People with low levels of vitamin A who live with individuals who were sick with tuberculosis were 10 times more likely to develop the disease than people with high levels of the nutrient, according to research led by investigators at Harvard Medical School.

The findings, published in May in the journal Clinical Infectious Diseases, are based on an analysis of blood drawn from more than 6,000 household contacts of people diagnosed with TB in Lima, Peru.

Because vitamin A levels were not randomly allocated as they would be in a clinical trial, the study does not prove a cause–effect relationship between vitamin A levels and TB disease. However, the potent link between the two, the researchers say, suggests that vitamin A supplementation might be an important part of controlling the spread of TB – one of the leading causes of death worldwide.

“This is one of the strongest risk factors reported in a large epidemiological study in years,” said senior author Megan Murray, the HMS Ronda Stryker and William Johnston Professor of Global Health.

A 10–fold increase in risk is striking, the investigators said. To put it in perspective, smoking tobacco increases the risk for heart disease by 2– to 4–fold, according to the Centers for Disease Control and Prevention.

In the Lima study, the researchers found that the protective effect of vitamin A grew stronger as levels of the nutrient increased. Protection continued to grow well above what has been considered the minimum healthy level.

Working with Mercedes Becerra, HMS professor of global health and social medicine, Murray designed the study to investigate bacterial and host determinants of TB infection and disease. The research was conducted through a cooperative agreement with the NIH.

The study began with people who sought care in any one of 106 clinics around the city of Lima. When a patient was diagnosed with TB, his or her household contacts were asked whether they wanted to participate in the study. Those who agreed were asked to give a baseline blood sample.

Of the more than 6,000 participants who agreed to have their blood studied, 258 people developed TB disease. Among those, 192 became sick with TB disease after enrollment in the study. Researchers compared 180 blood samples obtained from people who developed TB disease during that time with blood samples obtained from household contacts who did not become sick with TB disease. Participants were monitored regularly throughout the one–year follow–up for disease symptoms.

Vitamin A levels were a potent predictor of TB disease risk.

Vitamin A deficiency – defined as less than 200 micrograms per liter of blood – fueled the risk of developing TB disease by 10–fold. That risk was 20 times higher among young people between the ages of 10 and 19. That finding, the researchers say, suggests that vitamin A may play an even greater role in immunity among younger people.

The researchers found that vitamin A levels in the baseline sample strongly predicted progression to TB disease, even after adjustment for socioeconomic status, body mass index and other conditions thought to increase TB disease risk or affect vitamin A levels.

Meanwhile, Murray and colleagues at Brigham and Women’s Hospital and elsewhere have continued the research initiated on the original grant and are now seeking to identify different factors that affect the interplay between host and pathogen and that can alter infection risk and disease progression. Such factors include metabolic, genetic and immune factors. This ongoing work is part of the NIH–funded Tuberculosis Research Units program.

All of this work is part of a 20–year partnership between HMS researchers and Partners In Health, where Murray is director of research, PIH’s sister organization Socios En Salud Sucursal Peru, and