Infectious Diseases

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.

Courtesy NIAID

The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”

Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.

“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.

In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.

Current statistics lend weight to the promise of eventual eradication, according to the report.

Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.

“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.

The analysis undertaken for the report consisted of the following four steps:

1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.

2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.

3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.

4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.

The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.

However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.

In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”

The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.

[email protected]

SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.


 

A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.

Courtesy NIAID

The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”

Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.

“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.

In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.

Current statistics lend weight to the promise of eventual eradication, according to the report.

Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.

“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.

The analysis undertaken for the report consisted of the following four steps:

1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.

2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.

3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.

4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.

The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.

However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.

In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”

The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.

[email protected]

SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.


 

A new report by members of the Lancet Commission on Malaria Eradication has called for ending malaria in Africa within a generation, specifically aiming at the year 2050.

Courtesy NIAID

The Lancet Commission on Malaria Eradication is a joint endeavor between The Lancet and the University of California, San Francisco, and was convened in 2017 to consider the feasibility and affordability of malaria eradication, as well as to identify priority actions for the achievement of the goal. Eradication was considered “a necessary one given the never-ending struggle against drug and insecticide resistance and the social and economic costs associated with a failure to eradicate.”

Between 2000 and 2017, the worldwide annual incidence of malaria declined by 36%, and the annual death rate declined by 60%, according to the report. In 2007, Bill and Melinda Gates proposed that controlling malaria was not enough and complete eradication was the only scientifically and ethically defensible objective. This goal was adopted by the World Health Organization and other interested parties, and by 2015, global strategies and a potential timeline for eradication were developed.

“Global progress has stalled since 2015 and the malaria community is now at a critical moment, faced with a decision to either temper its ambitions as it did in 1969 or recommit to an eradication goal,” according to the report.

In the report, the authors used new modeling analysis to estimate plausible scenarios for the distribution and intensity of malaria in 2030 and 2050. Socioeconomic and environmental trends, together with enhanced access to high-quality diagnosis, treatment, and vector control, could lead to a “world largely free of malaria” by 2050, but with pockets of low-level transmission persisting across a belt of Africa.

Current statistics lend weight to the promise of eventual eradication, according to the report.

Between 2000 and 2017, 20 countries – constituting about one-fifth of the 106 malaria-endemic countries in 2000 – eliminated malaria transmission within their borders, reporting zero indigenous malaria cases for at least 1 year. However, this was counterbalanced by the fact that between 2015 and 2017, 55 countries had an increase in cases, and 38 countries had an increase in deaths.

“The good news is that 38 countries had incidences of fewer than ten cases per 1,000 population in 2017, with 25 countries reporting fewer than one case per 1,000 population. The same 38 countries reported just 5% of total malaria deaths. Nearly all of these low-burden countries are actively working towards national and regional elimination goals of 2030 or earlier,” according to the report.

The analysis undertaken for the report consisted of the following four steps:

1. Development of a machine-learning model to capture associations between malaria endemicity data and a wide range of socioeconomic and environmental geospatial covariates.

2. Mapping of covariate estimates to the years 2030 and 2050 on the basis of projected global trends.

3. Application of the associations learned in the first step to projected covariates generated in the second step to estimate the possible future global landscape of malaria endemicity.

4. Use of a mathematical transmission model to explore the potential effect of differing levels of malaria interventions.

The report indicates that an annual spending of $6 billion or more is required, while the current global expenditure is approximately $4.3 billion. An additional investment of $2 billion per year is necessary, with a quarter of the funds coming from increased development assistance from external donors and the rest from government health spending in malaria-endemic countries, according to the report.

However, other areas of concern remain, including the current lack of effective and widely deployable outdoor biting technologies, though these are expected to be available within the next decade, according to the report.

In terms of the modeling used in the report, the authors noted that past performance does not “capture the effect of mass drug administration or mass chemoprevention because these interventions are either relatively new or have yet to be applied widely. These underestimates might be counteracted by the absence of drug or insecticide resistance from our projections,which result in overly optimistic estimates for the continued efficacy of current tools.”

The commission was launched in October 2017 by the Global Health Group at the University of California, San Francisco. The commission built on the 2010 Lancet Malaria Elimination Series, “which evaluated the operational, technical, and financial requirements for malaria elimination and helped shape and build early support for the eradication agenda,” according to the report.

[email protected]

SOURCE: Feachem RGA et al. Lancet. 2019 Sept 8. doi: 10.1016/S0140-6736(19)31139-0.


