Pulmonary Infections

Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science.

CDC/Molly Kurnit, M.P.H.

The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.

“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.

“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”

In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 the children experienced mild measles, and 43 had severe measles.

They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.

This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.

The study did find increases in measles virus–specific antigens in children both after measles infection and MMR vaccination. However the authors did not detect any changes in total IgG, IgA, or IgM levels.

“These results suggest that, rather than a simple loss of total IgG, there is a restructuring of the antibody repertoire after measles,” Dr. Mina and associates wrote.

They also noted that controls who received the MMR vaccine showed a marked increase in overall antibody repertoire.

In a separate investigation reported in Science Immunology, Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles to determine if B-cell impairment can lead to measles-associated immunosuppression. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IgVH-J) gene frequencies across time periods (R2 = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B-cell frequencies in measles patients recovered to levels before infection, they had significant changes in IgVH-J gene frequencies (P = .01) and decreased correlation in gene expression (R2 = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IgVH-J genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IgVH genes, Dr. Petrova and associates reported.

The study by Mina et al. was supported by grants from various U.S., European, and Finnish foundations and national organizations. Some of the coauthors had relationships with biotechnology and pharmaceutical companies, and three reported a patent holding related to technology used in the study. The study by Petrova et al. was funded by grants to the investigators from various Indonesian and German organizations and the Wellcome Trust. The authors reported no conflicts of interest.
 

SOURCES: Mina M et al. Science. 2019 Nov 1;366:599-606; Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125.

Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science.

CDC/Molly Kurnit, M.P.H.

The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.

“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.

“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”

In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 the children experienced mild measles, and 43 had severe measles.

They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.

This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.

The study did find increases in measles virus–specific antigens in children both after measles infection and MMR vaccination. However the authors did not detect any changes in total IgG, IgA, or IgM levels.

“These results suggest that, rather than a simple loss of total IgG, there is a restructuring of the antibody repertoire after measles,” Dr. Mina and associates wrote.

They also noted that controls who received the MMR vaccine showed a marked increase in overall antibody repertoire.

In a separate investigation reported in Science Immunology, Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles to determine if B-cell impairment can lead to measles-associated immunosuppression. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IgVH-J) gene frequencies across time periods (R2 = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B-cell frequencies in measles patients recovered to levels before infection, they had significant changes in IgVH-J gene frequencies (P = .01) and decreased correlation in gene expression (R2 = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IgVH-J genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IgVH genes, Dr. Petrova and associates reported.

The study by Mina et al. was supported by grants from various U.S., European, and Finnish foundations and national organizations. Some of the coauthors had relationships with biotechnology and pharmaceutical companies, and three reported a patent holding related to technology used in the study. The study by Petrova et al. was funded by grants to the investigators from various Indonesian and German organizations and the Wellcome Trust. The authors reported no conflicts of interest.
 

SOURCES: Mina M et al. Science. 2019 Nov 1;366:599-606; Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125.

Infection with the measles virus appears to reduce immunity to other pathogens, according to a paper published in Science.

CDC/Molly Kurnit, M.P.H.

The hypothesis that the measles virus could cause “immunological amnesia” by impairing immune memory is supported by early research showing children with measles had negative cutaneous tuberculin reactions after having previously tested positive.

“Subsequent studies have shown decreased interferon signaling, skewed cytokine responses, lymphopenia, and suppression of lymphocyte proliferation shortly after infection,” wrote Michael Mina, MD, from Brigham and Women’s Hospital in Boston, and coauthors.

“Given the variation in the degree of immune repertoire modulation we observed, we anticipate that future risk of morbidity and mortality after measles would not be homogeneous but would be skewed toward individuals with the most severe elimination of immunological memory,” they wrote. “These findings underscore the crucial need for continued widespread vaccination.”

In this study, researchers compared the levels of around 400 pathogen-specific antibodies in blood samples from 77 unvaccinated children, taken before and 2 months after natural measles infection, with 5 unvaccinated children who did not contract measles. A total of 34 the children experienced mild measles, and 43 had severe measles.

They found that the samples taken after measles infection showed “substantial” reductions in the number of pathogen epitopes, compared with the samples from children who did not get infected with measles.

This amounted to approximately a 20% mean reduction in overall diversity or size of the antibody repertoire. However, in children who experienced severe measles, there was a median loss of 40% (range, 11%-62%) of antibody repertoire, compared with a median of 33% (range, 12%-73%) range in children who experienced mild infection. Meanwhile, the control subjects retained approximately 90% of their antibody repertoire over a similar or longer time period. Some children lost up to 70% of antibodies for specific pathogens.

The study did find increases in measles virus–specific antigens in children both after measles infection and MMR vaccination. However the authors did not detect any changes in total IgG, IgA, or IgM levels.

“These results suggest that, rather than a simple loss of total IgG, there is a restructuring of the antibody repertoire after measles,” Dr. Mina and associates wrote.

They also noted that controls who received the MMR vaccine showed a marked increase in overall antibody repertoire.

In a separate investigation reported in Science Immunology, Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles to determine if B-cell impairment can lead to measles-associated immunosuppression. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IgVH-J) gene frequencies across time periods (R2 = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B-cell frequencies in measles patients recovered to levels before infection, they had significant changes in IgVH-J gene frequencies (P = .01) and decreased correlation in gene expression (R2 = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IgVH-J genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IgVH genes, Dr. Petrova and associates reported.

The study by Mina et al. was supported by grants from various U.S., European, and Finnish foundations and national organizations. Some of the coauthors had relationships with biotechnology and pharmaceutical companies, and three reported a patent holding related to technology used in the study. The study by Petrova et al. was funded by grants to the investigators from various Indonesian and German organizations and the Wellcome Trust. The authors reported no conflicts of interest.
 

SOURCES: Mina M et al. Science. 2019 Nov 1;366:599-606; Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

A new study has uncovered how the measles virus (MeV) can induce immunosuppression by delaying the reconstitution of B cells.

CDC/ Cynthia S. Goldsmith; William Bellini, Ph.D.

“Our findings provide a biological explanation for the observed increase in childhood mortality and secondary infections several years after an episode of measles,” said Velislava N. Petrova, PhD, of the Wellcome Sanger Institute in Cambridge, England, and coauthors. The study was published in Science Immunology.

