1984 Alpha Omega Alpha, Case Western Reserve University School of Medicine
1991 Junior Faculty Research Award, Society of General Internal Medicine
1997 Nominee for Clinical Teacher of the Year Award, Department of Medicine, Case Western Reserve University School of Medicine
1998 John S. Diekhoff Award for Distinguished Graduate Teaching, Graduate Studies Program, Case Western Reserve University
2002 Nominee for Kaiser-Permanente Award for Excellence in Teaching, Case Western Reserve University School of Medicine
2004 Elected to American Epidemiological Society
2008 Teacher of the Year, Department of Epidemiology and Biostatistics, Case Western Reserve University, School of Medicine
2009 Invited Speaker, George Naff Annual Lecture, Case Western Reserve University
2009 Delta Omega National Honorary Society in Public Health
2010 Ernest Corn Professor in Infectious Disease Epidemiology, University of Georgia
2011 Award for Excellence in Research, College of Public Health, University of Georgia
2012 Distinguished Research Professor, University of Georgia
2017 Elizabeth Hurlock Beckman Award, Elizabeth Hurlock Beckman Award Trust
2019 Karen and Jim Holbrook Professor of Global Health
2019 George W. Comstock Lecture, Johns Hopkins University School of Medicine
M. tuberculosis Transmission in African Households and Communities
Epidemics of tuberculosis are sustained through ongoing transmission of M. tuberculosis. Although we understand the airborne nature of transmission of tuberculosis, we have little understanding of where or when this transmission occurs at a population level. Knowing this information is important for designing more effective tuberculosis control strategies. Beginning in 1995, I started a population-based household contact study of tuberculosis transmission. Apart from developing a useful research paradigm for studying tuberculosis in its many phases, we found that the household of index cases was an intense location of transmission, and that age, HIV status, and BCG vaccination did not affect the risk for M. tuberculosis infection, but were key determinants for disease. In 2012, I expanded the scope of this household study to include the social networks of tuberculosis cases, including contacts outside of the household. To our surprise, we have found that most of the transmission at the community level, 85%, occurs outside the household. This observation has led to the use of cellular telephone metadata to map the movements of infectious tuberculosis cases in the weeks and months BEFORE diagnosis, as a surrogate marker of community of transmission. As we use the sensitive data from cellular telephones, we have begun a parallel ethics study to evaluate privacy, confidentiality and security concerns of participants in Africa.
1. Whalen CC, Zalwango S, Chiunda A, et al. Secondary attack rate of tuberculosis in urban households in Kampala, Uganda. PloS one 2011;6:e16137.
2. Martinez L†, Shen Y, Mupere E, Kizza A, Hill PC, Whalen CC. Transmission of Mycobacterium Tuberculosis in Households and the Community: A Systematic Review and Meta-Analysis. Am J Epidemiol. 2017 Jun 15;185(12):1327-1339. doi:10.1093/aje/kwx025. Review. PubMed PMID: 28982226.
3. Sekandi JN, Zalwango S, Martinez L, et al. Four Degrees of Separation: Social Contacts and Health Providers Influence the Steps to Final Diagnosis of Active Tuberculosis Patients in Urban Uganda. BMC infectious diseases 2015;15:361.1.
4. Kakaire R, Kiwanuka N, Zalwango S, Sekandi JN, Quach THT, Castellanos ME, et al. Excess Risk of Tuberculosis Infection Among Extra-household Contacts of Tuberculosis Cases in an African City. Clin Infect Dis. 2020 Oct 16;
HIV and Tuberculosis Interaction
In this research theme, I have evaluated the co-pathogenesis of HIV and tuberculosis. I was the first to show that tuberculosis accelerated HIV infection by increasing the rate of opportunistic infections and by reducing survival. Because of potential selection bias of this US-based cohort, I repeated the study in Uganda and confirmed this effect in an independent cohort of patients. Working with colleagues in immunology and virology, I was able to show a plausible biologic mechanism for the interaction that involved cellular immune activation caused by M. tuberculosis infection, as measured by TNF- and other pro-inflammatory cytokines, and enhanced HIV replication. These findings led to a series of randomized clinical trials evaluating preventive therapy and adjunctive immune therapies for treatment of active tuberculosis disease. Recently, I have extended the interaction hypothesis to include effects of immune activation on metabolism and protein-energy balance. Our early findings suggest that body composition is a major determinant of survival and subsequent outcomes of disease.
1. Whalen C, Horsburgh CR, Hom D, Lahart C, Simberkoff M, Ellner J. Accelerated course of human-immunodeficiency virus infection after tuberculosis. American journal of respiratory and critical care medicine 1995;151:129-35.
2. Whalen CC, Nsubuga P, Okwera A, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. Aids 2000;14:1219-28.
3. Mupere E, Zalwango S, Chiunda A, Okwera A, Mugerwa R, Whalen C. Body composition among HIV-seropositive and HIV-seronegative adult patients with pulmonary tuberculosis in Uganda. Annals of epidemiology 2010;20:210-6.
