Houpt Lab Group

Eric R. Houpt, MD

PubMed

PRIMARY APPOINTMENT:

Jack Gwaltney Professor of Infectious Diseases
Chief, Division of Infectious Diseases and International Health

CONTACT:

Division of Infectious Diseases
PO Box 801340
Charlottesville, VA 22908
Office Phone: 434-243-9326
Lab Phone: 434-924-5575
Fax: 434-924-0075

erh6k@virginia.edu

EDUCATION AND TRAINING:

BA, Colgate University
MD, Emory University
Intern & Resident in Internal Medicine, University of Chicago
Postdoctoral Fellowship in Infectious Diseases, University of Virginia

PubMed

RESEARCH AREAS:

Molecular diagnostics, Tuberculosis, Global Health

RESEARCH SUMMARY

The Houpt Group is involved in several projects focused on molecular diagnostic tools for infectious diseases. Most work involves developing panels of PCR-based diagnostic tests to detect a broad range of pathogens. We have developed TaqMan Array Cards for the syndrome of diarrhea and have deployed these tools to large collaborative multi-center studies such as the MAL-ED and GEMS studies throughout Africa, Asia, and South America, to better document the cause of diarrhea and malnutrition. We have devised similar assays for acute febrile illness which we are utilizing with the CDC Global Disease Detection Program. Through these diagnostics we also measure burden of disease and vaccine coverage, such as Streptococcus pneumoniae serotyping, rotavirus and ETEC typing, and Shigella speciation. I have a program on tuberculosis, both on developing rapid genotypic diagnostics to identify which drugs to use for multidrug-resistant TB, and I am clinically active in TB here in Virginia as the Virginia Department of Health consultant.

Research Group Members

Collaborating Faculty Research Faculty and Staff Fellows

Research

Enteropathogens

Our work involves developing panels of PCR-based diagnostic tests to detect a full range of enteropathogens. These tests are used in collaborative studies, such as the MAL-ED and GEMS studies funded by the Bill and Melinda Gates Foundation. We and our research partners work throughout Africa, Asia, and South America, to better document the causes of diarrhea and malnutrition.

Interactions of Malnutrition and Enteric Infections: Consequences for Child Health and Development.
Better known as “Mal-ED”, this study was established to research the complex inter-relationship of enteric infections and malnutrition in order to better design interventions to reduct childhood morbidity and mortality.¹ Designed as a longitudinal birth cohort, eight sites across Africa, South America, and South Asia enrolled 200 children each and followed them for up to 60 months using a set of protocols standardized across all sites. The Houpt Group has provided expertise in molecular diagnostics for the detection of enteric pathogens found in samples from children throughout the cohort.

For more information on this study, please visit: https://fnih.org/

Global Enteric Multisite Study (GEMS)
The GEMS study grew out of a concensus on the need for a well-designed study to obtain information on the etiology and population-based burdens of more severe forms of pediatric diarrheal disease to guide global investments and implementation decisions.² The study was undertaken across 4 sites in sub-Saharan Africa and 3 sites in South Asia. The Houpt Group has provided molecular diagnostics expertise and testing services for the detection of enteropathogens in samples from the study. Recently, our group used this molecular diagnostics data to assess the causes of pediatric diarrhea.

Lancet: Liu, Platts-Mills et al. Use of Quantitative Molecular Diagnostic Methods to Identify Causes of Diarrhea in Children: a Reanalysis of the GEMS Case-Control Study. Lancet. 2016 Sep 24; 388(10051): 1291-301

Leveraging Rotavirus Networks
Established in 2008, the WHO has coordinated the Global Rotavirus Surveillance Network (GRSN). This network collects and tests specimens from children hospitalized with acute watery diarrhea from all six WHO regions with the aim of providing rotavirus burden information to member countries, measure vaccine impact, and monitor strain epidemiology. In 2014, the Houpt Group began a partnership with the GRSN to implement new molecular diagnostic technologies to the regional reference laboratories to aid the mission of the Network and to characterize non-rotavirus causes of diarrhea within the Network countries. 2017 marks the start of Phase 2 of the project, expanding this molecular testing to a total of eight reference laboratories and testing samples from approximately 40 countries.

