COVID-19. RSV. Flu A. Flu B. Disease X. We are all beleaguered by reports of the next emerging airborne germ that will start another conversation of masks, vaccines, hospitalization, and yes, death. Faced with the near-daily urgency of a headline grabbing alphabet soup of pathogens, it is easy to grow numb. Let us pinch ourselves then, and for a moment, consider another lettered foe, TB.
Tuberculosis (TB) remains a formidable opponent to human health in the 21st century.
The rise of acquired-immune deficiency syndrome (AIDS) because of the human immunodeficiency virus (HIV) opened our eyes to this ghost from the past. Despite urgent action on AIDS and billions of dollars invested in tests, treatment, and vaccine development, TB remains the leading bacterial killer worldwide. As Infectious Diseases physicians and global health researchers who have studied TB and cared for those it afflicts across the world, we believe TB continues to haunt us because we have failed to recognize an even more important and pervasive AIDS: undernutrition.
Before the antibiotic era
Dr. Peter Cegielski, currently at Emory University, was one of the first physician-scientists to begin cataloging the links between nutrition and TB; in seminal work he described numerous revealing natural experiments. During the Dutch famine (1944–1945) of World War II, daily caloric intake for the average adult plummeted to a mere 600 kcal/day, with a consequent dramatic increase in TB mortality. Conversely, the German blockade of Denmark during World War I prevented the Danish from exporting nutrient rich foods such meat, fish, and dairy products, leading to an unexpected surplus. In the following months, TB rates fell drastically in Denmark even as those rates climbed in nearby warring countries. This period on the calendar was so unusual it was referred to as the “the year of health” by the Danes. Such ecological events provide insight into the critical role of food in the prevention of developing TB disease and improving treatment outcomes, distinct from antibiotics.
So why does weight loss and malnutrition drive TB?
Akin to how HIV causes AIDS by attacking and weakening our body’s immune system leading to the inability to ward off infectious diseases like TB, undernutrition deprives the immune system of the array of nutrients including proteins, vitamins, and minerals it needs to function. Malnutrition is the most common cause of immunodeficiency worldwide and has even been described as nutritionally-acquired immunodeficiency syndrome (N-AIDS). This is why we continue to see the impact of hunger on TB in the 21st century. Economic crises and resultant food insecurity in Venezuela and Zimbabwe both resulted in skyrocketing TB rates in those countries.
While we contend with the grim consequences of starvation in Gaza and Sudan now, experts fear that nutritional deprivation in Afghanistan, Yemen, Ukraine, and other zones of conflict, combined with harsh and cramped living conditions might recapitulate the effect of the Dutch Hunger Winter. As grievous as a new Hunger Winter may be, most undernutrition is borne silently by masses chronically and slowly deprived of access to food.
Dutch children eating soup during the famine of 1944–1945. Photo: Public domain.
TB and undernutrition are co-epidemics of poverty
Writing at the turn of the 20th century, Sir William Osler described TB as a social disease with a medical aspect. He was not isolated in this opinion. The early 20th century was notable for the social medicine movement. Whereas public health focused on environmental issues such as housing and sanitation to reduce diseases like TB and cholera, social medicine had a broader focus on nutritional, educational, economic, and psychological wellness. Illustratively, Chile’s social medicine campaign against TB in the 1930s focused on increasing wages, ensuring better nutrition, improving the built environment at home, reducing unsafe conditions at work, reducing alcoholism and venereal diseases, cleaning public places, constructing parks, and promoting sports. Similarly, the Papworth study in England (1918-1943) created an almost utopian city of social protections and demonstrated convincingly that housing and nutrition reduced progression to TB disease.
The impact of social medicine is writ large in the TB mortality trends seen in the United States in the 19th and 20th century. In the 1860s, estimates of TB mortality in the US exceeded 300 per 100,000 which is considerably higher than rates seen in high TB burden countries such as India, Tanzania, and South Africa today. Between the 1860s and the 1940s, the rate dropped by about 80%. Similar trends were noted in the United Kingdom. However, streptomycin, the first effective medication for TB was only deployed in 1947 and the first TB vaccine came into use in 1954. So what drove this massive reduction?