4. Martinez L, Woldu H, Chen C, Hallowell BD, Castellanos ME, Lu P, et al. Transmission Dynamics in Tuberculosis Patients with Human Immunodeficiency Virus: A Systematic Review and Meta-Analysis of 32 Observational Studies. Clin Infect Dis [Internet]. 2020 Aug 8.
Treatment and Prevention of Tuberculosis and HIV
In this theme, I have evaluated both treatment and prevention of tuberculosis in HIV seropositive persons. In the only randomized clinical trial to compare a rifampin-containing regimen for tuberculosis treatment to the standard of care in Africa, we showed that the rifampin-containing regimen was more effective and safer than the African standard regimen. As our understanding of the mechanism of HIV-tuberculosis coinfection developed, my colleagues and I performed a series of randomized clinical trials to evaluate the efficacy of TNF receptor inhibitors and more broad immune modulation with prednisolone, but in neither trial did the intervention affect survival, though surrogate markers of HIV replication were improved. In keeping with the ever-evolving trends for treatment of HIV infection itself, we evaluated the effects of antiretroviral therapy on surrogate endpoints among HIV-infected tuberculosis patients with preserved immunity, and found that antiretroviral therapy conferred benefit to HIV seropositive patients with active tuberculosis, even when the CD4+ T cell was above 350 cells/L. From the earliest phases of the HIV epidemic, it was known that HIV conferred a high risk of tuberculosis, so there was great interest in whether isoniazid treatment would prevent tuberculosis. We conducted one of the earliest and largest studies to evaluate three different regimens for prevention and found that isoniazid was effective in reducing the risk of tuberculosis, but its effect was not sustained beyond 3 years.
1. Okwera, A., C. Whalen, F. Byekwaso, M. Vjecha, J. Johnson, R. Huebner, R. Mugerwa and J. Ellner (1994). Randomised trial of thiacetazone and rifampicin-containing regimens for pulmonary tuberculosis in HIV-infected Ugandans. The Makerere University-Case Western University Research Collaboration. The Lancet 344(8933): 1323-1328.
2. Mayanja-Kizza H, Jones-Lopez E, Okwera A, et al. Immunoadjuvant prednisolone therapy for HIV-associated tuberculosis: a phase 2 clinical trial in Uganda. The Journal of Infectious Diseases 2005;191:856-65.
3. Nanteza MW, Mayanja-Kizza H, Charlebois E, et al. A randomized trial of punctuated antiretroviral therapy in Ugandan HIV-seropositive adults with pulmonary tuberculosis and CD4(+) T-cell counts of >= 350 cells/muL. The Journal of Infectious Diseases 2011;204:884-92.
4. Whalen CC, Johnson JL, Okwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Uganda-Case Western Reserve University Research Collaboration. The New England Journal of Medicine 1997;337:801-8.
Capacity Building in Africa
An equal part of my work involves building capacity for research, teaching and clinical care in Africa. I am committed to training future leaders in science and public health in Africa and providing them to equipment, workforce, and infrastructure to be successful. To this end, I have directed a training program for Ugandan scientists and public health professionals since 1995. During this time, I have trained over 68 graduate students with doctoral and masters’ degrees in epidemiology, biostatistics, health services research, anthropology, immunology, and virology. Of these trainees, nearly all (95%) have returned to Uganda to assume positions in academia, public health, and non-governmental research organizations. Although it is difficult to quantify the benefit of this training, many trainees have risen to positions of leadership in Uganda today as deans, research directors, and minister of health. The training activities have led to over 100 co-authored papers with me, new research contracts and grants, and translation of science to practice.
1. Guwatudde D, Nakakeeto M, Jones-Lopez EC, Maganda A, Chiunda A, Mugerwa RD, Ellner JJ, Bukenya G, Whalen CC. Tuberculosis in household contacts of infectious cases in Kampala, Uganda. American Journal of Epidemiology 2003; 158: 887-898.
2. Guwatudde D, Zalwango S, Kamya MR, et al. Burden of tuberculosis in Kampala, Uganda. Bulletin of the World Health Organization 2003;81:799-805.
3. Joloba ML, Whalen CC, Cave DM, et al. Determination of drug susceptibility and DNA fingerprint patterns of clinical isolates of Mycobacterium tuberculosis from Kampala, Uganda. East African medical journal 2000;77:111-5.
4. Sekandi JN, Zalwango S, Martinez L, Handel A, Kakaire R,Nkwata AK, Ezeamama AE, Kiwanuka, N, Whalen CC. Four Degrees of Separation: Social Contacts and Health Providers Influence the Steps to Final Diagnosis of Active Tuberculosis Patients in Urban Uganda. BMC Infectious Diseases 2015; 15(1): 361 – 365.
