The Mulago Inpatient Non-invasive Diagnosis of Pneumonia (MIND) and
The International HIV-associated Opportunistic Pneumonias (IHOP) Studies

The Mulago Inpatient Non-invasive Diagnosis of Pneumonia (MIND) Study began in September 2006 with the goal of studying non-invasively collected respiratory specimens such as oropharyngeal washing (OPW or gargle) paired with sensitive and specific molecular assays such as polymerase chain reaction (PCR) for the diagnosis of major HIV-associated opportunistic pneumonias such as tuberculosis (TB) and Pneumocystis pneumonia (PCP). The MIND Study is led by Makerere University-University of California San Francisco (MU-UCSF) investigators, Drs. William Worodria and Samuel Yoo, pulmonologists at Mulago Hospital, and Drs. J. Lucian (Luke) Davis, Adithya Cattamanchi, and Laurence Huang, pulmonologists at UCSF, and laboratory collaborators at the US National Institutes of Health and the Uganda National Tuberculosis Reference Laboratory. To date, the MIND Study has made several important contributions. The first cohort enrolled 101 outpatients from the HIV-Voluntary Counseling and Testing (HIV-VCT) Study and 26 inpatients from Mulago Hospital and focused on the non-invasive diagnosis of TB. Pulmonary TB (59%) and HIV infection (46%) were both common in the study population. The study demonstrated that PCR of sputum samples was highly sensitive (99%) and specific (88%) for detection of pulmonary TB and the assay performed well among HIV-infected patients and among patients with negative sputum smear results. PCR of OPW specimens was less sensitive (73%) but also detected a substantial proportion of tuberculosis cases.1 Current studies focus on comparison of this PCR assay to a commercially available nucleic acid amplification assay for TB diagnosis using non-invasive respiratory specimens.

While examining the performance of new molecular assays, the MIND Study has also studied the performance of sputum smear microscopy for diagnosis of pulmonary TB and the impact of different processing and microscopy techniques.2 3 4 The study published the first report of PCP diagnosed at Mulago Hospital using an inexpensive modified Giemsa stain.5 More recently, the MIND Study has examined the role of bronchoscopy in the diagnosis of TB and other HIV-associated pulmonary diseases6 and described the prevalence and clinical course of HIV-associated pulmonary cryptococcosis.7

The MIND Study created a clinical and research infrastructure that has evolved into the National Heart, Lung and Blood Institute (NHLBI)-funded International HIV-associated Opportunistic Pneumonias (IHOP) Study, a 3-hospital, 3-country prospective longitudinal cohort study of HIV-infected persons hospitalized with pneumonia at Mulago Hospital (Kampala, Uganda), San Francisco General Hospital (San Francisco, CA, USA), and University College London Hospitals (London, UK). The IHOP Study is part of the Lung HIV Study, a network of 8 research programs and a central data coordinating center whose shared goal is to study the spectrum of HIV-associated lung disease and create a specimen bank and accompanying clinical database to catalyze future studies in the field. The IHOP Uganda Study began in October 2008 and has enrolled greater than 400 participants. Enrollment and follow-up are expected to continue through June 2012.

In addition to its scientific goals, the MIND and IHOP Studies have sought to improve the care of patients at Mulago Hospital and the education of its trainees. Chief among these improvements were the establishment of a small laboratory to process and examine induced sputum and bronchoscopy specimens for PCP and the creation of the Mulago Hospital Pulmonary Handbook authored by MU and UCSF pulmonologists and their colleagues. This handbook is distributed to all trainees and provides an important framework for the diagnosis and management of a broad spectrum of pulmonary diseases.

Selected Bibliography of MIND and IHOP Study Publications

1. Cattamanchi A, Davis JL, Worodria W, Yoo S, Matovu J, Kiidha J, Nankya F, Kyeyune R, Andama A, Joloba M, Osmond D, Hopewell P, and Huang L. Poor performance of universal sample processing method for diagnosis of pulmonary tuberculosis by smear microscopy and culture in Uganda. J Clin Microbiol. 46: 3325-9, 2008.

2. Davis JL, Huang L, Kovacs JA, Masur H, Murray P, Havlir DV, Worodria WO, Charlebois ED, Srikantiah P, Cattamanchi A, Huber C, Shea YR, Chow Y, Fischer SH. Polymerase chain reaction of secA1 on sputum or oral wash samples for the diagnosis of pulmonary tuberculosis. Clin Infect Dis 2009;48:725-32. Read Article ...

3. Cattamanchi A, Dowdy DW, Davis JL, Worodria W, Yoo S, Joloba M, Matovu J, Hopewell PC, and Huang L. Sensitivity of direct versus concentrated sputum smear microscopy in HIV-infected patients suspected of having pulmonary tuberculosis. BMC Infect Dis. 9: 53, 2009.

4. Shea YR, Davis JL, Huang L, Kovacs JA, Masur H, Mulindwa F, Opus S, Chow Y, and Murray PR. High sensitivity and specificity of acid-fast microscopy for diagnosis of pulmonary tuberulosis in an African population with a high prevalence of human immunodeficiency virus. J Clin Microbiol. 47: 1553-5, 2009.

5. Cattamanchi A, Davis JL, Worodria W, den Boon S, Yoo S, Matovu J, et al. Sensitivity and specificity of fluorescence microscopy for diagnosing pulmonary tuberculosis in a high HIV prevalence setting. Int J Tuberc Lung Dis. Sep;13(9):1130-6, 2009.

6. Yoo SD, Worodria W, Davis JL, Cattamanchi A, den Boon S, Kyeyune R, Kisembo H, Huang L. The prevalence and clinical course of HIV-associated pulmonary cryptococcosis in Uganda. J Acquir Immune Defic Syndr 2010;54:269-74.

7. Worodria W*, Davis JL*, Cattamanchi A, Andama A, den Boon S, Yoo SD, Hopewell PC, Huang L. Bronchoscopy is useful for diagnosing smear-negative tuberculosis in HIV-infected patients. Eur Respir J. 2010;36(2):446-8. (*These authors contributed equally to this work.)

8. Davis JL, Worodria W, Kisembo H, Metcalfe JZ, Cattamanchi A, Kawooya M, Kyeyune R, den Boon S, Powell K, Okello R, Yoo S, Huang L. Clinical and radiographic factors do not accurately diagnose smear-negative tuberculosis in HIV-infected inpatients in Uganda: a cross-sectional study. PLoS One 2010;5:e9859.

9. Cattamanchi A, Ssewenyana I, Davis JL, Huang L, Worodria W, den Boon S, Yoo S, Andama A, Hopewell PC, Cao H. Role of Interferon-gamma Release Assays in the Diagnosis of Pulmonary Tuberculosis in Patients with Advanced HIV infection. BMC Infect Dis 10: 75.

10. Kyeyune R; Den Boon S; Cattamanchi A, Davis JL, Worodria W, Yoo S, Huang L. Causes of early mortality in HIV-infected TB suspects in an East African referral hospital. J Acquir Immune Defic Syndr. In press, 2010.

11. Cattamanchi A, Huang L, Worodria W, den Boon S, Kalema N, Katagira W, Byanyima P, Yoo S, Matovu J, Hopewell PC, Davis JL. Integrated Strategies to Optimize Sputum Smear Microscopy: A Prospective Observational Study. Amer J Resp Crit Care Med, In press, 2010.