To determine if B-cell impairment can lead to measles-associated immunosuppression, the researchers investigated genetic changes in 26 unvaccinated children from the Netherlands who previously had measles. Their antibody genes were sequenced before any symptoms of measles developed and roughly 40 days after rash. Two control groups also were sequenced accordingly: vaccinated adults and three unvaccinated children from the same community who were not infected with measles.

Naive B cells from individuals in the vaccinated and uninfected control groups showed high correlation of immunoglobulin heavy chain (IGHV-J) gene frequencies across time periods (R² = 0.96 and 0.92, respectively) but no significant differences in gene expression (P greater than .05). At the same time, although B cell frequencies in measles patients recovered to levels before infection, they had significant changes in IGHV-J gene frequencies (P = .01) and decreased correlation in gene expression (R² = 0.78).

In addition, individuals in the control groups had “a stable genetic composition of B memory cells” but no significant changes in the third complementarity-determining region (CDR3) lengths or mutational frequency of IGHV genes (P greater than .05). B memory cells in measles patients, however, showed increases in mutational frequency (P = .0008) and a reduction in CDR3 length (P = .017) of IGHV genes, Dr. Petrova and associates said.

Finally, the researchers confirmed a hypothesis about the depletion of B memory cell clones during measles and a repopulation of new cells with less clonal expansion. The frequency of individual IGHV-J gene combinations before infection was correlated with a reduction after infection, “with the most frequent combinations undergoing the most marked depletion” and the result being an increase in genetic diversity.

To further test their findings, the researchers vaccinated two groups of four ferrets with live-attenuated influenza vaccine (LAIV) and at 4 weeks infected one of the groups with canine distemper virus (CDV), a surrogate for MeV. At 14 weeks after vaccination, the uninfected group maintained high levels of influenza-specific neutralizing antibodies while the infected group saw impaired B cells and a subsequent reduction in neutralizing antibodies.
 

Understanding the impact of measles on the immune system

“How measles infection has such a long-lasting deleterious effect on the immune system while allowing robust immunity against itself has been a burning immunological question,” Duane R. Wesemann, MD, PhD, of Brigham and Women’s Hospital in Boston, said in an accompanying editorial. The research from Petrova et al. begins to answer that question.

Among the observations he found most interesting was how “post-measles memory cells were more diverse than the pre-measles memory pool,” despite expectations that measles immunity would be dominant. He speculated that the void in memory cells is filled by a set of clones binding to unidentified or nonnative antigens, which may bring polyclonal diversity into B memory cells.

More research is needed to determine just what these findings mean, including looking beyond memory cell depletion and focusing on the impact of immature immunoglobulin repertoires in naive cells. But his broad takeaway is that measles remains both a public health concern and an opportunity to understand how the human body counters disease.

“The unique relationship measles has with the human immune system,” he said, “can illuminate aspects of its inner workings.”

The study was funded by grants to the investigators the Indonesian Endowment Fund for Education, the Wellcome Trust, the German Centre for Infection Research, the Collaborative Research Centre of the German Research Foundation, the German Ministry of Health, and the Royal Society. The authors declared no conflicts of interest. Dr. Wesemann reported receiving support from National Institutes of Health grants and an award from the Burroughs Wellcome Fund; he also reports being a consultant for OpenBiome.

SOURCE: Petrova VN et al. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aay6125; Wesemann DR. Sci Immunol. 2019 Nov 1. doi: 10.1126/sciimmunol.aaz4195.

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

ST. LOUIS – A brain abscess in the presence of a lung infection should raise suspicion for Nocardia whether patients are immunocompromised or not, according to University of California, San Francisco, investigators.

M. Alexander Otto/MDedge News

Nocardia – an ubiquitous gram-positive rod normally found in standing water, decaying plants, and soil, that can cause problems when it is inhaled as dust or introduced through a nick in the skin – is an underappreciated cause of brain abscess that is not covered by standard empiric therapy targeting the more common causes: Staphylococcus and Streptococcus bacteria, said senior investigator Megan Richie, MD, an assistant neurology professor at UCSF.

“Patients that have a lung infection with a new brain abscess should be started on empiric therapy not just for pyogenic organisms, but also for Nocardia pending biopsy and operative culture data, especially given that empiric therapy of high-dose Bactrim for Nocardia is relatively benign,” she said at the annual meeting of the American Neurological Association.

The advice comes from a comparison of 14 Nocardia cases with 42 randomly selected Staph/Strep cases in a university radiologic database. Nine Nocardia cases were confirmed by operative specimen culture, the rest by lung, blood, or other tissue cultures.

Dr. Richie and colleagues suspected an association with lung infection, which has been reported anecdotally in the literature. The researchers wanted to take a quantitative look to see if it held up statistically after pushback on a brain abscess patient with a lung infection. “We were concerned this patient had Nocardia, but it took quite some time to convince other doctors that we really needed to start [Bactrim]. The patient was not immunocompromised and the infectious disease team said ‘Nocardia brain infections don’t happen in immunocompetent patients,’” Dr. Richie said,

The man did, however, turn out to have Nocardia, and of the 14 cases in the series, four patients (29%) were not immunosuppressed. “I think this would surprise [physicians] who have a little bit less experience with this organism,” Dr. Richie said.Patients with a Nocardia brain abscess were far more likely to have a concomitant lung infection (86% vs. 2%; odds ratio, 246; 95% confidence interval, 21-2953; P less than .0001). Staph/Strep brain abscess patients were more likely to have concomitant ear or sinus infections (40% versus 0%; P = .005). Immunosuppression did turn out to be more common in the Nocardia group, as well (71% vs. 19%; OR, 11; 95% CI, 3-43; P = .001), as did diabetes (36% vs. 10%; P = .03).

Nocardia patients were older (median age, 61 yrs vs. 46 yrs: P = .01) and more likely to be Hispanic (36% vs. 10%; P = .04). There were no differences in sex; neurosurgery history; intravenous drug use; or endocarditis.

On imaging, Nocardia brain abscesses were poorly circumscribed and tended to have multiple lobes, “often two in a figure-eight pattern,” Dr. Richie said. Nocardia diagnosis took longer (median, 7 vs. 4 days; P = .04), “which makes sense because it is a harder diagnosis to make,” she said.

Operative specimen culture was the most potent diagnostic tool. Blood cultures were positive in just one Nocardia patient and a few controls.