The historian Thomas Mckeown has posited the most credible theory; he believed that improvements in nutrition and living conditions which occurred concurrently and relatively rapidly led to the drops in TB and effective nationwide cures for N-AIDS. So how significantly did nutritional status improve in the United States? We have data on the body mass index (BMI) of 19-year-old men enrolled in America’s West Point Military Academy over this period of time which are revealing. BMI is a rough estimate of an individual’s nutritional status and is calculated using height and weight. Despite errors in higher BMIs misrepresenting body mass of muscle or healthier patterns of fat distribution, low BMIs reliably correlate with malnutrition such that individuals with BMIs below 18.5 are considered malnourished. Records indicate that the average BMI was only 20.5 during the second half of the 19th century. This means a 6-foot tall cadet would be about 150 pounds. For a visual, think Captain America before the super serum.
Captain America, before and after the super serum.
The BMI of cadets surged after the first world war and there was an increase in the average weight by nearly 30 pounds over the course of the 20th century and most of this increase occurred prior to 1959. A large systematic review of data from 2.4 million individuals suggests that for every unit increase (i.e. going from a BMI of 20 to 21) reduces the risk of TB disease by 14%. A 30 pound gain for a 6 feet tall cadet would mean a 4 point increase in BMI. This amount of weight gain would now provide Captain America with a shield that effectively halved the risk of TB disease. While military cadets do not fully represent the American population, they do provide some sense of the nutritional transformation afoot in the United States at a time where TB rates were dropping without any clear medical intervention.
The turn away from nutrition
In the 1960s, a landmark clinical trial in Madras (now Chennai) in India showed that treatment of TB disease with newly invented antibiotics was comparable to high intensity nutritional rehabilitation and surgical approaches being offered for only a privileged few. This was a triumph of modern science. Antibiotics provided public health practitioners tools to tackle TB at scale. The allure of cure in a pill is powerful. Even as they hailed this important advance, the scientific community forgot the lessons of the past and concluded that nutrition did not have a role in the management of TB in the modern era. Enough effective treatment for transmissible disease would limit the need for other preventative therapies, so the prevailing thinking went.
TB became the purview of the modern hospital system and peripheral clinics, viewed myopically through a biomedical lens. Decades have followed where the response to the persistence of the global TB pandemic has been to search for new drugs, new tests for disease, and an ever-elusive vaccine. Replacing meals with medicines may have constituted an egregious case of throwing out the baby with the bathwater.
While the bulk of TB mortality in higher income countries was driven down through socioeconomic progress which has myriad benefits beyond TB elimination, a double standard was in play in lower income countries. In a regressive application of the strict biomedical approach, poor countries endemic for TB and undernutrition have found recovery loans through donor agencies tied to performance in adhering to World Health Organization metrics for certain health conditions, like TB. Performance required the majority of resources for TB care directed to delivery of pills for TB disease that necessitated daily treatment for half a year’s time in most cases, and mandated strict adherence to pill counts.
In the extreme, such an obligation to misguided metrics contributed to undeserved suffering from antibiotic resistance, or to put it bluntly, a loan from the International Monetary Fund was associated with an increase in TB mortality. Whereas programs that saw gains in TB prevention and disease treatment married social protections with evolving diagnostics and therapeutics, at the same time international funders demanded austerity measures which shrank those very protections.
Photo: Calcutta Rescue/Flickr (CC BY-NC-ND 2.0 DEED)
What is not measured is not valued
We now have ample evidence that malnutrition is the leading driver of TB, accounting for 19% of people with new TB disease, more than double that caused by HIV. Yet with N-AIDS, we have seen far fewer gains than with the remarkable advances for HIV-AIDS. As Infectious Diseases physicians, when we care for someone with TB that is caused by HIV, to not prescribe antiretroviral medication to treat their immune compromising virus would be malpractice. We employ sophisticated biomarkers of HIV burden including measurement of subsets of immune cells and circulating viruses, and we tailor medicines to the person’s preference, needs and viral genetic background. In contrast, while about half of all persons with TB are malnourished and we know that malnourished individuals have a more guarded prognosis, we often use their weights merely to calculate the doses of their TB antibiotics. We do not tailor a nutritional intervention and chart its impact on N-AIDS. This lack of measurement is part holdover of World Health Organization reporting patterns, part misperception of the benefits of a nutritional intervention, and part despondence that undernutrition is so tied to the intransigence of poverty.
Both of us have had the privilege of working with and caring for persons with TB. When we do, it is clear why this disease is called consumption. It appears as if something is consuming individuals from within, the temples become concave, the eyes recess into the orbital socket, cheeks lose their plumpness, and the skeleton rises to prominence. The Victorians believed that the disease consumed all that was inessential, leaving sufferers with a moral purity. But when we apply our stethoscopes to chests with protruding ribs and hear the accelerated thudding of hearts frantically pumping anaemic blood, we know that the disease has, in fact, consumed their vitality, their productivity, and their future.
What is truly essential is personhood rehabilitation where one regains the ability to care of themselves, their families, and follow the life paths of their choosing. Feeling the weakness of their grips as they shake our hands, we know that TB antibiotics are necessary, but not sufficient for that goal. We remain incredulous that malnutrition, so inescapable and so cardinal to TB disease, was ever sidelined.
Workers collect records to fight TB. Photo: DIVatUSAID/Flickr (CC BY-NC-ND 2.0 DEED)
Hope for communities burdened duly burdened by TB and undernutrition
March 24 marks World TB Day, recognised in awareness and advocacy. Despite the enormity of the global TB pandemic, we remain steadfastly hopeful. Our optimism is buoyed by the pivotal Reducing Activation of Tuberculosis by Improvement of Nutrition Status (RATIONS) study led by Drs. Anurag and Madhavi Bhargava from Yenepoya University in India. The Bhargavas are a husband and wife team who have dedicated their life to addressing health inequities among the most vulnerable individuals in India. The RATIONS study provided empirical evidence that nutritional support can reduce TB disease development and TB transmission by randomizing 10,000 household contacts of people with new TB disease to either receiving nutritional support in the form of a food basket that provided 750 kcal per day (including 23g of protein) and micronutrients or routine monitoring and care of the person with new TB disease only. The team in India found a 40% reduction in people with new TB disease over 2 years of follow up. Such a reduction in TB disease is on par with the projected impact for the novel M. tuberculosis M72/AS01E vaccine.
Could the answer to TB be as simple as feeding households at-risk of TB? Firstly, we do not wish to suggest a false dichotomy with a M. tuberculosis vaccine and nutritional interventions. The two approaches may be complementary as improving the underlying nutritional status could improve the efficacy of vaccines. Vaccines work better in well-fed people.
Secondly, there may be optimal micronutrient and macronutrient combinations in food preparations that are better for one population or another. Further still, food alone may not help if one unwittingly carries additional gut pathogens that prevent nutrient absorption. Yet these are questions that can be solved by interdisciplinary scientists in TB and undernutrition endemic settings where arguably more considerable scientific resources should be aimed.
Advocates for nutrition are often dismissed as idealists who dwell in castles in the sky. Yet, there is a hard economic argument to be made for nutritional interventions for TB. The Copenhagen Consensus ranked TB elimination efforts as the best global health investment. Good nutrition is a global health best-buy. Given that malnutrition affects every single organ of the body, combatting malnutrition reduces overall health spending and improves economic productivity. Indeed, an investment of $1.4 billion in nutrition yields an estimated $19 billion in lifetime earnings and saved expenditure. A mathematical model projected that a robust nutritional intervention run by the Indian government would lead to an approximately 80% reduction in TB cases and deaths over five-years while being more cost-effective than most other enthusiastically implemented health interventions. And while this might sound quixotic, the pre-antibiotic decline of TB in the United States and the striking results of the RATIONS study give the model’s projections verisimilitude.
So as we mark the passage of another World TB Day, let us imagine a vaccine that can be grown locally, shipped regionally without a cold chain, and administered in a concoction limited only by consumer’s imagination- a vaccine without predilection to conspiracy and when fully embraced carries protection against the world’s deadliest bacterial pathogen while also conferring household economic security. Food is the TB vaccine we already have.
Scott K. Heysell, MD is the Thomas H. Hunter Associate Professor of International Medicine at the University of Virginia and the Director of the Center for Global Health & Equity.
Pranay Sinha, MD is an Assistant Professor of Medicine at Boston University.
