplasmosis, which is the most common invasive fungal infection in individuals on aTNF therapy and carries a high mortality rate when associated with delayed diagnosis. Few data exist on the frequency, presentation, and appropriate treatment of pediatric patients with histoplasmosis on aTNF therapy.

Methods: Following Institutional Review Board approval, cases were identified then reviewed with their primary gastroenterologist and infectious disease specialists.

Results: Herein we describe histoplasmosis in five pediatric patients receiving aTNF therapy for IBD in an endemic area.

Conclusions: Histoplasmosis is an important complication of treatment with TNF-alpha neutralizing agents. Children with IBD treated with aTNF therapy who develop the infection may present with minimal pulmonary symptoms. While discontinuation of aTNF therapy is important initially, few data exist to determine when and how aTNF therapy can be reinstituted. Recognition of Histoplasma capsulatum is often delayed due to the overlap of symptoms with some of the extraintestinal manifestations of IBD and other more prevalent infectious complications.
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http://dx.doi.org/10.1002/ibd.21378DOI Listing
January 2011