Journal of Infectious Diseases: Operario*, Platts-Mills* et al., Etiology of Severe Acute Watery Diarrhea in Children in the Global Rotavirus Surveillance Network using Quantitative Polymerase Chain Reaction
J Infect Dis. 2017 Jul 15; 216(2):220-7 *Authors share equal first credit

Tuberculosis

Mycobacterium tuberculosis remains the world’s most deadly, but curable, infectious disease. 10.4 million new cases and 1.8 million deaths were attributed to this disease in 2015¹ and it is the leading killer of HIV-infected patients globally. More troubling is that approximately 480,000 of the new cases were multi-drug resistant (MDR-TB), meaning that these infections were resistant to both isoniazid and rifampin, two front-line drugs in the fight against tuberculosis. Such infections hamper public health gains in TB-endemic settings.

Our research focuses on improving patient outcomes through the development of rapid diagnostics that can identify which drugs to use for MDR-TB, as well as identifying markers for poor therapeutic response.

Diagnostics and Pharmacotherapy for Severe Forms of Tuberculosis

Funded through an NIH International Collaborations in Infectious Diseases Research (ICIDR) mechanism, this project is currently developing a multi-site observational cohort of TB patients to determine pharmacokinetic measures that correlate with treatment outcomes as well as deploy and enhance drug susceptibility testing while building on-site capacity for clinical investigation. We count as partners three sites in Tanzania including Kibong’oto Infectious Diseases Hospital, Kilimanjaro Clinical Research Institute, and Haydom Global Health Research Centre as will as the ICDDR,B in Bangladesh, Irkutsk Tuberculosis Referral Hospital and Scientific Centre for Family Health and Human Reproduction Problems in Russia, and the Mbarara University of Science and Technology in Uganda.

unMASC TB

This study represents a limited interventional protocol in Haydom, Tanzania to evaluate immunologic and molecular diagnostics as well as predictors of poor response to TB amongst children in Tanzania. The assay under study is a novel blood-based test that measures anti-mycobacterial antibodies. In addition, we are investigating drug concentrations in plasma to identify risk factors for poor treatment response. We are conducting this study at the Kilimanjaro Clinical Research Institute in Tanzania in partnership with the University of Florida Infectious Disease Pharmacokinetics Laboratory.

Bridge-Siberia

This study follows a prospective cohort of HIV-TB patients in Irkutsk, Russia to quantify the effect of substance abuse patterns on pharmacokinetics, treatment adherence, and treatment outcome. University of Virginia investigators include experts in adherence, mHealth, substance use psychology, and basic HIV biology. These experts include Dr. Rebecca Dillingham and Dr. Karen Ingersoll. Our research partners in Russia include the Irkutsk Tuberculosis Referral Hospital and the Scientific Centre for Family Health and Human Reproduction Problems.

Evaluation of Host Biomarkers for TB Diagnosis and Monitoring of TB Treatment Outcome

This case-control study among adults in Northern Tanzania aims to build local capacity for evaluating immunologic biomarkers of TB disease activity. Ongoing work focuses on evaluating cytokine and chemokine responses among adults with TB disease compared to hospitalized controls. For this study we are collaborating with researchers at Kibong’oto Infectious Diseases Hospital and Kilimanjaro Clinical Research Institute, both in Tanzania.

Non-Respiratory Biomarkers to Diagnose and Monitor Response in Pediatric TB

This is a prospective cohort study to optimize the accuracy of an anti-mycobacterial antibody secreting cell assay and to investigate trans-renal DNA as a diagnostic urine biomarker among young, malnurished children at risk for TB disease. Our research partners include researchers at the ICDDR,B in Dhaka, Bangladesh.

Household Contact Tracing in Northern Philippines (USAID PEER Health Cycle 5)

This public health study aims to address barriers to TB case detection among children from the Northern Philippines. The study begins by conducting household contact tracing among adults recently diagnosed with pulmonary TB in order to screen and identify children with active or latent TB infection. We will administer surveys amongst parents, other community members, and healthcare workers to assess knowledge, attitudes, and practices toward TB, and childhood TB in particular. The end goals are to increase detection of active TB among children, detect children eligible for isoniazid therapy, and develop a public health education campaign on childhood TB. Our partners include researchers at Isabella State University in Echague, the Republic of the Philippines Department of Health, and USAID-Philippines.

