Tuberculosis

Analysis of finger sweat detected isoniazid in adults with tuberculosis (TB) for ≤ 6 hours after administration, based on data from a new pilot study.

Risk factors for TB treatment failure include poor medication compliance and insufficient exposure to medications, but measurement of drugs in samples of blood, saliva, or sweat can help assess adherence and inform dose adjustments, Katherine Longman, a PhD student at the University of Surrey, Guildford, England, and colleagues wrote.

Although TB is treatable, “it is well known that insufficient drug dosing leads to treatment failure and drug resistance, and so ensuring that patients have sufficient drug exposure is important,” said corresponding author Melanie J. Bailey, PhD, also of the University of Surrey.

“This can be carried out using blood, but blood is painful to collect and difficult to transport. Finger sweat offers a completely noninvasive way to sample patients,” but its use to determine medication adherence has not been examined, she said.

In a pilot study published in the International Journal of Antimicrobial Agents, the researchers reviewed data from 10 adults with TB who provided finger sweat, blood, and saliva samples at several time points ≤ 6 hours after receiving a controlled dose of isoniazid (median of 300 mg daily). They used liquid chromatography–mass spectrometry to examine the samples.

Overall, “isoniazid and acetyl isoniazid were detected in at least one finger sweat sample from all patients,” with detection rates of 96% and 77%, respectively, the researchers wrote. Given the short half-life of isoniazid, they used a window of 1-6 hours after administration. Isoniazid was consistently detected between 1 and 6 hours after administration, while acetyl isoniazid had a noticeably higher detection rate at 6 hours.

The researchers also examined creatinine to account for variability in volume of sweat samples, and found that finger sweat was significantly correlated to isoniazid concentration. The maximum isoniazid to creatinine ratio in finger sweat occurred mainly in the first hour after drug administration, and the activity of isoniazid in finger sweat over time reflected isoniazid concentration in serum more closely after normalization to creatinine, they said. The Pearson’s correlation coefficient (r) was 0.98 (P < .001; one-tailed), with normalization to creatinine, compared with r = 0.52 without normalization (P = .051).

The study findings were limited by several factors including the lack of knowledge of the last drug dose and lack of confirmation testing with an established method of analysis, the researchers noted. However, the results support the potential of the finger sweat test as a screening tool to indicate patients’ nonadherence or to identify patients at risk of low medication exposure.

“We were surprised that we were able to detect the drug in so many patient samples because the sample volume is so low, and so detection is challenging,” said Dr. Bailey. “We were also surprised that fingerprint and drug levels correlated so well after normalizing to creatinine. This is exciting as it unlocks the possibility to test drug levels, as well as providing a yes/no test.”

In practice, the finger sweat technique could reduce the burden on clinics by offering a completely noninvasive way to test a patient’s medication adherence. Looking ahead, more research is needed to explore whether creatinine normalization is widely applicable, such as whether it works for patients with abnormal kidney function, she added.
 

Noninvasive Option May Mitigate Treatment Challenges

The current study presents a strategy that might address current limitations in TB management, said Krishna Thavarajah, MD, a pulmonologist and director of the interstitial lung disease program at Henry Ford Hospital, Detroit, Michigan, in an interview.

Both self-administered treatment and directly observed therapy (DOT) for TB therapy have limitations, including adherence as low as 50% for TB regimens, she said. In addition, “DOT availability and efficacy can be limited by cost, personnel availability from an administration perspective, and by distrust of those being treated.”

In the current study, “I was struck by the correlation between the sweat and serum values of [isoniazid] and by the level of sophistication of noninvasive testing, being able to normalize for creatinine to account for different volumes of sweat,” said Dr. Thavarajah. In clinical practice, finger sweat isoniazid could potentially serve as an adjunct or alternative to DOT in patients with TB.

Although adherence to the sampling protocol and possible patient distrust of the process (such as concerns over what else is being collected in their sweat) might be barriers to the use of a finger sweat strategy in the clinical setting, appropriate patient selection, patient training, and encouraging clinicians to incorporate this testing into practice could overcome these barriers, said Dr. Thavarajah.

However, more research is needed to study the finger sweat strategy in larger, real-world samples and to study accuracy and treatment adherence with monitoring in a population undergoing DOT, she said.

The study was supported by the Engineering & Physical Sciences Research Council and by Santander PhD Mobility Awards 2019. The researchers had no financial conflicts to disclose. Dr. Thavarajah had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Analysis of finger sweat detected isoniazid in adults with tuberculosis (TB) for ≤ 6 hours after administration, based on data from a new pilot study.

Risk factors for TB treatment failure include poor medication compliance and insufficient exposure to medications, but measurement of drugs in samples of blood, saliva, or sweat can help assess adherence and inform dose adjustments, Katherine Longman, a PhD student at the University of Surrey, Guildford, England, and colleagues wrote.

Although TB is treatable, “it is well known that insufficient drug dosing leads to treatment failure and drug resistance, and so ensuring that patients have sufficient drug exposure is important,” said corresponding author Melanie J. Bailey, PhD, also of the University of Surrey.

“This can be carried out using blood, but blood is painful to collect and difficult to transport. Finger sweat offers a completely noninvasive way to sample patients,” but its use to determine medication adherence has not been examined, she said.

In a pilot study published in the International Journal of Antimicrobial Agents, the researchers reviewed data from 10 adults with TB who provided finger sweat, blood, and saliva samples at several time points ≤ 6 hours after receiving a controlled dose of isoniazid (median of 300 mg daily). They used liquid chromatography–mass spectrometry to examine the samples.

Overall, “isoniazid and acetyl isoniazid were detected in at least one finger sweat sample from all patients,” with detection rates of 96% and 77%, respectively, the researchers wrote. Given the short half-life of isoniazid, they used a window of 1-6 hours after administration. Isoniazid was consistently detected between 1 and 6 hours after administration, while acetyl isoniazid had a noticeably higher detection rate at 6 hours.

The researchers also examined creatinine to account for variability in volume of sweat samples, and found that finger sweat was significantly correlated to isoniazid concentration. The maximum isoniazid to creatinine ratio in finger sweat occurred mainly in the first hour after drug administration, and the activity of isoniazid in finger sweat over time reflected isoniazid concentration in serum more closely after normalization to creatinine, they said. The Pearson’s correlation coefficient (r) was 0.98 (P < .001; one-tailed), with normalization to creatinine, compared with r = 0.52 without normalization (P = .051).

The study findings were limited by several factors including the lack of knowledge of the last drug dose and lack of confirmation testing with an established method of analysis, the researchers noted. However, the results support the potential of the finger sweat test as a screening tool to indicate patients’ nonadherence or to identify patients at risk of low medication exposure.

“We were surprised that we were able to detect the drug in so many patient samples because the sample volume is so low, and so detection is challenging,” said Dr. Bailey. “We were also surprised that fingerprint and drug levels correlated so well after normalizing to creatinine. This is exciting as it unlocks the possibility to test drug levels, as well as providing a yes/no test.”

In practice, the finger sweat technique could reduce the burden on clinics by offering a completely noninvasive way to test a patient’s medication adherence. Looking ahead, more research is needed to explore whether creatinine normalization is widely applicable, such as whether it works for patients with abnormal kidney function, she added.
 

Noninvasive Option May Mitigate Treatment Challenges

The current study presents a strategy that might address current limitations in TB management, said Krishna Thavarajah, MD, a pulmonologist and director of the interstitial lung disease program at Henry Ford Hospital, Detroit, Michigan, in an interview.

Both self-administered treatment and directly observed therapy (DOT) for TB therapy have limitations, including adherence as low as 50% for TB regimens, she said. In addition, “DOT availability and efficacy can be limited by cost, personnel availability from an administration perspective, and by distrust of those being treated.”

In the current study, “I was struck by the correlation between the sweat and serum values of [isoniazid] and by the level of sophistication of noninvasive testing, being able to normalize for creatinine to account for different volumes of sweat,” said Dr. Thavarajah. In clinical practice, finger sweat isoniazid could potentially serve as an adjunct or alternative to DOT in patients with TB.

Although adherence to the sampling protocol and possible patient distrust of the process (such as concerns over what else is being collected in their sweat) might be barriers to the use of a finger sweat strategy in the clinical setting, appropriate patient selection, patient training, and encouraging clinicians to incorporate this testing into practice could overcome these barriers, said Dr. Thavarajah.

However, more research is needed to study the finger sweat strategy in larger, real-world samples and to study accuracy and treatment adherence with monitoring in a population undergoing DOT, she said.

The study was supported by the Engineering & Physical Sciences Research Council and by Santander PhD Mobility Awards 2019. The researchers had no financial conflicts to disclose. Dr. Thavarajah had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

Analysis of finger sweat detected isoniazid in adults with tuberculosis (TB) for ≤ 6 hours after administration, based on data from a new pilot study.

Risk factors for TB treatment failure include poor medication compliance and insufficient exposure to medications, but measurement of drugs in samples of blood, saliva, or sweat can help assess adherence and inform dose adjustments, Katherine Longman, a PhD student at the University of Surrey, Guildford, England, and colleagues wrote.

Although TB is treatable, “it is well known that insufficient drug dosing leads to treatment failure and drug resistance, and so ensuring that patients have sufficient drug exposure is important,” said corresponding author Melanie J. Bailey, PhD, also of the University of Surrey.

“This can be carried out using blood, but blood is painful to collect and difficult to transport. Finger sweat offers a completely noninvasive way to sample patients,” but its use to determine medication adherence has not been examined, she said.

In a pilot study published in the International Journal of Antimicrobial Agents, the researchers reviewed data from 10 adults with TB who provided finger sweat, blood, and saliva samples at several time points ≤ 6 hours after receiving a controlled dose of isoniazid (median of 300 mg daily). They used liquid chromatography–mass spectrometry to examine the samples.

Overall, “isoniazid and acetyl isoniazid were detected in at least one finger sweat sample from all patients,” with detection rates of 96% and 77%, respectively, the researchers wrote. Given the short half-life of isoniazid, they used a window of 1-6 hours after administration. Isoniazid was consistently detected between 1 and 6 hours after administration, while acetyl isoniazid had a noticeably higher detection rate at 6 hours.

The researchers also examined creatinine to account for variability in volume of sweat samples, and found that finger sweat was significantly correlated to isoniazid concentration. The maximum isoniazid to creatinine ratio in finger sweat occurred mainly in the first hour after drug administration, and the activity of isoniazid in finger sweat over time reflected isoniazid concentration in serum more closely after normalization to creatinine, they said. The Pearson’s correlation coefficient (r) was 0.98 (P < .001; one-tailed), with normalization to creatinine, compared with r = 0.52 without normalization (P = .051).

The study findings were limited by several factors including the lack of knowledge of the last drug dose and lack of confirmation testing with an established method of analysis, the researchers noted. However, the results support the potential of the finger sweat test as a screening tool to indicate patients’ nonadherence or to identify patients at risk of low medication exposure.

“We were surprised that we were able to detect the drug in so many patient samples because the sample volume is so low, and so detection is challenging,” said Dr. Bailey. “We were also surprised that fingerprint and drug levels correlated so well after normalizing to creatinine. This is exciting as it unlocks the possibility to test drug levels, as well as providing a yes/no test.”

In practice, the finger sweat technique could reduce the burden on clinics by offering a completely noninvasive way to test a patient’s medication adherence. Looking ahead, more research is needed to explore whether creatinine normalization is widely applicable, such as whether it works for patients with abnormal kidney function, she added.
 

Noninvasive Option May Mitigate Treatment Challenges

The current study presents a strategy that might address current limitations in TB management, said Krishna Thavarajah, MD, a pulmonologist and director of the interstitial lung disease program at Henry Ford Hospital, Detroit, Michigan, in an interview.

Both self-administered treatment and directly observed therapy (DOT) for TB therapy have limitations, including adherence as low as 50% for TB regimens, she said. In addition, “DOT availability and efficacy can be limited by cost, personnel availability from an administration perspective, and by distrust of those being treated.”

In the current study, “I was struck by the correlation between the sweat and serum values of [isoniazid] and by the level of sophistication of noninvasive testing, being able to normalize for creatinine to account for different volumes of sweat,” said Dr. Thavarajah. In clinical practice, finger sweat isoniazid could potentially serve as an adjunct or alternative to DOT in patients with TB.

Although adherence to the sampling protocol and possible patient distrust of the process (such as concerns over what else is being collected in their sweat) might be barriers to the use of a finger sweat strategy in the clinical setting, appropriate patient selection, patient training, and encouraging clinicians to incorporate this testing into practice could overcome these barriers, said Dr. Thavarajah.

However, more research is needed to study the finger sweat strategy in larger, real-world samples and to study accuracy and treatment adherence with monitoring in a population undergoing DOT, she said.

The study was supported by the Engineering & Physical Sciences Research Council and by Santander PhD Mobility Awards 2019. The researchers had no financial conflicts to disclose. Dr. Thavarajah had no financial conflicts to disclose.

A version of this article first appeared on Medscape.com.

A new study conducted by the World Health Organization (WHO) suggests that in addition to providing significant improvements in public health, investment in the diagnosis and prevention of tuberculosis also generates economic benefits.

According to a survey conducted by governments and researchers from Brazil, Georgia, Kenya, and South Africa, even modest increases in funding for measures against tuberculosis can bring gains. Every $1 invested produces returns of as much as $39, it found.

The findings may remind governments and policymakers about the importance of investing in public health policies. According to the WHO, the study “provides strong economic arguments” about the true costs of tuberculosis and proves the benefits of increasing funding to accelerate the diagnosis and preventive treatment of the disease.
 

UN Targets Tuberculosis

In September 2023, during the last meeting of the United Nations General Assembly, following a widespread worsening of disease indicators because of the COVID-19 pandemic, world leaders signed a declaration committing to the expansion of efforts to combat tuberculosis during the next 5 years. The current WHO study was developed to provide a road map for the implementation of key measures against the disease.

The survey highlights two fundamental actions: The expansion of screening, especially in populations considered more vulnerable, and the provision of tuberculosis preventive treatment (TPT), which entails administering drugs to people who have been exposed to the disease but have not yet developed it.

“TPT is a proven and effective intervention to prevent the development of tuberculosis among exposed people, reducing the risk of developing the disease by about 60%-90% compared with individuals who did not receive it,” the document emphasized.

Investments Yield Returns

To achieve the necessary coverage levels, the study estimated that Brazil would need to increase annual per capita investment by $0.28 (about R$1.41) between 2024 and 2050. Brazilian society, in turn, would receive a return of $11 (R$55.27) for every dollar invested.

For South Africa, whose per capita investment increase is estimated at $1.10 per year, the return would be even more significant: $39 for every dollar allocated.

The WHO emphasized that funding for combating the disease is much lower than the value of the damage it causes to nations. “Tuberculosis has high costs for society. Only a small proportion of these costs go directly to the health system (ranging from 1.7% in South Africa to 7.8% in Kenya). Most are costs for patients and society.”

The study projected that between 2024 and 2050, the total cost of tuberculosis to Brazilian society would be $81.2 billion, with an average annual value of $3.01 billion. This figure represents, in 2024, 0.16% of the country’s gross domestic product.

Achieving screening and preventive treatment goals in Brazil would lead to a reduction of as much as 18% in the national incidence of the disease, as well as 1.9 million fewer deaths, between 2024 and 2050.

Although treatable and preventable, tuberculosis remains the leading cause of death from infectious agents worldwide. It is estimated that over 1.3 million people died from the disease in 2022.

The document provides the “health and economic justification for investing in evidence-based interventions recommended by WHO in tuberculosis screening and prevention,” according to WHO Director-General Tedros Adhanom Ghebreyesus, PhD.

“Today we have the knowledge, tools, and political commitment that can end this age-old disease that continues to be one of the leading causes of death from infectious diseases worldwide,” he added.

Emerging Concerns

Although the WHO highlighted the global increase in access to tuberculosis diagnosis and treatment in 2022, which coincided with the recovery of healthcare systems in several countries after the beginning of the pandemic, it emphasized that the implementation of preventive treatment for exposed individuals and high-vulnerability populations remains slow.

Another concern is the increase in drug resistance. Multidrug-resistant tuberculosis is considered a public health crisis. It is estimated that about 410,000 people had multidrug-resistant tuberculosis or rifampicin-resistant tuberculosis in 2022, but only two of every five patients had access to treatment.This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com .

A new study conducted by the World Health Organization (WHO) suggests that in addition to providing significant improvements in public health, investment in the diagnosis and prevention of tuberculosis also generates economic benefits.

According to a survey conducted by governments and researchers from Brazil, Georgia, Kenya, and South Africa, even modest increases in funding for measures against tuberculosis can bring gains. Every $1 invested produces returns of as much as $39, it found.

The findings may remind governments and policymakers about the importance of investing in public health policies. According to the WHO, the study “provides strong economic arguments” about the true costs of tuberculosis and proves the benefits of increasing funding to accelerate the diagnosis and preventive treatment of the disease.
 

UN Targets Tuberculosis

In September 2023, during the last meeting of the United Nations General Assembly, following a widespread worsening of disease indicators because of the COVID-19 pandemic, world leaders signed a declaration committing to the expansion of efforts to combat tuberculosis during the next 5 years. The current WHO study was developed to provide a road map for the implementation of key measures against the disease.

The survey highlights two fundamental actions: The expansion of screening, especially in populations considered more vulnerable, and the provision of tuberculosis preventive treatment (TPT), which entails administering drugs to people who have been exposed to the disease but have not yet developed it.

“TPT is a proven and effective intervention to prevent the development of tuberculosis among exposed people, reducing the risk of developing the disease by about 60%-90% compared with individuals who did not receive it,” the document emphasized.

Investments Yield Returns

To achieve the necessary coverage levels, the study estimated that Brazil would need to increase annual per capita investment by $0.28 (about R$1.41) between 2024 and 2050. Brazilian society, in turn, would receive a return of $11 (R$55.27) for every dollar invested.

For South Africa, whose per capita investment increase is estimated at $1.10 per year, the return would be even more significant: $39 for every dollar allocated.

The WHO emphasized that funding for combating the disease is much lower than the value of the damage it causes to nations. “Tuberculosis has high costs for society. Only a small proportion of these costs go directly to the health system (ranging from 1.7% in South Africa to 7.8% in Kenya). Most are costs for patients and society.”

The study projected that between 2024 and 2050, the total cost of tuberculosis to Brazilian society would be $81.2 billion, with an average annual value of $3.01 billion. This figure represents, in 2024, 0.16% of the country’s gross domestic product.

Achieving screening and preventive treatment goals in Brazil would lead to a reduction of as much as 18% in the national incidence of the disease, as well as 1.9 million fewer deaths, between 2024 and 2050.

Although treatable and preventable, tuberculosis remains the leading cause of death from infectious agents worldwide. It is estimated that over 1.3 million people died from the disease in 2022.

The document provides the “health and economic justification for investing in evidence-based interventions recommended by WHO in tuberculosis screening and prevention,” according to WHO Director-General Tedros Adhanom Ghebreyesus, PhD.

“Today we have the knowledge, tools, and political commitment that can end this age-old disease that continues to be one of the leading causes of death from infectious diseases worldwide,” he added.

Emerging Concerns

Although the WHO highlighted the global increase in access to tuberculosis diagnosis and treatment in 2022, which coincided with the recovery of healthcare systems in several countries after the beginning of the pandemic, it emphasized that the implementation of preventive treatment for exposed individuals and high-vulnerability populations remains slow.

Another concern is the increase in drug resistance. Multidrug-resistant tuberculosis is considered a public health crisis. It is estimated that about 410,000 people had multidrug-resistant tuberculosis or rifampicin-resistant tuberculosis in 2022, but only two of every five patients had access to treatment.This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com .

A new study conducted by the World Health Organization (WHO) suggests that in addition to providing significant improvements in public health, investment in the diagnosis and prevention of tuberculosis also generates economic benefits.

According to a survey conducted by governments and researchers from Brazil, Georgia, Kenya, and South Africa, even modest increases in funding for measures against tuberculosis can bring gains. Every $1 invested produces returns of as much as $39, it found.

The findings may remind governments and policymakers about the importance of investing in public health policies. According to the WHO, the study “provides strong economic arguments” about the true costs of tuberculosis and proves the benefits of increasing funding to accelerate the diagnosis and preventive treatment of the disease.
 

UN Targets Tuberculosis

In September 2023, during the last meeting of the United Nations General Assembly, following a widespread worsening of disease indicators because of the COVID-19 pandemic, world leaders signed a declaration committing to the expansion of efforts to combat tuberculosis during the next 5 years. The current WHO study was developed to provide a road map for the implementation of key measures against the disease.

The survey highlights two fundamental actions: The expansion of screening, especially in populations considered more vulnerable, and the provision of tuberculosis preventive treatment (TPT), which entails administering drugs to people who have been exposed to the disease but have not yet developed it.

“TPT is a proven and effective intervention to prevent the development of tuberculosis among exposed people, reducing the risk of developing the disease by about 60%-90% compared with individuals who did not receive it,” the document emphasized.

Investments Yield Returns

To achieve the necessary coverage levels, the study estimated that Brazil would need to increase annual per capita investment by $0.28 (about R$1.41) between 2024 and 2050. Brazilian society, in turn, would receive a return of $11 (R$55.27) for every dollar invested.

For South Africa, whose per capita investment increase is estimated at $1.10 per year, the return would be even more significant: $39 for every dollar allocated.

The WHO emphasized that funding for combating the disease is much lower than the value of the damage it causes to nations. “Tuberculosis has high costs for society. Only a small proportion of these costs go directly to the health system (ranging from 1.7% in South Africa to 7.8% in Kenya). Most are costs for patients and society.”

The study projected that between 2024 and 2050, the total cost of tuberculosis to Brazilian society would be $81.2 billion, with an average annual value of $3.01 billion. This figure represents, in 2024, 0.16% of the country’s gross domestic product.

Achieving screening and preventive treatment goals in Brazil would lead to a reduction of as much as 18% in the national incidence of the disease, as well as 1.9 million fewer deaths, between 2024 and 2050.

Although treatable and preventable, tuberculosis remains the leading cause of death from infectious agents worldwide. It is estimated that over 1.3 million people died from the disease in 2022.

The document provides the “health and economic justification for investing in evidence-based interventions recommended by WHO in tuberculosis screening and prevention,” according to WHO Director-General Tedros Adhanom Ghebreyesus, PhD.

“Today we have the knowledge, tools, and political commitment that can end this age-old disease that continues to be one of the leading causes of death from infectious diseases worldwide,” he added.

Emerging Concerns

Although the WHO highlighted the global increase in access to tuberculosis diagnosis and treatment in 2022, which coincided with the recovery of healthcare systems in several countries after the beginning of the pandemic, it emphasized that the implementation of preventive treatment for exposed individuals and high-vulnerability populations remains slow.

Another concern is the increase in drug resistance. Multidrug-resistant tuberculosis is considered a public health crisis. It is estimated that about 410,000 people had multidrug-resistant tuberculosis or rifampicin-resistant tuberculosis in 2022, but only two of every five patients had access to treatment.This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com .

In 2022, more than 78,000 new cases of tuberculosis (TB) were reported in Brazil, with an incidence of 36.3 cases per 100,000 inhabitants. According to researchers from the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil consortium, the country could improve the control of this infection if all patients were subjected to a sensitivity test capable of early detection of resistance not only to rifampicin, but also to isoniazid, before starting treatment. A study by the consortium published this year in Open Forum Infectious Diseases found that monoresistance to isoniazid predicted unfavorable outcomes at the national level.

Isoniazid is part of the first-choice therapeutic regimen for patients with pulmonary TB. The regimen also includes rifampicin, pyrazinamide, and ethambutol. According to Bruno Andrade, MD, PhD, Afrânio Kritski, MD, PhD, and biotechnologist Mariana Araújo Pereira, PhD, researchers from RePORT International and RePORT-Brazil, this regimen is used during the intensive phase of treatment, which usually lasts for 2 months. It is followed by a maintenance phase of another 4 months, during which isoniazid and rifampicin continue to be administered. When monoresistance to isoniazid is detected, however, the recommendation is to use a regimen containing a quinolone instead of isoniazid.

Suboptimal Sensitivity Testing 

Since 2015, Brazil’s Ministry of Health has recommended sensitivity testing for all suspected TB cases. In practice, however, this approach is not carried out in the ideal manner. The three researchers told the Medscape Portuguese edition that, according to data from the National Notifiable Diseases Information System (Sinan) of the Ministry of Health, culture testing is conducted in about 30% of cases. Sensitivity testing to identify resistance to first-line drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide) and second-line drugs (quinolone and amikacin) is performed in only 12% of cases.

The initiative of the RePORT-Brazil group analyzed 21,197 TB cases registered in Sinan between June 2015 and June 2019 and identified a rate of monoresistance to isoniazid of 1.4%.

For the researchers, the problem of monoresistance to isoniazid in Brazil is still underestimated. This underestimation results from the infrequent performance of culture and sensitivity testing to detect resistance to first- and second-line drugs and because the XPERT MTB RIF test, which detects only rifampicin resistance, is still used.

Resistance and Worse Outcomes

The study also showed that the frequency of unfavorable outcomes in antituberculosis treatment (death or therapeutic failure) was significantly higher among patients with monoresistance to isoniazid (9.1% vs 3.05%).

The finding serves as a warning about the importance of increasing the administration of sensitivity tests to detect resistance to drugs used in tuberculosis treatment, including isoniazid.

Testing sensitivity to rifampicin and isoniazid before starting treatment could transform tuberculosis control in Brazil, allowing for more targeted and effective treatments from the outset, said the researchers. “This not only increases the chances of successful individual treatment but also helps prevent the transmission of resistant strains and develop a more accurate understanding of drug resistance trends,” they emphasized.

They pointed out, however, that implementing this testing in the Unified Health System depends on improvements in resource allocation, coordination between the national TB program and state and municipal programs, and improvements in infrastructure and the technical staff of the Central Public Health Laboratories.

“Although the initial cost is considerable, these investments can be offset by long-term savings resulting from the reduction in the use of more expensive and prolonged treatments for resistant tuberculosis,” said the researchers.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

In 2022, more than 78,000 new cases of tuberculosis (TB) were reported in Brazil, with an incidence of 36.3 cases per 100,000 inhabitants. According to researchers from the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil consortium, the country could improve the control of this infection if all patients were subjected to a sensitivity test capable of early detection of resistance not only to rifampicin, but also to isoniazid, before starting treatment. A study by the consortium published this year in Open Forum Infectious Diseases found that monoresistance to isoniazid predicted unfavorable outcomes at the national level.

Isoniazid is part of the first-choice therapeutic regimen for patients with pulmonary TB. The regimen also includes rifampicin, pyrazinamide, and ethambutol. According to Bruno Andrade, MD, PhD, Afrânio Kritski, MD, PhD, and biotechnologist Mariana Araújo Pereira, PhD, researchers from RePORT International and RePORT-Brazil, this regimen is used during the intensive phase of treatment, which usually lasts for 2 months. It is followed by a maintenance phase of another 4 months, during which isoniazid and rifampicin continue to be administered. When monoresistance to isoniazid is detected, however, the recommendation is to use a regimen containing a quinolone instead of isoniazid.

Suboptimal Sensitivity Testing 

Since 2015, Brazil’s Ministry of Health has recommended sensitivity testing for all suspected TB cases. In practice, however, this approach is not carried out in the ideal manner. The three researchers told the Medscape Portuguese edition that, according to data from the National Notifiable Diseases Information System (Sinan) of the Ministry of Health, culture testing is conducted in about 30% of cases. Sensitivity testing to identify resistance to first-line drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide) and second-line drugs (quinolone and amikacin) is performed in only 12% of cases.

The initiative of the RePORT-Brazil group analyzed 21,197 TB cases registered in Sinan between June 2015 and June 2019 and identified a rate of monoresistance to isoniazid of 1.4%.

For the researchers, the problem of monoresistance to isoniazid in Brazil is still underestimated. This underestimation results from the infrequent performance of culture and sensitivity testing to detect resistance to first- and second-line drugs and because the XPERT MTB RIF test, which detects only rifampicin resistance, is still used.

Resistance and Worse Outcomes

The study also showed that the frequency of unfavorable outcomes in antituberculosis treatment (death or therapeutic failure) was significantly higher among patients with monoresistance to isoniazid (9.1% vs 3.05%).

The finding serves as a warning about the importance of increasing the administration of sensitivity tests to detect resistance to drugs used in tuberculosis treatment, including isoniazid.

Testing sensitivity to rifampicin and isoniazid before starting treatment could transform tuberculosis control in Brazil, allowing for more targeted and effective treatments from the outset, said the researchers. “This not only increases the chances of successful individual treatment but also helps prevent the transmission of resistant strains and develop a more accurate understanding of drug resistance trends,” they emphasized.

They pointed out, however, that implementing this testing in the Unified Health System depends on improvements in resource allocation, coordination between the national TB program and state and municipal programs, and improvements in infrastructure and the technical staff of the Central Public Health Laboratories.

“Although the initial cost is considerable, these investments can be offset by long-term savings resulting from the reduction in the use of more expensive and prolonged treatments for resistant tuberculosis,” said the researchers.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

In 2022, more than 78,000 new cases of tuberculosis (TB) were reported in Brazil, with an incidence of 36.3 cases per 100,000 inhabitants. According to researchers from the Regional Prospective Observational Research for Tuberculosis (RePORT)-Brazil consortium, the country could improve the control of this infection if all patients were subjected to a sensitivity test capable of early detection of resistance not only to rifampicin, but also to isoniazid, before starting treatment. A study by the consortium published this year in Open Forum Infectious Diseases found that monoresistance to isoniazid predicted unfavorable outcomes at the national level.

Isoniazid is part of the first-choice therapeutic regimen for patients with pulmonary TB. The regimen also includes rifampicin, pyrazinamide, and ethambutol. According to Bruno Andrade, MD, PhD, Afrânio Kritski, MD, PhD, and biotechnologist Mariana Araújo Pereira, PhD, researchers from RePORT International and RePORT-Brazil, this regimen is used during the intensive phase of treatment, which usually lasts for 2 months. It is followed by a maintenance phase of another 4 months, during which isoniazid and rifampicin continue to be administered. When monoresistance to isoniazid is detected, however, the recommendation is to use a regimen containing a quinolone instead of isoniazid.

Suboptimal Sensitivity Testing 

Since 2015, Brazil’s Ministry of Health has recommended sensitivity testing for all suspected TB cases. In practice, however, this approach is not carried out in the ideal manner. The three researchers told the Medscape Portuguese edition that, according to data from the National Notifiable Diseases Information System (Sinan) of the Ministry of Health, culture testing is conducted in about 30% of cases. Sensitivity testing to identify resistance to first-line drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide) and second-line drugs (quinolone and amikacin) is performed in only 12% of cases.

The initiative of the RePORT-Brazil group analyzed 21,197 TB cases registered in Sinan between June 2015 and June 2019 and identified a rate of monoresistance to isoniazid of 1.4%.

For the researchers, the problem of monoresistance to isoniazid in Brazil is still underestimated. This underestimation results from the infrequent performance of culture and sensitivity testing to detect resistance to first- and second-line drugs and because the XPERT MTB RIF test, which detects only rifampicin resistance, is still used.

Resistance and Worse Outcomes

The study also showed that the frequency of unfavorable outcomes in antituberculosis treatment (death or therapeutic failure) was significantly higher among patients with monoresistance to isoniazid (9.1% vs 3.05%).

The finding serves as a warning about the importance of increasing the administration of sensitivity tests to detect resistance to drugs used in tuberculosis treatment, including isoniazid.

Testing sensitivity to rifampicin and isoniazid before starting treatment could transform tuberculosis control in Brazil, allowing for more targeted and effective treatments from the outset, said the researchers. “This not only increases the chances of successful individual treatment but also helps prevent the transmission of resistant strains and develop a more accurate understanding of drug resistance trends,” they emphasized.

They pointed out, however, that implementing this testing in the Unified Health System depends on improvements in resource allocation, coordination between the national TB program and state and municipal programs, and improvements in infrastructure and the technical staff of the Central Public Health Laboratories.

“Although the initial cost is considerable, these investments can be offset by long-term savings resulting from the reduction in the use of more expensive and prolonged treatments for resistant tuberculosis,” said the researchers.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

A combination oral-only therapy of bedaquiline, pretomanid, and linezolid was significantly more effective than standard care in preventing unfavorable outcomes in patients with treatment-resistant tuberculosis, based on data from more than 500 individuals.

Rifampin-resistant tuberculosis affects approximately 500,000 people worldwide each year, but current treatments are associated with toxicity and limited effectiveness, and data on the use of new and repurposed drug combinations are lacking, wrote Bern-Thomas Nyang’wa, MBBS, of Médecins Sans Frontières, Amsterdam, and colleagues.

In a study known as the TB-PRACTECAL trial, the researchers enrolled 552 pulmonary rifampin-resistant tuberculosis patients aged 15 years and older to examine several new and repurposed drug combinations. The participants were randomized in a 1:1:1:1 ratio to treatment with 36-80 weeks of standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) . This was followed by stage two of the trial, in which participants were randomized 1:1 to receive standard care or BPaLM. The current study, published in The Lancet Respiratory Medicine, reported the stage two findings; the primary outcome was a composite of unfavorable outcomes at 72 weeks including death, treatment failure, treatment discontinuation, recurrence of tuberculosis, or loss to follow-up.

The modified intent-to-treat population included 138 patients in the BPaLM group and 137 patients in the standard care group. In this population, 56 (41%) of 137 participants in the standard care group and 16 (12%) of 137 participants in the BPaLM group met criteria for the unfavorable outcome at 72 weeks; noninferiority and superiority were significantly greater in the BPaLM group (P < .0001).

Early discontinuation was the main reason patients met the unfavorable outcome criteria (89% of standard care patients and 69% of BPaLM patients); adverse events accounted for 23% of discontinuations in the standard care group and 64% of discontinuations in the BPaLM group.

However, fewer patients in the BPaLM group experienced grade 3 or higher adverse events compared with the standard care group (23% vs. 48%). The most common adverse events included hepatic disorders, cardiac disorders, and anemia.

In addition, all subgroup analyses favored BPaLM over standard care at 72 weeks including subgroups based on sex, age, disease severity, re-treatment status, and smoking status.

The findings were limited by several factors including the changes to standard of care over the course of the study, potential bias because the study was stopped for efficacy, and inclusion of loss to follow-up as part of the composite unfavorable outcome, the researchers noted.

Remaining research questions include the optimal dose of linezolid, whether use of alternative fluoroquinolones would yield similar results, and whether the results would generalize to populations including children, pregnant women, and patients with extrapulmonary tuberculosis, they added.

However, the results support BPaLM as the preferred treatment for adults and adolescents with pulmonary rifampin-resistant TB, the researchers concluded.
 

BPaLM poised to improve TB care

Before 2020, treatment for rifampin-resistant tuberculosis was 9-20 months in duration, toxic, and inadequately effective, and new treatment regimens are urgently needed, Mary Jo Farmer, MD, a pulmonary and critical care specialist at the University of Massachusetts Baystate Health Regional Campus, Springfield, said in an interview.

“The BPaL-based regimens perform better than the 9- to 20-month standard of care, are shorter in duration, have a lower pill burden, improve quality of life, and are cost-effective,” she said. “The BPaL regimens have the potential to improve outcomes for thousands of patients with rifampin-resistant tuberculosis.”

“The 24-week oral regimen consisting of bedaquiline, pretomanid, linezolid and moxifloxacin is noninferior to standard of care for treatment of patients with pulmonary rifampin-resistant tuberculosis, and this BPaLM regimen was added to the WHO guidance for treatment of this condition in 2022,” said Dr. Farmer, who was not involved in the study. “It remains to be seen if BPaLM will become the preferred regimen for adolescents and adults with pulmonary rifampin-resistant tuberculosis,” she said.

Dr. Farmer agreed with the study authors that the optimal dose of linezolid, optimal duration of treatment, and the role of dose reduction remain unknown, and pharmacokinetic studies are needed to identify these parameters. 

The study was supported by Médecins Sans Frontières. TB Alliance donated pretomanid to the study prior to its commercialization. The researchers had no financial conflicts to disclose. Dr. Farmer had no financial conflicts to disclose, but serves on the editorial advisory board of CHEST Physician.

A combination oral-only therapy of bedaquiline, pretomanid, and linezolid was significantly more effective than standard care in preventing unfavorable outcomes in patients with treatment-resistant tuberculosis, based on data from more than 500 individuals.

Rifampin-resistant tuberculosis affects approximately 500,000 people worldwide each year, but current treatments are associated with toxicity and limited effectiveness, and data on the use of new and repurposed drug combinations are lacking, wrote Bern-Thomas Nyang’wa, MBBS, of Médecins Sans Frontières, Amsterdam, and colleagues.

In a study known as the TB-PRACTECAL trial, the researchers enrolled 552 pulmonary rifampin-resistant tuberculosis patients aged 15 years and older to examine several new and repurposed drug combinations. The participants were randomized in a 1:1:1:1 ratio to treatment with 36-80 weeks of standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) . This was followed by stage two of the trial, in which participants were randomized 1:1 to receive standard care or BPaLM. The current study, published in The Lancet Respiratory Medicine, reported the stage two findings; the primary outcome was a composite of unfavorable outcomes at 72 weeks including death, treatment failure, treatment discontinuation, recurrence of tuberculosis, or loss to follow-up.

The modified intent-to-treat population included 138 patients in the BPaLM group and 137 patients in the standard care group. In this population, 56 (41%) of 137 participants in the standard care group and 16 (12%) of 137 participants in the BPaLM group met criteria for the unfavorable outcome at 72 weeks; noninferiority and superiority were significantly greater in the BPaLM group (P < .0001).

Early discontinuation was the main reason patients met the unfavorable outcome criteria (89% of standard care patients and 69% of BPaLM patients); adverse events accounted for 23% of discontinuations in the standard care group and 64% of discontinuations in the BPaLM group.

However, fewer patients in the BPaLM group experienced grade 3 or higher adverse events compared with the standard care group (23% vs. 48%). The most common adverse events included hepatic disorders, cardiac disorders, and anemia.

In addition, all subgroup analyses favored BPaLM over standard care at 72 weeks including subgroups based on sex, age, disease severity, re-treatment status, and smoking status.

The findings were limited by several factors including the changes to standard of care over the course of the study, potential bias because the study was stopped for efficacy, and inclusion of loss to follow-up as part of the composite unfavorable outcome, the researchers noted.

Remaining research questions include the optimal dose of linezolid, whether use of alternative fluoroquinolones would yield similar results, and whether the results would generalize to populations including children, pregnant women, and patients with extrapulmonary tuberculosis, they added.

However, the results support BPaLM as the preferred treatment for adults and adolescents with pulmonary rifampin-resistant TB, the researchers concluded.
 

BPaLM poised to improve TB care

Before 2020, treatment for rifampin-resistant tuberculosis was 9-20 months in duration, toxic, and inadequately effective, and new treatment regimens are urgently needed, Mary Jo Farmer, MD, a pulmonary and critical care specialist at the University of Massachusetts Baystate Health Regional Campus, Springfield, said in an interview.

“The BPaL-based regimens perform better than the 9- to 20-month standard of care, are shorter in duration, have a lower pill burden, improve quality of life, and are cost-effective,” she said. “The BPaL regimens have the potential to improve outcomes for thousands of patients with rifampin-resistant tuberculosis.”

“The 24-week oral regimen consisting of bedaquiline, pretomanid, linezolid and moxifloxacin is noninferior to standard of care for treatment of patients with pulmonary rifampin-resistant tuberculosis, and this BPaLM regimen was added to the WHO guidance for treatment of this condition in 2022,” said Dr. Farmer, who was not involved in the study. “It remains to be seen if BPaLM will become the preferred regimen for adolescents and adults with pulmonary rifampin-resistant tuberculosis,” she said.

Dr. Farmer agreed with the study authors that the optimal dose of linezolid, optimal duration of treatment, and the role of dose reduction remain unknown, and pharmacokinetic studies are needed to identify these parameters. 

The study was supported by Médecins Sans Frontières. TB Alliance donated pretomanid to the study prior to its commercialization. The researchers had no financial conflicts to disclose. Dr. Farmer had no financial conflicts to disclose, but serves on the editorial advisory board of CHEST Physician.

A combination oral-only therapy of bedaquiline, pretomanid, and linezolid was significantly more effective than standard care in preventing unfavorable outcomes in patients with treatment-resistant tuberculosis, based on data from more than 500 individuals.

Rifampin-resistant tuberculosis affects approximately 500,000 people worldwide each year, but current treatments are associated with toxicity and limited effectiveness, and data on the use of new and repurposed drug combinations are lacking, wrote Bern-Thomas Nyang’wa, MBBS, of Médecins Sans Frontières, Amsterdam, and colleagues.

In a study known as the TB-PRACTECAL trial, the researchers enrolled 552 pulmonary rifampin-resistant tuberculosis patients aged 15 years and older to examine several new and repurposed drug combinations. The participants were randomized in a 1:1:1:1 ratio to treatment with 36-80 weeks of standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) . This was followed by stage two of the trial, in which participants were randomized 1:1 to receive standard care or BPaLM. The current study, published in The Lancet Respiratory Medicine, reported the stage two findings; the primary outcome was a composite of unfavorable outcomes at 72 weeks including death, treatment failure, treatment discontinuation, recurrence of tuberculosis, or loss to follow-up.

The modified intent-to-treat population included 138 patients in the BPaLM group and 137 patients in the standard care group. In this population, 56 (41%) of 137 participants in the standard care group and 16 (12%) of 137 participants in the BPaLM group met criteria for the unfavorable outcome at 72 weeks; noninferiority and superiority were significantly greater in the BPaLM group (P < .0001).

Early discontinuation was the main reason patients met the unfavorable outcome criteria (89% of standard care patients and 69% of BPaLM patients); adverse events accounted for 23% of discontinuations in the standard care group and 64% of discontinuations in the BPaLM group.

However, fewer patients in the BPaLM group experienced grade 3 or higher adverse events compared with the standard care group (23% vs. 48%). The most common adverse events included hepatic disorders, cardiac disorders, and anemia.

In addition, all subgroup analyses favored BPaLM over standard care at 72 weeks including subgroups based on sex, age, disease severity, re-treatment status, and smoking status.

The findings were limited by several factors including the changes to standard of care over the course of the study, potential bias because the study was stopped for efficacy, and inclusion of loss to follow-up as part of the composite unfavorable outcome, the researchers noted.

Remaining research questions include the optimal dose of linezolid, whether use of alternative fluoroquinolones would yield similar results, and whether the results would generalize to populations including children, pregnant women, and patients with extrapulmonary tuberculosis, they added.

However, the results support BPaLM as the preferred treatment for adults and adolescents with pulmonary rifampin-resistant TB, the researchers concluded.
 

BPaLM poised to improve TB care

Before 2020, treatment for rifampin-resistant tuberculosis was 9-20 months in duration, toxic, and inadequately effective, and new treatment regimens are urgently needed, Mary Jo Farmer, MD, a pulmonary and critical care specialist at the University of Massachusetts Baystate Health Regional Campus, Springfield, said in an interview.

“The BPaL-based regimens perform better than the 9- to 20-month standard of care, are shorter in duration, have a lower pill burden, improve quality of life, and are cost-effective,” she said. “The BPaL regimens have the potential to improve outcomes for thousands of patients with rifampin-resistant tuberculosis.”

“The 24-week oral regimen consisting of bedaquiline, pretomanid, linezolid and moxifloxacin is noninferior to standard of care for treatment of patients with pulmonary rifampin-resistant tuberculosis, and this BPaLM regimen was added to the WHO guidance for treatment of this condition in 2022,” said Dr. Farmer, who was not involved in the study. “It remains to be seen if BPaLM will become the preferred regimen for adolescents and adults with pulmonary rifampin-resistant tuberculosis,” she said.

Dr. Farmer agreed with the study authors that the optimal dose of linezolid, optimal duration of treatment, and the role of dose reduction remain unknown, and pharmacokinetic studies are needed to identify these parameters. 

The study was supported by Médecins Sans Frontières. TB Alliance donated pretomanid to the study prior to its commercialization. The researchers had no financial conflicts to disclose. Dr. Farmer had no financial conflicts to disclose, but serves on the editorial advisory board of CHEST Physician.

A simple and objective severity score based on activities of daily living, hypoxemia, and lymphocytes was an effective predictor of mortality in adults with pulmonary tuberculosis, based on data from approximately 400 individuals.

Although a mortality risk-prediction score could improve treatment for pulmonary tuberculosis patients, such a score has not been previously reported, wrote Takeshi Osawa, MD, of Fukujuji Hospital, Tokyo, and colleagues.

In a study published in the journal CHEST, the researchers used 252 patients from a previous perspective study of newly diagnosed pulmonary tuberculosis as the development cohort, and recruited 165 additional patients between March 2021 and September 2022.

The primary endpoint was all-cause in-hospital mortality. Based on data from the development group, the researchers found that age 65 years and older and age 80 years and older, hypoxemia, activities of daily living, bilateral pulmonary lesions, lymphocyte count of less than 720 microliters, serum albumin less than 2.86 mg/dL, C-reactive protein (CRP) 3.97 mg/dL or higher, and procalcitonin (PCT) 0.130 ng/mL or higher were predictors of all-cause in hospital mortality.

The researchers used this information to create the disease severity score, known as the AHL score. The AHL included three clinical parameters: activity in daily living (semi-dependent, 1 point; totally dependent, 2 points); hypoxemia (1 point) and lymphocytes (< 720 /mcL, 1 point).

The scoring systems for the three parameters were, respectively, 1 point for semi-dependent and 2 points totally dependent (for activity in daily living), 1 point for presence of hypoxemia, and 1 point for lymphocytes less than 720 per microliter. The researchers stratified the scores into levels of low, intermediate, and high risk, with scores of 0, 1-2, and 3-4, respectively.

All-cause in hospital mortality occurred in 39 (15.5%) and 17 (10.3%) of patients in the developmental and validation cohorts, respectively.

The AHL score effectively predicted mortality, dividing patients into three groups of 1.3% low-risk, 8.9% intermediate risk, and 39.3% high-risk in the validation cohort, with a Harrell’s c-statistic of 0.842.

The corresponding numbers for the development cohort were 0, 13.5%, and 55.8%, with a c-statistic of 0.902.

The findings were limited by several factors, including the lack of data from “smear-negative” patients who were treated as outpatients, and more research is needed to determine the applicability of the AHL score in an outpatient population, the researchers noted. Other limitations included the lack of data on long-term mortality in surviving patients who were discharged, and the reliance on assessments that can be performed only in clinical settings in developed countries, they said.

However, the results support the feasibility of the AHL score in clinical settings to accurately predict mortality in patients with pulmonary TB, and may help optimize treatments for this population, they concluded.

The study received no outside funding. All authors disclosed nonfinancial support in the form of measuring reagents from Fujifilm Wako Pure Chemical Corporation during the study but had no relevant financial conflicts to disclose.

A simple and objective severity score based on activities of daily living, hypoxemia, and lymphocytes was an effective predictor of mortality in adults with pulmonary tuberculosis, based on data from approximately 400 individuals.

Although a mortality risk-prediction score could improve treatment for pulmonary tuberculosis patients, such a score has not been previously reported, wrote Takeshi Osawa, MD, of Fukujuji Hospital, Tokyo, and colleagues.

In a study published in the journal CHEST, the researchers used 252 patients from a previous perspective study of newly diagnosed pulmonary tuberculosis as the development cohort, and recruited 165 additional patients between March 2021 and September 2022.

The primary endpoint was all-cause in-hospital mortality. Based on data from the development group, the researchers found that age 65 years and older and age 80 years and older, hypoxemia, activities of daily living, bilateral pulmonary lesions, lymphocyte count of less than 720 microliters, serum albumin less than 2.86 mg/dL, C-reactive protein (CRP) 3.97 mg/dL or higher, and procalcitonin (PCT) 0.130 ng/mL or higher were predictors of all-cause in hospital mortality.

The researchers used this information to create the disease severity score, known as the AHL score. The AHL included three clinical parameters: activity in daily living (semi-dependent, 1 point; totally dependent, 2 points); hypoxemia (1 point) and lymphocytes (< 720 /mcL, 1 point).

The scoring systems for the three parameters were, respectively, 1 point for semi-dependent and 2 points totally dependent (for activity in daily living), 1 point for presence of hypoxemia, and 1 point for lymphocytes less than 720 per microliter. The researchers stratified the scores into levels of low, intermediate, and high risk, with scores of 0, 1-2, and 3-4, respectively.

All-cause in hospital mortality occurred in 39 (15.5%) and 17 (10.3%) of patients in the developmental and validation cohorts, respectively.

The AHL score effectively predicted mortality, dividing patients into three groups of 1.3% low-risk, 8.9% intermediate risk, and 39.3% high-risk in the validation cohort, with a Harrell’s c-statistic of 0.842.

The corresponding numbers for the development cohort were 0, 13.5%, and 55.8%, with a c-statistic of 0.902.

The findings were limited by several factors, including the lack of data from “smear-negative” patients who were treated as outpatients, and more research is needed to determine the applicability of the AHL score in an outpatient population, the researchers noted. Other limitations included the lack of data on long-term mortality in surviving patients who were discharged, and the reliance on assessments that can be performed only in clinical settings in developed countries, they said.

However, the results support the feasibility of the AHL score in clinical settings to accurately predict mortality in patients with pulmonary TB, and may help optimize treatments for this population, they concluded.

The study received no outside funding. All authors disclosed nonfinancial support in the form of measuring reagents from Fujifilm Wako Pure Chemical Corporation during the study but had no relevant financial conflicts to disclose.

A simple and objective severity score based on activities of daily living, hypoxemia, and lymphocytes was an effective predictor of mortality in adults with pulmonary tuberculosis, based on data from approximately 400 individuals.

Although a mortality risk-prediction score could improve treatment for pulmonary tuberculosis patients, such a score has not been previously reported, wrote Takeshi Osawa, MD, of Fukujuji Hospital, Tokyo, and colleagues.

In a study published in the journal CHEST, the researchers used 252 patients from a previous perspective study of newly diagnosed pulmonary tuberculosis as the development cohort, and recruited 165 additional patients between March 2021 and September 2022.

The primary endpoint was all-cause in-hospital mortality. Based on data from the development group, the researchers found that age 65 years and older and age 80 years and older, hypoxemia, activities of daily living, bilateral pulmonary lesions, lymphocyte count of less than 720 microliters, serum albumin less than 2.86 mg/dL, C-reactive protein (CRP) 3.97 mg/dL or higher, and procalcitonin (PCT) 0.130 ng/mL or higher were predictors of all-cause in hospital mortality.

The researchers used this information to create the disease severity score, known as the AHL score. The AHL included three clinical parameters: activity in daily living (semi-dependent, 1 point; totally dependent, 2 points); hypoxemia (1 point) and lymphocytes (< 720 /mcL, 1 point).

The scoring systems for the three parameters were, respectively, 1 point for semi-dependent and 2 points totally dependent (for activity in daily living), 1 point for presence of hypoxemia, and 1 point for lymphocytes less than 720 per microliter. The researchers stratified the scores into levels of low, intermediate, and high risk, with scores of 0, 1-2, and 3-4, respectively.

All-cause in hospital mortality occurred in 39 (15.5%) and 17 (10.3%) of patients in the developmental and validation cohorts, respectively.

The AHL score effectively predicted mortality, dividing patients into three groups of 1.3% low-risk, 8.9% intermediate risk, and 39.3% high-risk in the validation cohort, with a Harrell’s c-statistic of 0.842.

The corresponding numbers for the development cohort were 0, 13.5%, and 55.8%, with a c-statistic of 0.902.

The findings were limited by several factors, including the lack of data from “smear-negative” patients who were treated as outpatients, and more research is needed to determine the applicability of the AHL score in an outpatient population, the researchers noted. Other limitations included the lack of data on long-term mortality in surviving patients who were discharged, and the reliance on assessments that can be performed only in clinical settings in developed countries, they said.

However, the results support the feasibility of the AHL score in clinical settings to accurately predict mortality in patients with pulmonary TB, and may help optimize treatments for this population, they concluded.

The study received no outside funding. All authors disclosed nonfinancial support in the form of measuring reagents from Fujifilm Wako Pure Chemical Corporation during the study but had no relevant financial conflicts to disclose.

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

TOPLINE:

Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis. 

METHODOLOGY:

Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.

Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.

Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.

Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.

TAKEAWAYS:

DR-TB patients tended to be older than NDR-TB patients.

Isolated plasma exosomes were morphologically characterized as being “close to pure.”

Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.

Protein-protein interaction modeling suggests that downregulated apolipoproteins APOA1, APOB, and APOC1 have a role in mediating DR-TB development through their functions in lipid metabolism and protein transport.

IN PRACTICE:

Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.” 

STUDY DETAILS:

The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.

LIMITATIONS:

This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.

DISCLOSURES:

The authors report no relevant financial relationships.
 

A version of this article originally appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Bacillus Calmette-Guérin (BCG) vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults.

The most extensive study ever conducted on the efficacy of the BCG vaccine for protection against tuberculosis, stratified by age and history of previous tuberculosis, was published in September 2022 in The Lancet Global Health. The study, which comprises a systematic review and meta-analysis, analyzed individual-level data from 26 case-contact cohort studies published over the past 20 years. The studies included data from 70,000 participants. The primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality.

Participants were characterized as having been exposed to tuberculosis if they were reported to have been a close contact (either living in the same household or having substantial interaction outside the household) of a person with microbiologically or radiologically diagnosed pulmonary tuberculosis. Previous tuberculosis was defined as a positive interferon-gamma (IFN-gamma) release assay or tuberculin skin test, also known as PPD or Mantoux test.

Most studies included in the analysis were conducted in the past 10 years in countries with a high tuberculosis burden. Those countries included India, South Africa, China, Vietnam, Indonesia, Uganda, the Gambia, and Brazil.
 

Primary outcomes

The study’s main findings included the following:

• The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (adjusted odds ratio, 0.82; 95% CI, 0.74-0.91).
• Stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR, 0.63; 95% CI, 0.49-0.81).
• There was no protective effect among those whose previous tests for tuberculosis were negative unless they were younger than 5 years (aOR, 0.54; 95% CI, 0.32-0.90).
• Among contacts who had a positive tuberculin skin test or IFN-gamma release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR, 0.81; 95% CI, 0.69-0.96), participants younger than 5 years (aOR, 0.68; 95% CI, 0.47-0.97), and participants aged 5-9 years (aOR, 0.62; 95% CI, 0.38-0.99).
• BCG vaccination was protective against pulmonary tuberculosis (19% effectiveness), but this effect was only seen in children younger than 3 years (42% effectiveness) when stratified by age.
• Protection against all tuberculosis and pulmonary tuberculosis was greater among female participants than male participants.

“This is a definitive BCG protection study because it involves a significant number of individuals evaluated using this meta-analysis. Protection is clearly lost with age. From as early as age 5, no protective effect can be observed. Protection, including against pulmonary tuberculosis, can be observed up to 3 years of age,” stated study author Julio Croda, MD, PhD, chair of the Brazilian Society of Tropical Medicine.

Dr. Croda emphasized that the findings from their study indicate that BCG vaccine protects against pulmonary tuberculosis and that those results differ from results of some previous studies.

“Every physician believes the BCG vaccine protects against serious forms of tuberculosis up to age 5. That fact is not surprising at all,” Dr. Croda remarked. “However, the fact that it protects against pulmonary tuberculosis, especially in children younger than 3, was surprising. In medical practice, we did not believe in this protection.”

Currently, 1.2% of new tuberculosis cases in Brazil occur among those younger than 5. Nevertheless, these cases represent 40.1% of new diagnoses recorded among those younger than 15, highlighting the importance of protection for this age group. An increase in extrapulmonary tuberculosis cases was recently observed in patients younger than 5.

Isabella Ballalai, MD, PhD, is deputy chair of the Brazilian Society of Immunizations. Although she did not participate in this study, she commented on its findings. “All publications are welcome; they help us think,” she explained. She emphasized that the BCG vaccine is not optimal. “There are studies indicating 80% efficacy and others indicating 0%. So, what we can look at is decades of effectiveness in practice.”

Dr. Ballalai explained that the BCG vaccine could keep severe forms of tuberculosis, meningitis, and miliary tuberculosis at bay. She shared her experience of caring for several patients with tuberculous meningitis shortly after she had graduated. “Today, thanks to the BCG vaccine, we don’t see it anymore.” However, she pointed out that the vaccine›s efficacy and effectiveness against pulmonary tuberculosis are low and that pulmonary tuberculosis remains the most significant problem among adults.

Dr. Ballalai also emphasized a few shortcomings of the study. “One is the definition of ‘vaccinated’ and ‘unvaccinated,’ which was based on the presence or absence of a mark on the arm. Today, we know that the absence of a mark does not indicate that the child has not been vaccinated, nor that the vaccine has not been effective. Therefore, several vaccinated participants may have been included amongst the unvaccinated participants.”

The authors emphasized that the definition of “vaccinated” and “unvaccinated” was based on a scar and on vaccination records, and they recognized that participants who did not have a scar on their arm could have been misclassified. Regardless, it is still considered a sensitive indicator. “Few vaccinated children from various settings do not show a scar years after vaccine administration,” they stated in their article.
 

Adults unprotected

Dr. Ballalai also shared her concerns regarding the lack of protection for older individuals. “We know those older than 60 are at greater risk for complications of tuberculosis. Individuals in this age group naturally have a lower immunity, and they usually have comorbidities. From this study, I can only conclude what was already expected: that adults who received a BCG vaccine as infants are not clear of pulmonary tuberculosis.”

Dr. Croda agreed that it was already evident that the BCG vaccine administered at birth did not provide protection for adults. “In the past, even with 80%-90% vaccine coverage, there were numerous tuberculosis cases in adults in Brazil.”
 

Are boosters needed?

The authors concluded that immunoprotection needs to be boosted in older populations, as vaccination at birth is ineffective for adolescents and adults. They have also discussed whether children older than 10 years and adults could benefit from a booster shot.

Dr. Croda emphasized that there is no indication for this, because there are no data regarding protection with a booster dose during adulthood. However, he cited a study conducted in South Africa in which the BCG vaccine was compared with another vaccine, and another study, which is being conducted in India, is assessing whether a BCG booster offers protection against pulmonary tuberculosis. “There are few studies. Perhaps the revaccination of more vulnerable groups could be of interest, but additional studies are needed first.”

Dr. Croda intends to assess revaccination in those deprived of liberty, in which the incidence of tuberculosis is very high. From 2015 to 2021, many new cases were recorded in this population in Brazil. The number rose from 5,860 to 6,773 during that period.

“However, BCG revaccination carries a significant risk of patients presenting with serious adverse events,” Dr. Ballalai pointed out. He noted that several years ago, to extend protection, Brazil adopted a booster program for persons aged 10 years or older, but the program was discontinued owing to the numerous adverse events reported and the absence of evidence of benefit from increased protection against tuberculosis.

“The adult groups at greater risk for severe tuberculosis manifestations normally presented with an underlying disease, particularly in immunocompromised patient groups. The [administration of the] BCG [vaccine] is contraindicated for those who are immunocompromised. And, for the older population, we do not have data on [vaccine] safety,” she emphasized.
 

Nonspecific immune protection

One of the study’s secondary outcomes regarded mortality. Four studies in the meta-analysis followed up tuberculosis contacts for death. In these studies, which evaluated 20,000 participants, BCG vaccination was shown to be significantly protective against death for participants younger than 15 years.

However, the authors urged caution in interpreting these data. They emphasized that they were unable to identify specific mechanisms by which BCG vaccination might have reduced mortality, and there are possible study biases that could have led to an overestimation of mortality benefit. Moreover, given the observational nature of the included studies, vaccinated children might have had higher socioeconomic status and greater access to health care, and they may have been more likely to have received other vaccinations, compared with children who did not receive BCG vaccines.

Nevertheless, previous experimental and observational studies have found that BCG vaccination might provide nonspecific or off-target immune protection against an array of other pathogens.

“In small studies conducted in Africa, those younger than 5 were protected not only against tuberculosis but also against other respiratory diseases,” Dr. Croda affirmed. “However, these are small studies, and for now, there is no recommendation for using BCG vaccination to prevent other respiratory infections.”

A long-awaited, critical study on the impact of the BCG vaccine on COVID-19, in which Brazilian researchers participated, will be published in the New England Journal of Medicine.
 

New vaccines needed

The BCG vaccine is one of the oldest vaccines, but there are still several crucial unanswered questions about its use.

Previously published studies that examined the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950. These studies need updating, but doing so has not been a simple task. To answer their questions, individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies.

Much of the data used in the published research were found through discussions with authors and experts in the field, as well as through data deposited in data storage repositories, conference abstracts, dissertations, and even direct requests to the authors. “The Pan-American Health Organization helped with this data collection and contacting some authors,” said Dr. Croda.

With the new data, the authors confirmed that infant BCG vaccination, although important to young children who are at high risk for tuberculosis, does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic. “Novel vaccines are urgently needed,” they concluded.

“We need to develop novel, more effective vaccines, which, when administered during infancy, would ensure lifelong protection,” Dr. Croda added.

Dr. Croda and Dr. Ballalai reported no relevant financial relationships.

This article was translated from the Medscape Portuguese edition. A version of this article appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

If you’ve watched this space over the years, you’ll know that I’m not the biggest proponent of vitamin D supplementation. My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.

And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.

And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.

And, it looks like, I would have been wrong.

Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.

We are talking about this study, appearing in JAMA Pediatrics.

Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.

Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.

Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.

The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.

Nothing.

But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.

Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.

Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?

And, unfortunately, the answer is still no.

At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.

So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.

Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.

What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.

Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

A version of this video transcript first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

If you’ve watched this space over the years, you’ll know that I’m not the biggest proponent of vitamin D supplementation. My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.

And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.

And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.

And, it looks like, I would have been wrong.

Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.

We are talking about this study, appearing in JAMA Pediatrics.

Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.

Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.

Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.

The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.

Nothing.

But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.

Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.

Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?

And, unfortunately, the answer is still no.

At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.

So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.

Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.

What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.

Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

A version of this video transcript first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

If you’ve watched this space over the years, you’ll know that I’m not the biggest proponent of vitamin D supplementation. My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.

And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.

And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.

And, it looks like, I would have been wrong.

Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.

We are talking about this study, appearing in JAMA Pediatrics.

Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.

Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.

Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.

The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.

Nothing.

But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.

Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.

Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?

And, unfortunately, the answer is still no.

At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.

So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.

Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.

What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.

Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.

A version of this video transcript first appeared on Medscape.com.

Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.

The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.

The study was published in The Lancet.

The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.

The study’s first stage, STREAM stage 1, showed that a 9-month injectable regimen was noninferior to the WHO’s 2011 recommendation of a 20-month injectable regimen. The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
 

Seeking shorter treatment for better outcomes

STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).

The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.

The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.

For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).

Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).

For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.

In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.

Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.

Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.

The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.

“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.

“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.

Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).

“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
 

‘A revolution in MDR tuberculosis’

“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.

Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.

The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.

However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”

The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.

A version of this article first appeared on Medscape.com.

Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.

The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.

The study was published in The Lancet.

The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.

The study’s first stage, STREAM stage 1, showed that a 9-month injectable regimen was noninferior to the WHO’s 2011 recommendation of a 20-month injectable regimen. The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
 

Seeking shorter treatment for better outcomes

STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).

The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.

The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.

For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).

Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).

For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.

In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.

Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.

Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.

The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.

“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.

“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.

Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).

“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
 

‘A revolution in MDR tuberculosis’

“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.

Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.

The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.

However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”

The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.

A version of this article first appeared on Medscape.com.

Two short-course bedaquiline-containing treatment regimens for rifampicin-resistant tuberculosis showed “robust evidence” for superior efficacy and less ototoxicity compared to a 9-month injectable control regimen, researchers report.

The findings validate the World Health Organization’s current recommendation of a 9-month, bedaquiline-based oral regimen, “which was based only on observational data,” noted lead author Ruth Goodall, PhD, from the Medical Research Council Clinical Trials Unit at University College London, and colleagues.

The study was published in The Lancet.

The Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) stage 2 study was a randomized, phase 3, noninferiority trial conducted at 13 hospital clinics in seven countries that had prespecified tests for superiority if noninferiority was shown. The study enrolled individuals aged 15 years or older who had rifampicin-resistant TB without fluoroquinolone or aminoglycoside resistance.

The study’s first stage, STREAM stage 1, showed that a 9-month injectable regimen was noninferior to the WHO’s 2011 recommendation of a 20-month injectable regimen. The 9-month regimen was recommended by the WHO in 2016. That recommendation was superceded in 2020 when concerns of hearing loss associated with aminoglycosides prompted the WHO to endorse a 9-month bedaquiline-containing, injectable-free alternative, the authors write.
 

Seeking shorter treatment for better outcomes

STREAM stage 2 used a 9-month injectable regimen as its control. The investigators measured it against a fully oral 9-month bedaquiline-based treatment (primary comparison), as well as a 6-month oral bedaquiline regimen that included 8 weeks of a second-line injectable (secondary comparison).

The 9-month fully oral treatment included levofloxacin, clofazimine, ethambutol, and pyrazinamide for 40 weeks; bedaquiline, high-dose isoniazid, and prothionamide were given for the 16-week intensive phase.

The 6-month regimen included bedaquiline, clofazimine, pyrazinamide, and levofloxacin for 28 weeks, supplemented by high-dose isoniazid with kanamycin for an 8-week intensive phase.

For both comparisons, the primary outcome was favorable status at 76 weeks, defined as cultures that were negative for Mycobacterium tuberculosis without a preceding unfavorable outcome (defined as any death, bacteriologic failure or recurrence, or major treatment change).

Among 517 participants in the modified intention-to-treat population across the study groups, 62% were men, and 38% were women (median age, 32.5 years).

For the primary comparison, 71% of the control group and 83% of the oral regimen group had a favorable outcome.

In the secondary comparison, 69% had a favorable outcome in the control group, compared with 91% of those receiving the 6-month regimen.

Although the rate of grade 3 or 4 adverse events was similar in all three groups, there was significantly less ototoxicity among patients who received the oral regimen, compared with control patients (2% vs. 9%); 4% of those taking the 6-month regimen had hearing loss, compared with 8% of control patients.

Exploratory analyses comparing both bedaquiline-containing regimens revealed a significantly higher proportion of favorable outcomes among participants receiving the 6-month regimen (91%), compared with patients taking the fully oral 9-month regimen (79%). There were no significant differences in the rate of grade 3 or 4 adverse events.

The trial’s main limitation was its open-label design, which might have influenced decisions about treatment change, note the investigators.

“STREAM stage 2 has shown that two short-course, bedaquiline-containing regimens are not only non-inferior but superior to a 9-month injectable-containing regimen,” they conclude.

“The STREAM stage 2 fully oral regimen avoided the toxicity of aminoglycosides, and the 6-month regimen was highly effective, with reduced levels of ototoxicity. These two regimens offer promising treatment options for patients with MDR or rifampicin-resistant tuberculosis,” the authors write.

Dr. Goodall added, “Although both STREAM regimens were very effective, participants experienced relatively high levels of adverse events during the trial (though many of these were likely due to the close laboratory monitoring of the trial).

“While hearing loss was reduced on the 6-month regimen, it was not entirely eliminated,” she said. “Other new regimens in the field containing the medicine linezolid report side effects such as anemia and peripheral neuropathy. So more work needs to be done to ensure the treatment regimens are as safe and tolerable for patients as possible. In addition, even 6 months’ treatment is long for patients to tolerate, and further regimen shortening would be a welcome development for patients and health systems.”
 

‘A revolution in MDR tuberculosis’

“The authors must be commended on completing this challenging high-quality, phase 3, non-inferiority, randomized controlled trial involving 13 health care facilities across Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda ... despite the COVID-19 pandemic,” noted Keertan Dheda, MD, PhD, and Christoph Lange, MD, PhD, in an accompanying comment titled, “A Revolution in the Management of Multidrug-Resistant Tuberculosis”.

Although the WHO recently approved an all-oral 6-month bedaquiline, pretomanid, and linezolid plus moxifloxacin (BPaLM) regimen, results from the alternate 6-month regimen examined in STREAM stage 2 “do provide confidence in using 2 months of an injectable as part of a salvage regimen in patients for whom MDR tuberculosis treatment is not successful” or in those with extensively drug-resistant (XDR) or pre-XDR TB, “for whom therapeutic options are few,” noted Dr. Dheda, from the University of Cape Town (South Africa) and the London School of Hygiene and Tropical Medicine, and Dr. Lange, from the University of Lübeck (Germany), Baylor College of Medicine, and Texas Children’s Hospital, both in Houston.

The study authors and the commentators stress that safer and simpler treatments are still needed for MDR TB. “The search is now on for regimens that could further reduce duration, toxicity, and pill burden,” note Dr. Dheda and Dr. Lange.

However, they also note that “substantial resistance” to bedaquiline is already emerging. “Therefore, if we are to protect key drugs from becoming functionally redundant, drug-susceptibility testing capacity will need to be rapidly improved to minimize resistance amplification and onward disease transmission.”

The study was funded by USAID and Janssen Research and Development. Dr. Goodall has disclosed no relevant financial relationships. Dr. Dheda has received funding from the EU and the South African Medical Research Council for studies related to the diagnosis or management of drug-resistant tuberculosis. Dr. Lange is supported by the German Center for Infection Research and has received funding from the European Commission for studies on the development of novel antituberculosis medicines and for studies related to novel diagnostics of tuberculosis; consulting fees from INSMED; speaker’s fees from INSMED, GILEAD, and Janssen; and is a member of the data safety board of trials from Medicines sans Frontiers, all of which are unrelated to the current study.

A version of this article first appeared on Medscape.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.

Tuberculosis cases are increasing in Washington, which has put public health officials on “heightened alert,” according to a recent announcement from the Washington State Department of Health.

Widespread disruptions in health care and missed tuberculosis diagnoses during the COVID-19 pandemic have likely added to the increase – both locally and globally.

“It’s been 20 years since we saw a cluster of TB cases like this,” Tao Sheng Kwan-Gett, MD, the state’s chief science officer, said in the announcement.

“The pandemic has likely contributed to the rise in cases and the outbreak in at least one correctional facility,” he said. “Increased access to TB testing and treatment in the community is going to be key to getting TB under control.”

Case numbers appeared to fall in Washington during the first year of the pandemic, possibly because of less reporting and missed diagnoses. But in 2021, cases rose quickly. The state reported 199 cases, marking a 22% increase from 2020.

So far this year, 70 cases have been reported, including 17 new cases that all have connections with each other and several state prisons.

The state’s Department of Corrections, Department of Health, and the Centers for Disease Control and Prevention are working together on testing and decreasing spread, MaryAnn Curl, MD, the chief medical officer for the Department of Corrections, said in the statement.

Tuberculosis cases are increasing worldwide. For the first time in more than a decade, TB deaths increased to about 1.5 million, according to the World Health Organization’s 2021 Global Tuberculosis Report.

Across the U.S., the number of reported TB cases significantly declined at the beginning of the pandemic in 2020 but increased again in 2021, according to a recent CDC study.

The Kansas Department of Health also reported an outbreak of TB cases in March, according to USA Today.

At the beginning of the pandemic, some people with TB may have been diagnosed with COVID-19 because both are infectious diseases that attack the lungs and have similar symptoms, the Washington Health Department said.

Like COVID-19, tuberculosis can spread through the air when an infected person coughs or sneezes. But unlike COVID-19, TB typically requires that you have prolonged exposure to become infected.

Symptoms of tuberculosis can include chest pain and coughing, with or without blood, as well as fever, night sweats, weight loss, and fatigue.

Tuberculosis is preventable, treatable, and curable, the Washington Health Department said. Those who travel to countries where TB is more common face higher risks for exposure, as well as those who live or work in settings where TB may spread, such as homeless shelters, prisons, jails, and nursing homes.

People can develop inactive TB, also called latent TB, which doesn’t have any symptoms and isn’t contagious. If people with inactive TB don’t get quick diagnosis or treatment, the infection can become active TB and cause symptoms. State health officials estimated that about 200,000 people in Washington have inactive TB.

Tuberculosis treatment can take a minimum of 6 months, and if it’s not followed carefully, symptoms can become more severe, the Health Department said. Incomplete treatment can also contribute to the spread of antibiotic-resistant strains of tuberculosis.

A version of this article first appeared on WebMD.com.