There was no external funding, and the investigators did not have any relevant disclosures.

[email protected]

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the child and adolescent immunization schedule for 2020.

Yarinca/istockphoto

The changes to the child and adolescent immunization schedule for 2020 “incorporate recommendations that have occurred and are easy to use at point of care by busy providers,” Candice Robinson, MD, MPH, of the CDC’s National Center for Immunization and Respiratory Diseases, said at the CDC’s October meeting of ACIP. Updates reflect changes in language in the adult vaccination schedule, notably the change in the definition of “contraindication.” The updated wording in the Notes substitutes “not recommended or contraindicated” instead of the word “contraindicated” only.

Another notable change was the addition of information on adolescent vaccination of children who received the meningococcal ACWY vaccine before 10 years of age. For “children in whom boosters are not recommended due to an ongoing or increased risk of meningococcal disease” (such as a healthy child traveling to an endemic area), they should receive MenACWY according to the recommended adolescent schedule. But those children for whom boosters are recommended because of increased disease risk from conditions including complement deficiency, HIV, or asplenia should “follow the booster schedule for persons at increased risk.”

Other changes include restructuring of the notes for the live attenuated influenza vaccine (LAIV) in special situations. The schedule now uses a bulleted list to show that LAIV should not be used in the following circumstances:

• Having history of severe allergic reaction to a previous vaccine or vaccine component.
• Using aspirin or a salicylate-containing medication.
• Being aged 2-4 years with a history of asthma or wheezing.
• Having immunocompromised conditions.
• Having anatomic or functional asplenia.
• Having cochlear implants.
• Experiencing cerebrospinal fluid–oropharyngeal communication.
• Having immunocompromised close contacts or caregivers.
• Being pregnant.
• Having received flu antivirals within the previous 48 hours.

In addition, language on shared clinical decision-making was added to the notes on the meningococcal B vaccine for adolescents and young adults aged 18-23 years not at increased risk. Based on shared clinical decision making, the recommendation is a “two-dose series of Bexsero at least 1 month apart” or “two-dose series of Trumenba at least 6 months apart; if dose two is administered earlier than 6 months, administer a third dose at least 4 months after dose two.”

Several vaccines’ Notes sections, including hepatitis B and meningococcal disease, added links to detailed recommendations in the corresponding issues of the CDC’s Morbidity and Mortality Weekly Report, to allow clinicians easy access to additional information.

View the current Child & Adolescent Vaccination Schedule here.

The ACIP members had no financial conflicts to disclose.
 

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the child and adolescent immunization schedule for 2020.

Yarinca/istockphoto

The changes to the child and adolescent immunization schedule for 2020 “incorporate recommendations that have occurred and are easy to use at point of care by busy providers,” Candice Robinson, MD, MPH, of the CDC’s National Center for Immunization and Respiratory Diseases, said at the CDC’s October meeting of ACIP. Updates reflect changes in language in the adult vaccination schedule, notably the change in the definition of “contraindication.” The updated wording in the Notes substitutes “not recommended or contraindicated” instead of the word “contraindicated” only.

Another notable change was the addition of information on adolescent vaccination of children who received the meningococcal ACWY vaccine before 10 years of age. For “children in whom boosters are not recommended due to an ongoing or increased risk of meningococcal disease” (such as a healthy child traveling to an endemic area), they should receive MenACWY according to the recommended adolescent schedule. But those children for whom boosters are recommended because of increased disease risk from conditions including complement deficiency, HIV, or asplenia should “follow the booster schedule for persons at increased risk.”

Other changes include restructuring of the notes for the live attenuated influenza vaccine (LAIV) in special situations. The schedule now uses a bulleted list to show that LAIV should not be used in the following circumstances:

• Having history of severe allergic reaction to a previous vaccine or vaccine component.
• Using aspirin or a salicylate-containing medication.
• Being aged 2-4 years with a history of asthma or wheezing.
• Having immunocompromised conditions.
• Having anatomic or functional asplenia.
• Having cochlear implants.
• Experiencing cerebrospinal fluid–oropharyngeal communication.
• Having immunocompromised close contacts or caregivers.
• Being pregnant.
• Having received flu antivirals within the previous 48 hours.

In addition, language on shared clinical decision-making was added to the notes on the meningococcal B vaccine for adolescents and young adults aged 18-23 years not at increased risk. Based on shared clinical decision making, the recommendation is a “two-dose series of Bexsero at least 1 month apart” or “two-dose series of Trumenba at least 6 months apart; if dose two is administered earlier than 6 months, administer a third dose at least 4 months after dose two.”

Several vaccines’ Notes sections, including hepatitis B and meningococcal disease, added links to detailed recommendations in the corresponding issues of the CDC’s Morbidity and Mortality Weekly Report, to allow clinicians easy access to additional information.

View the current Child & Adolescent Vaccination Schedule here.

The ACIP members had no financial conflicts to disclose.
 

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the child and adolescent immunization schedule for 2020.

Yarinca/istockphoto

The changes to the child and adolescent immunization schedule for 2020 “incorporate recommendations that have occurred and are easy to use at point of care by busy providers,” Candice Robinson, MD, MPH, of the CDC’s National Center for Immunization and Respiratory Diseases, said at the CDC’s October meeting of ACIP. Updates reflect changes in language in the adult vaccination schedule, notably the change in the definition of “contraindication.” The updated wording in the Notes substitutes “not recommended or contraindicated” instead of the word “contraindicated” only.

Another notable change was the addition of information on adolescent vaccination of children who received the meningococcal ACWY vaccine before 10 years of age. For “children in whom boosters are not recommended due to an ongoing or increased risk of meningococcal disease” (such as a healthy child traveling to an endemic area), they should receive MenACWY according to the recommended adolescent schedule. But those children for whom boosters are recommended because of increased disease risk from conditions including complement deficiency, HIV, or asplenia should “follow the booster schedule for persons at increased risk.”

Other changes include restructuring of the notes for the live attenuated influenza vaccine (LAIV) in special situations. The schedule now uses a bulleted list to show that LAIV should not be used in the following circumstances:

• Having history of severe allergic reaction to a previous vaccine or vaccine component.
• Using aspirin or a salicylate-containing medication.
• Being aged 2-4 years with a history of asthma or wheezing.
• Having immunocompromised conditions.
• Having anatomic or functional asplenia.
• Having cochlear implants.
• Experiencing cerebrospinal fluid–oropharyngeal communication.
• Having immunocompromised close contacts or caregivers.
• Being pregnant.
• Having received flu antivirals within the previous 48 hours.

In addition, language on shared clinical decision-making was added to the notes on the meningococcal B vaccine for adolescents and young adults aged 18-23 years not at increased risk. Based on shared clinical decision making, the recommendation is a “two-dose series of Bexsero at least 1 month apart” or “two-dose series of Trumenba at least 6 months apart; if dose two is administered earlier than 6 months, administer a third dose at least 4 months after dose two.”

Several vaccines’ Notes sections, including hepatitis B and meningococcal disease, added links to detailed recommendations in the corresponding issues of the CDC’s Morbidity and Mortality Weekly Report, to allow clinicians easy access to additional information.

View the current Child & Adolescent Vaccination Schedule here.

The ACIP members had no financial conflicts to disclose.
 

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the adult immunization schedule for 2020, although some fine-tuning may occur before publication.

MarianVejcik/Getty Images

“Some of the wordsmithing may be done later,” ACIP executive secretary Amanda Cohn, MD, said at the ACIP October meeting.

These small changes revolved mainly around how much wording to include in the current color block tables versus including the information in the notes section.

Key updates to the schedule included a change in wording for the definition of the red bars on the table to include “not recommended or contraindicated” instead of only the word “contraindicated.” Committee members were especially interested in changing this wording to guide clinicians in use of the live attenuated influenza vaccine because of its potential value in vaccinating health care personnel.

Other updates include language that vaccination of adolescents and young adults aged 16-23 years who are not at increased risk for meningococcal disease should be vaccinated as follows: “Based on shared clinical decision making, 2-dose series MenB-4C at least 1 month apart or 2-dose series MenB-FHbp at 0, 6 months.”

Similarly, clinical decision-making language was added to the notes for the pneumococcal polysaccharide vaccine (PPSV23) and the 13-valent pneumococcal conjugate vaccine (PCV13).

The routine vaccination calls for only one dose of PPSV23 given on or after the individual’s 65th birthday. Then, based on shared clinical decision making, a dose of PCV13 is recommended for immunocompetent individuals aged 65 years and older. The notes also state that, based on shared clinical decision making, PCV13 and PPSV23 should not be given in the same visit and, if both will be given, PCV13 should be first and should be given 1 year before PPSV23. In addition, “PPSV23 should be given at least 5 years after any previous PPSV23 dose.”

The schedule also adds shared clinical decision making to the notes on human papillomavirus vaccination for adults aged 27-45 years.

The committee members acknowledged the increasing complexity of the adult vaccination schedule, but several members agreed that it is accessible to many clinicians.

“We can’t let the perfect be the enemy of the good” said Jason Goldman, MD, liaison representing the American College of Physicians. “Those who want to learn the schedule will learn it; the health system will learn it,” even if not every specialist does.

The table “is something to draw you in,” said Sandra Fryhofer, MD, an internist who is liaison for the American Medical Association. The notes provide more details.

More specific information about contraindications for patients with cochlear implants, which also came up in the discussion, may be added to the schedule at a later date.

View the current adult vaccination schedule here.

The ACIP members had no financial conflicts to disclose.
 

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the adult immunization schedule for 2020, although some fine-tuning may occur before publication.

MarianVejcik/Getty Images

“Some of the wordsmithing may be done later,” ACIP executive secretary Amanda Cohn, MD, said at the ACIP October meeting.

These small changes revolved mainly around how much wording to include in the current color block tables versus including the information in the notes section.

Key updates to the schedule included a change in wording for the definition of the red bars on the table to include “not recommended or contraindicated” instead of only the word “contraindicated.” Committee members were especially interested in changing this wording to guide clinicians in use of the live attenuated influenza vaccine because of its potential value in vaccinating health care personnel.

Other updates include language that vaccination of adolescents and young adults aged 16-23 years who are not at increased risk for meningococcal disease should be vaccinated as follows: “Based on shared clinical decision making, 2-dose series MenB-4C at least 1 month apart or 2-dose series MenB-FHbp at 0, 6 months.”

Similarly, clinical decision-making language was added to the notes for the pneumococcal polysaccharide vaccine (PPSV23) and the 13-valent pneumococcal conjugate vaccine (PCV13).

The routine vaccination calls for only one dose of PPSV23 given on or after the individual’s 65th birthday. Then, based on shared clinical decision making, a dose of PCV13 is recommended for immunocompetent individuals aged 65 years and older. The notes also state that, based on shared clinical decision making, PCV13 and PPSV23 should not be given in the same visit and, if both will be given, PCV13 should be first and should be given 1 year before PPSV23. In addition, “PPSV23 should be given at least 5 years after any previous PPSV23 dose.”

The schedule also adds shared clinical decision making to the notes on human papillomavirus vaccination for adults aged 27-45 years.

The committee members acknowledged the increasing complexity of the adult vaccination schedule, but several members agreed that it is accessible to many clinicians.

“We can’t let the perfect be the enemy of the good” said Jason Goldman, MD, liaison representing the American College of Physicians. “Those who want to learn the schedule will learn it; the health system will learn it,” even if not every specialist does.

The table “is something to draw you in,” said Sandra Fryhofer, MD, an internist who is liaison for the American Medical Association. The notes provide more details.

More specific information about contraindications for patients with cochlear implants, which also came up in the discussion, may be added to the schedule at a later date.

View the current adult vaccination schedule here.

The ACIP members had no financial conflicts to disclose.
 

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted unanimously to approve the adult immunization schedule for 2020, although some fine-tuning may occur before publication.

MarianVejcik/Getty Images

“Some of the wordsmithing may be done later,” ACIP executive secretary Amanda Cohn, MD, said at the ACIP October meeting.

These small changes revolved mainly around how much wording to include in the current color block tables versus including the information in the notes section.

Key updates to the schedule included a change in wording for the definition of the red bars on the table to include “not recommended or contraindicated” instead of only the word “contraindicated.” Committee members were especially interested in changing this wording to guide clinicians in use of the live attenuated influenza vaccine because of its potential value in vaccinating health care personnel.

Other updates include language that vaccination of adolescents and young adults aged 16-23 years who are not at increased risk for meningococcal disease should be vaccinated as follows: “Based on shared clinical decision making, 2-dose series MenB-4C at least 1 month apart or 2-dose series MenB-FHbp at 0, 6 months.”

Similarly, clinical decision-making language was added to the notes for the pneumococcal polysaccharide vaccine (PPSV23) and the 13-valent pneumococcal conjugate vaccine (PCV13).

The routine vaccination calls for only one dose of PPSV23 given on or after the individual’s 65th birthday. Then, based on shared clinical decision making, a dose of PCV13 is recommended for immunocompetent individuals aged 65 years and older. The notes also state that, based on shared clinical decision making, PCV13 and PPSV23 should not be given in the same visit and, if both will be given, PCV13 should be first and should be given 1 year before PPSV23. In addition, “PPSV23 should be given at least 5 years after any previous PPSV23 dose.”

The schedule also adds shared clinical decision making to the notes on human papillomavirus vaccination for adults aged 27-45 years.

The committee members acknowledged the increasing complexity of the adult vaccination schedule, but several members agreed that it is accessible to many clinicians.

“We can’t let the perfect be the enemy of the good” said Jason Goldman, MD, liaison representing the American College of Physicians. “Those who want to learn the schedule will learn it; the health system will learn it,” even if not every specialist does.

The table “is something to draw you in,” said Sandra Fryhofer, MD, an internist who is liaison for the American Medical Association. The notes provide more details.

More specific information about contraindications for patients with cochlear implants, which also came up in the discussion, may be added to the schedule at a later date.

View the current adult vaccination schedule here.

The ACIP members had no financial conflicts to disclose.
 

Either the Tdap or Td vaccine is an acceptable option for pertussis vaccination in most situations, recommended the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a unanimous 14-0 vote at the October meeting, ACIP members agreed that current data support the use of either the Tdap or Td pertussis vaccine in three areas: as a decennial booster, for tetanus prophylaxis and in the setting of wound management, and for additional catch-up doses based on the immunization schedule for persons aged 7 years and older.

Safety data showed no differences in safety concerns between Tdap and Td, including data from pregnant women, said Fiona Havers, MD, of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD), Atlanta.

Several of the ACIP members noted that the revised language to include both Tdap and Td reflects the increased use of Tdap and allows for maximum flexibility in clinical settings.

The revised language advises that booster doses of “either Td or Tdap” every 10 years throughout life are recommended for continued protection against tetanus and diphtheria. In addition, either Td or Tdap should be used if a tetanus toxoid–containing vaccine is indicated for prophylaxis in nonpregnant individuals.

For catch-up recommendations, which also apply to pregnant women, the committee approved the following wording for a series of three doses for individuals aged 7-18 years and 19 years and older who have never been vaccinated, that “the preferred schedule is a dose of Tdap (preferably the first dose), followed by either Tdap or Td at least 4 weeks afterward and another dose of either Td or Tdap 6-12 months later.” Individuals in these same age groups who are not fully vaccinated should receive one dose of Tdap, and a dose of either Td or Tdap if additional doses are needed.

The committee also voted unanimously 14-0 to accept the updated wording for pertussis vaccination in the Vaccines for Children program.

The ACIP members had no financial conflicts to disclose.

Either the Tdap or Td vaccine is an acceptable option for pertussis vaccination in most situations, recommended the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a unanimous 14-0 vote at the October meeting, ACIP members agreed that current data support the use of either the Tdap or Td pertussis vaccine in three areas: as a decennial booster, for tetanus prophylaxis and in the setting of wound management, and for additional catch-up doses based on the immunization schedule for persons aged 7 years and older.

Safety data showed no differences in safety concerns between Tdap and Td, including data from pregnant women, said Fiona Havers, MD, of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD), Atlanta.

Several of the ACIP members noted that the revised language to include both Tdap and Td reflects the increased use of Tdap and allows for maximum flexibility in clinical settings.

The revised language advises that booster doses of “either Td or Tdap” every 10 years throughout life are recommended for continued protection against tetanus and diphtheria. In addition, either Td or Tdap should be used if a tetanus toxoid–containing vaccine is indicated for prophylaxis in nonpregnant individuals.

For catch-up recommendations, which also apply to pregnant women, the committee approved the following wording for a series of three doses for individuals aged 7-18 years and 19 years and older who have never been vaccinated, that “the preferred schedule is a dose of Tdap (preferably the first dose), followed by either Tdap or Td at least 4 weeks afterward and another dose of either Td or Tdap 6-12 months later.” Individuals in these same age groups who are not fully vaccinated should receive one dose of Tdap, and a dose of either Td or Tdap if additional doses are needed.

The committee also voted unanimously 14-0 to accept the updated wording for pertussis vaccination in the Vaccines for Children program.

The ACIP members had no financial conflicts to disclose.

Either the Tdap or Td vaccine is an acceptable option for pertussis vaccination in most situations, recommended the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices.

copyright Jacopo Werther/Wikimedia Commons/Creative Commons Attribution 2.0

In a unanimous 14-0 vote at the October meeting, ACIP members agreed that current data support the use of either the Tdap or Td pertussis vaccine in three areas: as a decennial booster, for tetanus prophylaxis and in the setting of wound management, and for additional catch-up doses based on the immunization schedule for persons aged 7 years and older.

Safety data showed no differences in safety concerns between Tdap and Td, including data from pregnant women, said Fiona Havers, MD, of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD), Atlanta.

Several of the ACIP members noted that the revised language to include both Tdap and Td reflects the increased use of Tdap and allows for maximum flexibility in clinical settings.

The revised language advises that booster doses of “either Td or Tdap” every 10 years throughout life are recommended for continued protection against tetanus and diphtheria. In addition, either Td or Tdap should be used if a tetanus toxoid–containing vaccine is indicated for prophylaxis in nonpregnant individuals.

For catch-up recommendations, which also apply to pregnant women, the committee approved the following wording for a series of three doses for individuals aged 7-18 years and 19 years and older who have never been vaccinated, that “the preferred schedule is a dose of Tdap (preferably the first dose), followed by either Tdap or Td at least 4 weeks afterward and another dose of either Td or Tdap 6-12 months later.” Individuals in these same age groups who are not fully vaccinated should receive one dose of Tdap, and a dose of either Td or Tdap if additional doses are needed.

The committee also voted unanimously 14-0 to accept the updated wording for pertussis vaccination in the Vaccines for Children program.

The ACIP members had no financial conflicts to disclose.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

A new point-of-care assay designed with machine learning offers improved accuracy for rapid identification of active tuberculosis (TB) infection, according to investigators.

Martynasfoto/ThinkStock

The blood-based triage test, which relies upon four host proteins and one TB antigen, is another step closer toward diagnostic accuracy standards proposed by the World Health Organization, reported lead author Rushdy Ahmad, PhD, of the Broad Institute of MIT and Harvard in Cambridge, Mass., and colleagues. When fully developed, such a test could improve interventions for the most vulnerable patients, such as those with HIV, among whom TB often goes undiagnosed.

“Rapid and accurate diagnosis of active TB with current sputum-based diagnostic tools remains challenging in high-burden, resource-limited settings,” the investigators wrote. Their report is in Science Translational Medicine.

They went on to explain the gap that currently exists between microscopy, which is operator dependent and insensitive, and newer technologies, such as nucleic acid amplification, which are more sensitive but heavily resource dependent. “Furthermore, two of the most vulnerable and highly affected groups – young children and adults with HIV infection – are unlikely to be diagnosed using sputum because of difficulty obtaining sputum and low bacillary loads in the sample.”

To look for a more practical option, the investigators drew blood from 406 patients with chronic cough. Then, using a bead-based immunoassay with machine learning, the investigators identified four blood proteins associated with active TB infection: interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF). Blind validation of 317 samples from patients with chronic cough in Asia, Africa, and South America showed that the four biomarkers offered a sensitivity of 80% and a specificity of 65%. By adding a fifth biomarker, an antibody against TB antigen Ag85B, the investigators were able to raise accuracy figures to 86% sensitivity and 69% specificity.

Adding even more biomarkers could theoretically raise accuracy even further, according to the investigators. The WHO minimal performance thresholds are 90% sensitivity and 70% specificity, with optimal targets slightly higher, at 95% sensitivity and 80% specificity. Although these standards have not yet been met, the investigators plan on testing the existing assay in real-world scenarios while simultaneously aiming to make it better.

“A near-term goal is ... to incrementally improve the marker panel up to an anticipated 6- to 10-plex assay,” the investigators wrote. “However, given the urgency of the problem, the possibility of incremental improvements will not delay platform refinement and field testing.”

The Bill and Melinda Gates Foundation funded the study. The investigators reported additional relationships with Quanterix Corporation and FIND.

SOURCE: Ahmad et al. Sci Transl Med. 2019 Oct 23. doi: 10.1126/scitranslmed.aaw8287.

MADRID – A placebo-controlled trial has confirmed that amoxicillin/clavulanate is beneficial for resolution of acute exacerbations in nonsevere bronchiectasis while also demonstrating a greater relative effect than azithromycin, based on data presented at the annual congress of the European Respiratory Society.

“We now have robust data with which to support our guidelines,” reported Vikas Goyal, MD, of the Children’s Health Clinical Unit, University of Queensland, Brisbane, Australia.

The study addresses a knowledge gap. Antibiotics are already recommended by many guidelines for treatment of acute exacerbations in children with bronchiectasis, but Dr. Goyal said that no controlled trials have ever been performed in this age group to confirm superiority to placebo.

In this multicenter study, called BEST-1, 197 children with bronchiectasis were randomized at the start of an exacerbation to placebo, 45 mg/kg per day of amoxicillin/clavulanate, or 5 mg/kg per day of azithromycin. To maintain blinding, patients in the active treatment groups received a dummy for the opposite antibiotic while patients on placebo received dummies for both active agents.

For the primary outcome, 65% of children randomized to amoxicillin/clavulanate had resolution of their exacerbation by day 14 versus 61% of those randomized to azithromycin and 43% of those randomized to placebo. On the basis of relative risk for reaching this end point, the outcome was superior to placebo for amoxicillin/clavulanate (RR, 1.5; P = .015).

Although the relative risk for azithromycin (RR, 1.4; P = .042) was only slightly lower, it did not reach a prespecified level of significance set at P = .025. Dr. Goyal did report that the resolution rate at 14 days in the placebo group was “higher than expected.”

In this trial, 53% of the 154 children who were tested for respiratory viruses with nasal swabs on day 1 of the exacerbation were found to have respiratory viruses. Of these viruses, rhinovirus was the most common, according to Dr. Goyal, whose data were published just prior to his presentation (Lancet Respir Med. 2019;7:791-801).

The median durations of the exacerbations were 7 days, 8 days, and 10 days for those treated with amoxicillin/clavulanate, azithromycin, and placebo, respectively. The difference between amoxicillin/clavulanate and placebo, but not that between azithromycin and placebo, reached statistical significance, Dr. Goyal said.

There were no between group differences in the time to next exacerbation.

In discussing limitations of this study, Dr. Goyal pointed out that the optimal doses of amoxicillin/clavulanate or azithromycin have never been established for the treatment of exacerbations in children with bronchiectasis. He noted that some infectious disease specialists have advocated higher doses of both than those employed in this trial, but dose-ranging studies have never been conducted in this age group.

In this study, adverse events were less common on azithromycin than amoxicillin/clavulanate (21% vs. 30%), but none were severe, according to Dr. Goyal. He said treatment with azithromycin was associated with increased macrolide-resistant bacteria.

On the basis of these data, Dr. Goyal concluded that amoxicillin/clavulanate should remain, as already specified in some guidelines, the standard first-line therapy for nonsevere exacerbations in nonhospitalized children with bronchiectasis. He recommended reserving azithromycin as an alternative therapy.

Dr. Goyal reports no potential conflicts of interest.

SOURCE: Goyal V et al. Lancet Respir Med. 2019;7:791-801.

MADRID – A placebo-controlled trial has confirmed that amoxicillin/clavulanate is beneficial for resolution of acute exacerbations in nonsevere bronchiectasis while also demonstrating a greater relative effect than azithromycin, based on data presented at the annual congress of the European Respiratory Society.

“We now have robust data with which to support our guidelines,” reported Vikas Goyal, MD, of the Children’s Health Clinical Unit, University of Queensland, Brisbane, Australia.

The study addresses a knowledge gap. Antibiotics are already recommended by many guidelines for treatment of acute exacerbations in children with bronchiectasis, but Dr. Goyal said that no controlled trials have ever been performed in this age group to confirm superiority to placebo.

In this multicenter study, called BEST-1, 197 children with bronchiectasis were randomized at the start of an exacerbation to placebo, 45 mg/kg per day of amoxicillin/clavulanate, or 5 mg/kg per day of azithromycin. To maintain blinding, patients in the active treatment groups received a dummy for the opposite antibiotic while patients on placebo received dummies for both active agents.

For the primary outcome, 65% of children randomized to amoxicillin/clavulanate had resolution of their exacerbation by day 14 versus 61% of those randomized to azithromycin and 43% of those randomized to placebo. On the basis of relative risk for reaching this end point, the outcome was superior to placebo for amoxicillin/clavulanate (RR, 1.5; P = .015).

Although the relative risk for azithromycin (RR, 1.4; P = .042) was only slightly lower, it did not reach a prespecified level of significance set at P = .025. Dr. Goyal did report that the resolution rate at 14 days in the placebo group was “higher than expected.”

In this trial, 53% of the 154 children who were tested for respiratory viruses with nasal swabs on day 1 of the exacerbation were found to have respiratory viruses. Of these viruses, rhinovirus was the most common, according to Dr. Goyal, whose data were published just prior to his presentation (Lancet Respir Med. 2019;7:791-801).

The median durations of the exacerbations were 7 days, 8 days, and 10 days for those treated with amoxicillin/clavulanate, azithromycin, and placebo, respectively. The difference between amoxicillin/clavulanate and placebo, but not that between azithromycin and placebo, reached statistical significance, Dr. Goyal said.

There were no between group differences in the time to next exacerbation.

In discussing limitations of this study, Dr. Goyal pointed out that the optimal doses of amoxicillin/clavulanate or azithromycin have never been established for the treatment of exacerbations in children with bronchiectasis. He noted that some infectious disease specialists have advocated higher doses of both than those employed in this trial, but dose-ranging studies have never been conducted in this age group.

In this study, adverse events were less common on azithromycin than amoxicillin/clavulanate (21% vs. 30%), but none were severe, according to Dr. Goyal. He said treatment with azithromycin was associated with increased macrolide-resistant bacteria.

On the basis of these data, Dr. Goyal concluded that amoxicillin/clavulanate should remain, as already specified in some guidelines, the standard first-line therapy for nonsevere exacerbations in nonhospitalized children with bronchiectasis. He recommended reserving azithromycin as an alternative therapy.

Dr. Goyal reports no potential conflicts of interest.

SOURCE: Goyal V et al. Lancet Respir Med. 2019;7:791-801.

MADRID – A placebo-controlled trial has confirmed that amoxicillin/clavulanate is beneficial for resolution of acute exacerbations in nonsevere bronchiectasis while also demonstrating a greater relative effect than azithromycin, based on data presented at the annual congress of the European Respiratory Society.

“We now have robust data with which to support our guidelines,” reported Vikas Goyal, MD, of the Children’s Health Clinical Unit, University of Queensland, Brisbane, Australia.

The study addresses a knowledge gap. Antibiotics are already recommended by many guidelines for treatment of acute exacerbations in children with bronchiectasis, but Dr. Goyal said that no controlled trials have ever been performed in this age group to confirm superiority to placebo.

In this multicenter study, called BEST-1, 197 children with bronchiectasis were randomized at the start of an exacerbation to placebo, 45 mg/kg per day of amoxicillin/clavulanate, or 5 mg/kg per day of azithromycin. To maintain blinding, patients in the active treatment groups received a dummy for the opposite antibiotic while patients on placebo received dummies for both active agents.

For the primary outcome, 65% of children randomized to amoxicillin/clavulanate had resolution of their exacerbation by day 14 versus 61% of those randomized to azithromycin and 43% of those randomized to placebo. On the basis of relative risk for reaching this end point, the outcome was superior to placebo for amoxicillin/clavulanate (RR, 1.5; P = .015).

Although the relative risk for azithromycin (RR, 1.4; P = .042) was only slightly lower, it did not reach a prespecified level of significance set at P = .025. Dr. Goyal did report that the resolution rate at 14 days in the placebo group was “higher than expected.”

In this trial, 53% of the 154 children who were tested for respiratory viruses with nasal swabs on day 1 of the exacerbation were found to have respiratory viruses. Of these viruses, rhinovirus was the most common, according to Dr. Goyal, whose data were published just prior to his presentation (Lancet Respir Med. 2019;7:791-801).

The median durations of the exacerbations were 7 days, 8 days, and 10 days for those treated with amoxicillin/clavulanate, azithromycin, and placebo, respectively. The difference between amoxicillin/clavulanate and placebo, but not that between azithromycin and placebo, reached statistical significance, Dr. Goyal said.

There were no between group differences in the time to next exacerbation.

In discussing limitations of this study, Dr. Goyal pointed out that the optimal doses of amoxicillin/clavulanate or azithromycin have never been established for the treatment of exacerbations in children with bronchiectasis. He noted that some infectious disease specialists have advocated higher doses of both than those employed in this trial, but dose-ranging studies have never been conducted in this age group.

In this study, adverse events were less common on azithromycin than amoxicillin/clavulanate (21% vs. 30%), but none were severe, according to Dr. Goyal. He said treatment with azithromycin was associated with increased macrolide-resistant bacteria.

On the basis of these data, Dr. Goyal concluded that amoxicillin/clavulanate should remain, as already specified in some guidelines, the standard first-line therapy for nonsevere exacerbations in nonhospitalized children with bronchiectasis. He recommended reserving azithromycin as an alternative therapy.

Dr. Goyal reports no potential conflicts of interest.

SOURCE: Goyal V et al. Lancet Respir Med. 2019;7:791-801.

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

WASHINGTON – An investigational, oral, small molecule designed to boost innate antiviral immunity safely cut the incidence of various viral respiratory infections in elderly people during a winter season by nearly a third when administered once daily in a placebo-controlled, multicenter, phase 2 study of 952 patients. Based on these and other findings the drug, RTB101, is now undergoing testing in a phase 3 study, Joan Mannick, MD, said at an annual scientific meeting on infectious diseases.

Mitchel L. Zoler/MDedge News

At a dosage of 10 mg once daily, RTB101 was “well tolerated, upregulated innate antiviral gene expression, and reduced the incidence” of laboratory-confirmed respiratory tract infections caused by several different viruses, said Dr. Mannick, who disclosed that she is a cofounder and chief medical officer of resTORbio, a Boston-based company that’s developing the drug.

During 16 weeks of treatment during the winter virus season, once-daily dosing led to cuts in the rates of respiratory infections compared with placebo by rhinovirus and enterovirus, respiratory syncytial virus, coronavirus, influenza virus, metapneuomovirus, and parainfluenza virus, especially in patients whom the results identified as having the best drug responses: those who were at least 85 years old, and those who were at least 65 years old and also had asthma. Enrolled patients who were at least 65 years old and had other risk factors – current smoking, chronic obstructive pulmonary disease, or diabetes – had notably less robust responses to treatment, and the phase 3 study is not enrolling elderly people who currently smoke or have chronic obstructive pulmonary disease, Dr. Mannick said in an interview.

RTB101 inhibits the active site of the “mechanistic target of rapamycin” (mTOR) protein, the key player of the TORC1 protein complex that appears to downregulate innate antiviral immunity when active. Hence inhibiting mTOR and TORC1 activity should boost innate antiviral immunity. Once-daily dosing with 10 mg of RTB101 appears to mimic the normal daily cycle of high and low levels of TORC1 activity seen in younger adults but which is missing the elderly who generally have persistently elevated levels of TORC1 activity, Dr. Mannick explained.

The study she reported enrolled a total of 952 people at any of 10 sites in the Southern Hemisphere or 17 Northern Hemisphere study sites. The researchers randomized patients to receive either RTB101 or placebo at either of two once-daily dosages or either of two twice-daily regimens. The best drug performance was among the 356 patients treated with 10 mg once daily or placebo. Those who received the active drug at this level had a 19% incidence of any laboratory-confirmed respiratory tract infection, while those who received placebo had a 28% incidence, a 30.6% relative risk reduction with RTB101 treatment that was statistically significant.

The actively-treated patients showed upregulation for 19 of 20 “antiviral” genes assessed in the study compared with upregulation of just five of these genes in the those who received placebo. Two post hoc analyses showed that the people who received 10 mg once daily had about half the rate of all-cause hospitalizations compared with those on placebo, and among those who had respiratory infections treated patients had alleviation of their moderate or severe symptoms in about half the time compared with patients on placebo.

The 10-mg daily dosage of RTB101 is less than 1% of the maximum-tolerated dose in people, and the safety data collected in the current study showed adverse events occurring at similar rates in the patients who received the active drug and those who got placebo. Discontinuations because of adverse events occurred in 5% of people who received RTB101 and in 6% of those on placebo.

The researchers are planning to run a cost-effectiveness study to see whether the observed prevention of respiratory tract infections and their consequences can offset the cost of taking RTB101 daily for 16 weeks, Dr. Mannick said.

[email protected]

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.

Recurrent invasive pneumococcal disease in children could be a signal of underlying primary immunodeficiency, according to a systematic review published in JAMA Pediatrics.

Coen Butters, BMed, DCH, of the Royal Children’s Hospital in Melbourne, and coauthors wrote that, even with optimal vaccine coverage, there is still a group of children with increased susceptibility to invasive pneumococcal disease (IPD), and this could be a potential marker of primary immunodeficiency.

They conducted a systematic review of 17 studies of 6,002 children to examine the evidence on the incidence of primary immunodeficiency in children who presented with IPD but without any other risk factors or predisposing conditions.

Overall, the frequency of primary immunodeficiency in children presenting with IPD who did not have any other predisposing condition ranged from 1% to 26%.

One study of 162 children with IPD, which had an overall frequency of primary immunodeficiency of 10%, found that children older than 2 years were significantly more likely to have primary immunodeficiency than those aged under 2 years (26% vs. 3%; P less than .001).

Primary antibody deficiency was the most commonly diagnosed immunodeficiency in these children with IPD, accounting for 71% of cases. These deficiencies presented as hypogammaglobulinemia, specific pneumococcal antibody deficiency, X-linked agammaglobulinemia, and IgG2 deficiency.

The review also included four studies that looked at the frequency of mannose-binding lectin deficiency in 1,493 children with primary IPD. Two of these studies reported a prevalence of mannose-binding lectin deficiency ranging from 31% in children aged younger than 2 years to 41% in children younger than 1 year.

Five studies looked at the rate of primary immunodeficiency in children presenting with recurrent IPD. In addition to other predisposing conditions such as sickle cell disease, cancer, and anatomical breach in the blood-brain barrier, the three studies that screened for primary immunodeficiency found rates ranging from 10% to 67%. The most common conditions were complement deficiency, pneumococcal antibody deficiency, and a single case of TLR-signaling defect.

In a study of 162 children with primary IPD, screening for asplenia identified a single case of congenital asplenia. In another study of 2,498 cases of IPD, 22 patients had asplenia at presentation, half of whom died at presentation.

Dr. Butters and associates concluded that “this review’s findings suggests that existing data support the immune evaluation of children older than 2 years without a known predisposing condition who present with their first episode of Streptococcus pneumoniae meningitis, pneumonia, or recurrent IPD. Immune evaluation should include assessment for immunoglobulin deficiency, pneumococcal antibody deficiency, complement disorders, and asplenia.”

In an accompanying editorial, Stephen I. Pelton, MD, of the Maxwell Finland Laboratory for Infectious Diseases at Boston Medical Center, and coauthors wrote that in children with recurrent episodes of IPD caused by nonvaccine serotypes – particularly those aged over 5 years – evaluation for primary immunodeficiencies could uncover immune defects.

“Once identified, direct and indirect protection, penicillin prophylaxis, or a combination of these offers great potential for disease prevention and reduction of mortality and morbidity in children with [primary immunodeficiency],” they wrote.

No funding or conflicts of interest were declared for the study. Two of the editorialists declared research funding or honoraria from the pharmaceutical sector.

SOURCES: Butters C et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3203; Pelton SI et al. JAMA Pediatr. 2019 Sep 30. doi: 10.1001/jamapediatrics.2019.3185.