Collaborative TB Initiatives – UVA and the Virginia Department of Health

Through current and prior grant support through the National Institutes of Health and the Virginia Tuberculosis Foundation, we are focused on implementation studies such as early interventions for diabetes-TB in Virginia, therapeutic drug monitoring, clofazamine for drug-resistant mycobacterial disease, and the role of PET imaging. Through these collaborative efforts, UVA and the Virginia Department of Health shared the 2017 Robert Koch Award from the National TB Controller’s Association.

Molecular Diagnostics for Tuberculosis Drug Susceptibility Testing

Conventional diagnostic methods for tuberculosis drug susceptibility testing, such as culture-based phenotypic testing, can take weeks before results are available to inform proper therapy. Increasingly, faster culture-free genotypic methods for determining drug susceptibility are gaining popularity.

Tuberculosis TaqMan Array Card

Our group developed a TaqMan Array Card that incorporates both sequence-specific probes as well high-resolution melt analysis for genotypic DST. The primer-probe sets in the card are designed to interrogate 3,200 base pairs of critical regions of inhA, katG, rpoB, embB, rpsL, rrs, eis, gyrA, gyrB, and pncA.

Figure 2 from Pholwat et al., MBio 2015

Targeted Next-Generation Sequencing in M. tuberculosis Drug-Resistance Gene Regions

Probe-based and HRM-based diagnostics may not necessarily provide the sequence identify of a particular mutation. This identity is increasingly important since it has become clear that certain mutations at one location can contribute to drug resistance whereas others in the same location may not, such as in the pncA gene. We developed an amplicon-based next-generation sequencing assay covering 11 resistance-associated gene regions inhA, katG, rpoB, embB, rpsL, rrs, eis, gyrA, gyrB, and pncA covering 3,519 bases of the M. tuberculosis genome. In addition to drug susceptibility, this assay has allowed us to assess heteroresistance, or the co-occurrence of drug-sensitive and drug-resistance bacteria within a single isolate.

References:

Acute Febrile Illnesses

Acute febrile illness is a term to describe fever without a clear localizing source. These can be caused by a wide array of infections. Unfortunately a pathogen is not always identified through conventional methods like blood culture or serology. Our research has focused on developing a research diagnostic that can rapidly and accurately identify acute febrile illness agents. We are using these diagnostics in global surveillance studies and to identify the cause of outbreaks in Tanzania.

Acute Febrile Illness TaqMan Array Card
We developed a real-time PCR-based TaqMan array card (TAC) that can simultaneously detect 26 AFI-associated organisms, including 15 viruses, 8 bacteria, and 3 protozoa. This TAC can be used in field settings for rapid screening in outbreak investigations or pathogen surveillance.

Figure 1 from Liu et al., J Clin Microbiol 2016

Zikavirus surveillance
In partnership with the Centers for Disease Control and Prevention, we are using a version of the AFI TAC above to aid in Zikavirus (and acute febrile illness) surveillance to 7 different countries throughout the world. The UVA portion of this partnership has involved the deployment of the cards to the various sites and giving the necessary training to the local staff to process blood samples, prepare the TAC, and interpret the results.

Malaria TaqMan Array Card
According to the WHO, there were 212 million new cases of malaria worldwide in 2015. The bulk of cases were in sub-Saharan Africa, followed by the South-East Asia and Eastern Mediterranean regions². Anti-malarial drug resistance exacerbates the global malaria burden and complicates eradication efforts. We developed a TaqMan Array Card that includes 87 assays for species identification and for the detection of mutations in Plasmodium falciparum contributing to resistance to chloroquine, atovaquone, pyrimethamine, sulfadoxine, and artemesinin. This card is capable of facilitating resistance surveillance in countries with high levels of malaria endemicity.

Figure 1 from Pholwat et al., Antimicrobial Agents Chemother. 2017

References: