How Tuberculosis Fueled the 1918 Flu and Covid-19 Pandemics

A consensus review by experts across the globe admits the role of TB in viral respiratory infections.

TB and 1918 Flu in the US

The 1918 Spanish flu pandemic infected about one-third of the global population (500 million people) and claimed at least 50 million lives. In the United States alone, about 675,000 died from it within a year. But this high death toll might not be from the influenza virus alone.

“Now a researcher in demography at the University of California, Berkeley, has evidence that undetected tuberculosis, or TB, actually may have caused much of the mortality in 1918,” the university’s news media said. That researcher is Andrew Noymer, an associate professor of public health. In his landmark 2000 review and 2011 statistical papers, he outlined many uncanny links between the 1918 flu and TB in the US:

• The 500,000 deaths of the 1918 flu were nearly identical to the number of people that would have succumbed to TB if the pandemic never appeared.
• “Just after 1918, TB death rates experience their steepest decline of the century,” he wrote. This decline was more extreme for males. The 1918 flu also disproportionately killed males. And TB is a sex-specific disease with a bias towards males.
• The flu usually targets older people. But the 1918 flu is most lethal to the 25–34-year-olds, and “TB is a disease of adulthood, not of old age.”
• The life expectancy of males increased by six years after the 1918 flu. Before the pandemic, TB was the major cause of shortened lifespan.

“This can’t be a coincidence,” Professor Noymer said. “I think TB is the missing piece of the puzzle. It explains why younger people, especially men, died in such great numbers.” He adds: “Never before or since have we seen a flu epidemic that was so virulent. The spread was extremely rapid, as was the development of the infection. Almost everyone who died was gone in two weeks.” Probing the 1918 influenza virus genome failed to find anything that answers why that strain was so lethal. It is, thus, more probable that people who died of the 1918 flu already had damaged lungs from TB.

“I think TB is the missing piece of the puzzle. It explains why younger people, especially men, died in such great numbers.”

TB and 1918 Flu in Other Countries

Since Professor’s Noymer data is based on the US only, is it applicable to other countries? A 2012 study led by Professor Hiroshi Nishiura, appearing in Computational and Mathematical Methods in Medicine, examined just that. They analyzed epidemiological records of the 1918 flu and TB from the US, Netherlands, Japan, and Switzerland with three statistical techniques. All results are in line with what Professor Noymer found. “TB was shown to be associated with influenza death, and there was no influenza death among non-TB controls,” the 2012 paper wrote. And there was indeed a drastic decline in TB deaths across countries shortly after the 1918 pandemic.

“TB was shown to be associated with influenza death, and there was no influenza death among non-TB controls.”

A similar study in 2016 looked at TB and influenza records during the 1889 (Russian) and 1918 (Spanish) flu pandemics in Switzerland only. They found an abrupt increase in TB deaths during the two pandemics, which quickly drooped after that. Drawing on previously published papers, they concluded: “All these findings suggest a causal relationship between influenza and PTB [pulmonary TB] mortality that is in line with experimental studies.” (By experimental, they meant mice studies that showed influenza and TB co-infection are much more lethal than either one by itself.)

The 1918 Pandemic Riddles that TB Help Explains

In short, history’s deadliest 1918 pandemic might not be the workings of the flu alone, but with a TB co-infection as well. It explains why the 1918 flu strain was particularly virulent than others, and why it disproportionately kills men and the younger age groups.

Perhaps the prerequisite to getting severe flu in 1918 is a TB co-infection.

It may also help resolve the mystery of how the 1918 flu spread among humans. Scientists have never succeeded in transmitting the flu to others by direct contact. They even made patients bedridden with the 1918 flu spat and exhaled heavily at young navy volunteers. But none ever fell sick. No cogent explanations exist to this day. “It seemed that what was acknowledged to be one of the most contagious of communicable diseases could not be transferred under experimental conditions,” a 2010 review said. Perhaps the prerequisite to getting severe flu in 1918 is a TB co-infection.

If the presence of TB worsens influenza, the opposite could be exact as well. In South Africa that has a high TB prevalence, a 2015 study showed that influenza vaccination prevented excess TB deaths. They also found an increased risk of influenza mortality in those with TB. “If confirmed in other settings, our findings may support recommendations for active inclusion of patients with TB for influenza vaccination…,” the study authors wrote.

TB and Covid-19

A consensus document by experts across the globe in the European Respiratory Journal admits the role of TB in viral infections of the lungs, such as MERS, SARS, HIV, influenza A (H1N1), and COVID-19. As the lengthy title speaks for itself: “Epidemic and pandemic viral infections: impact on tuberculosis and the lung. A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN) and members of ESCMID Study Group for Mycobacterial Infections (ESGMYC).”

In this consensus review, it states that “there may be an interaction between Covid-19 and TB, but long-term observations are lacking.” They cited two studies for that. One studied 49 patients from eight countries with Covid-19 and TB co-infection. The other looked at 69 patients from seven countries with the same co-infection. Scanning their lungs showed lesions indicative of both Covid-19 and TB infections — suggesting double damage. The mortality rate of these co-infected patients hovered at around 10%, but there was no control group for comparison.

Active TB independently increased the risk of Covid-19 death by 170%, whereas this number is 51% for prior or latent TB.

The consensus report missed a South Africa population study (still in peer-review), arguably the most conclusive evidence that TB is a risk factor for Covid-19 mortality. This study involved 3,460,932 patients, of whom 353,269 had TB and 22,308 had Covid-19. (This study is curated by PubMed, speaking for its validity to some extent.) Adjusting for confounds, they found that active TB increased the risk of Covid-19 death by 170%, whereas this number is 51% for prior or latent TB. (Note: most of those with TB also had HIV, but at least evidence suggests that HIV does not worsen Covid-19 severity.)

TB Vaccine and Covid-19

There is an intriguing correlation between TB vaccination (called BCG) and Covid-19. “Seven of eight countries with very low numbers of total deaths (< 40 per 1 million population) adopted a mandatory BCG vaccination program,” Masayuki Miyasaka, professor emeritus of immunology at Osaka University, wrote in a June review. “In contrast, Covid‐19 mortality was markedly higher in countries where BCG vaccination is not widely administered or is given only to high‐risk groups.”

In a more advanced statistical paper in PNAS, researchers at the National Institutes of Health (NIH) in Bethesda calculated that “every 10% increase in the BCG index was associated with a 10.4% reduction in Covid-19 mortality.” And this association is not attributed to socioeconomic or demographic differences between the 21 countries examined.

TB vaccination called BCG could prevent Covid-19 severity or mortality.

In a US study of 120 patients, those who had BCG vaccination were less likely to develop severe Covid-19 than those without (3.7% vs 15.8%; effects remained after adjusting for comorbidities and demographics). “The finding from our study suggests the potential of BCG in preventing more severe Covid-19,” the study concluded.

As follows, regions with a high TB prevalence also seem to suffer more from Covid-19. New York City (NYC), for example, has the highest Covid-19 deaths per capita than other states, and its TB cases are “more than twice as high as the national rate,” the NCY Bureau of Tuberculosis Control reported in 2019. Though it’s important to note that these are correlations that help support the research above that TB is a risk factor for Covid-19.

A Primer on TB

Might undetected TB fueled the 1918 flu and 2019 Covid pandemics? Yes, especially more so during 1918. We may have TB controlled to some degree in this age of antibiotics and vaccines, but it is still a huge global concern for the following reasons (sources: the WHO and CDC):

• TB is a bacterial lung infection, but it may also attack the kidney, spine, and brain. But most infected people have latent TB that do not show symptoms.
• About one-quarter of the global population has latent TB; this number is 13 million in the US. Luckily, latent TB is not contagious (as the bacterium is now inactive) and can be treated with antibiotics.
• Latent TB which reactivates about 5–15% of the time. Risk factors for TB reactivation include those with HIV, diabetes, malnutrition, frequent smoking habits, or other forms of immunosuppression. Other studies have shown that vitamin D deficiency is a risk factor too [ref 1, 2, 3].
• Despite that TB is treatable, multidrug-resistance is a growing concern.
• Despite that TB is preventable with vaccines, they are not widely used and do not guarantee 100% protection.
• Globally, TB is one of the top 10 causes of mortality. TB also outranks HIV as the number one cause of death from a single infectious agent.

TB is already incredibly notorious by itself, not to mention the added burden from co-infection with other respiratory viral infections.

This article is inspired by Mad Mockingbird.