 

Background: HAIs are key drivers of morbidity and mortality for hospitalized patients. In 2011, the Centers for Disease Control and Prevention (CDC) conducted a point-prevalence survey that revealed an HAI in 4% of hospitalized patients. The most common infections included pneumonia, gastrointestinal infections, and surgical-site infections. Over time, efforts in patient safety and quality have expanded to reduce the rate of HAIs. This same survey was repeated in 2015 to assess for improvements.

The reduction in HAIs was primarily driven by a reduction in surgical-site infections and urinary tract infections. There was no reduction in the prevalence of health care–associated pneumonia, Clostridium difficile infection, or mortality. Consequently, this emphasizes the necessity of further work in these domains.

Bottom line: The overall prevalence of HAIs has decreased, but further quality improvement work is needed in order to expand this reduction to health care–associated pneumonia, C. difficile infection, and mortality from HAIs.

Citation: Magill SS et al. Changes in prevalence of heath care–associated infections in U.S. hospitals. N Engl J Med. 2018;379(18):1732-44.

Dr. McIntyre is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: HAIs are key drivers of morbidity and mortality for hospitalized patients. In 2011, the Centers for Disease Control and Prevention (CDC) conducted a point-prevalence survey that revealed an HAI in 4% of hospitalized patients. The most common infections included pneumonia, gastrointestinal infections, and surgical-site infections. Over time, efforts in patient safety and quality have expanded to reduce the rate of HAIs. This same survey was repeated in 2015 to assess for improvements.

The reduction in HAIs was primarily driven by a reduction in surgical-site infections and urinary tract infections. There was no reduction in the prevalence of health care–associated pneumonia, Clostridium difficile infection, or mortality. Consequently, this emphasizes the necessity of further work in these domains.

Bottom line: The overall prevalence of HAIs has decreased, but further quality improvement work is needed in order to expand this reduction to health care–associated pneumonia, C. difficile infection, and mortality from HAIs.

Citation: Magill SS et al. Changes in prevalence of heath care–associated infections in U.S. hospitals. N Engl J Med. 2018;379(18):1732-44.

Dr. McIntyre is an associate physician in the division of hospital medicine at the University of California, San Diego.

Background: HAIs are key drivers of morbidity and mortality for hospitalized patients. In 2011, the Centers for Disease Control and Prevention (CDC) conducted a point-prevalence survey that revealed an HAI in 4% of hospitalized patients. The most common infections included pneumonia, gastrointestinal infections, and surgical-site infections. Over time, efforts in patient safety and quality have expanded to reduce the rate of HAIs. This same survey was repeated in 2015 to assess for improvements.

The reduction in HAIs was primarily driven by a reduction in surgical-site infections and urinary tract infections. There was no reduction in the prevalence of health care–associated pneumonia, Clostridium difficile infection, or mortality. Consequently, this emphasizes the necessity of further work in these domains.

Bottom line: The overall prevalence of HAIs has decreased, but further quality improvement work is needed in order to expand this reduction to health care–associated pneumonia, C. difficile infection, and mortality from HAIs.

Citation: Magill SS et al. Changes in prevalence of heath care–associated infections in U.S. hospitals. N Engl J Med. 2018;379(18):1732-44.

Dr. McIntyre is an associate physician in the division of hospital medicine at the University of California, San Diego.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

Women who have tested positive for Chlamydia trachomatis have an increased risk for pelvic inflammatory disease (PID), ectopic pregnancy, and infertility, compared with women who have tested negative for C. trachomatis or who have not been tested for the bacterium, according to a retrospective cohort study.

CDC/Dr. E. Arum; Dr. N. Jacobs

The risk of PID increases with repeat chlamydial infections, and the use of antibiotics that are effective against C. trachomatis does not decrease the risk of subsequent PID, the researchers reported in Clinical Infectious Diseases.

Prior studies have yielded different estimates of the risk of reproductive complications after chlamydia infection, said Casper den Heijer, MD, PhD, a researcher at Utrecht Institute of Pharmaceutical Sciences in Heerlen, the Netherlands, and colleagues. To assess the risk of PID, ectopic pregnancy, and infertility in women with a previous C. trachomatis diagnosis, Dr. den Heijer and coauthors conducted a retrospective study of women aged 12-25 years at baseline in the Clinical Practice Research Datalink GOLD database. Their analysis included data from women living in England between 2000 and 2013. The investigators used Cox proportional hazard models to evaluate the risk of adverse outcomes.

The researchers analyzed data from 857,324 women with a mean follow-up of 7.5 years. Patients’ mean age at baseline was 15 years. In all, the participants had 8,346 occurrences of PID, 2,484 occurrences of ectopic pregnancy, and 2,066 occurrences of female infertility.

For PID, incidence rates per 1,000 person-years were 1.1 among women untested for C. trachomatis, 1.4 among women who tested negative, and 5.4 among women who tested positive. For ectopic pregnancy, the incidence rates were 0.3 for untested women, 0.4 for negatively tested women, and 1.2 for positively tested women. Infertility incidence rates were 0.3 for untested women, 0.3 for negatively tested women, and 0.9 for positively tested women.

Compared with women who tested negative for C. trachomatis, women who tested positive had an increased risk of PID (adjusted hazard ratio, 2.36), ectopic pregnancy (aHR, 1.87), and female infertility (aHR, 1.85). Untested women had a lower risk for PID, compared with women who tested negative (aHR, 0.57).

C. trachomatis–effective antibiotic use was associated with higher PID risk, and that risk increased as the women used more of the antibiotic prescriptions, Dr. den Heijer and associates said. This occurred in all three groups of women. A possible explanation for this association between the antibiotics and higher PID risk could be that PID can be caused by other infectious diseases that could be treated with C. trachomatis–effective antibiotics.

While the study relied on primary care data, genitourinary medicine clinics diagnose and treat “a sizable proportion” of sexually transmitted infections in the United Kingdom, the authors noted. This limitation means that the study underestimates the number of C. trachomatis diagnoses in the cohort, they said.

Nonetheless, “Our results confirm the reproductive health burden of [C. trachomatis] and show the need for adequate public health interventions,” Dr. den Heijer and associates concluded.

[email protected]

SOURCE: den Heijer CDJ et al. Clin Infect Dis. 2019 Aug 24. doi: 10.1093/cid/ciz429.

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

[polldaddy:10402702]

Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

[polldaddy:10402702]

Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].

CASE

Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.

As Mr. S’s physician, how do you respond?

Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.¹ Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,² leading to legalization in most of the United States.

As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.

The pharmacology of cannabis

Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.³ Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.⁴

Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized.

The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.⁵

Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.

The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.^6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB₁ and CB₂, found throughout the body: CB₁, predominantly in the central and peripheral nervous system, and CB₂ in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB₁ and CB₂.

[polldaddy:10402702]

Continue to: Botanical or synthetic?

Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.

Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used in Canada and Europe.

PHOTO: ANTHONY RODRIGUEZ 2019; PHOTO MANIPULATION: JOHN DENAPOLI

A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.⁸

Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.⁴

Physiologic effects. THC is a partial agonist of CB₁ and CB₂ receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB₁ receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.⁷ THC exerts its psychotropic effects at CB₁ sites in the central nervous system; CBD can antagonize these THC effects at CB₁ receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB₂ receptors.⁹

Continue to: THC has tremendously...

A tolerable therapeutic starting point is a THC:CBD ratio of 1:1.

THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.^1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.

Clinical implications and indications

Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:

• For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
• What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?

Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.¹⁰ The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.

Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.

There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).

Continue to: The primary conclusion...

The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.

HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.^10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:

• In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.¹¹
• In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.¹⁰

Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.⁹ In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.

CASE

Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB₁ and CB₂ as potential targets for antiemetic treatment.

Research suggests that the use of Cannabis for pediatric patients with refractory seizures is promising.

Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.

Continue to: Based on recent observational data...

Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.

A legal system at oddsover the status of medical Cannabis

The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.

At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).¹² The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.¹³ Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I¹⁴; ie, the substance

• has high potential for abuse,
• has no accepted therapeutic medical use in the United States, and
• lacks acceptable safety for use under medical supervision.

Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.¹⁵

Physicians are protected from prosecution or revocation of their prescriptive authority based on their First Amendment right to discuss medical marijuana with patients.

In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”¹⁵

Continue to: The bill was referred to the Senate...

The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.

On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.^16,17

At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures¹⁸ (www.ncsl.org) designates a program “comprehensive” if it

• includes protection from criminal penalties for using marijuana for a medical purpose,
• allows access to marijuana through home cultivation, dispensaries, or other system,
• permits a variety of strains, including those more potent than what is labeled “low-THC,” and
• allows smoking or vaporization of marijuana products, plant-based material, or extract.

An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.¹⁸

Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.

Continue to: Physician shield

Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.¹⁹ In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.

CASE

Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.

How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.

Common concerns

Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,¹⁸ and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).²⁰

Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.²¹

Continue to: Large cross-sectional...

Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.^22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.

Delayed onset of edible products and variation of THC concentration increase risk of overconsumption.

“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.

Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.²⁴ Although patients often report the use of medical Cannabis to treat anxiety,²⁵ panic attacks are often associated with Cannabis use.²⁶

While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.²⁷

We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.

Continue to: Overconsumption of edibles

Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.²⁸

Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).²⁹ These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.³⁰

CASE

Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.

How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.³⁰

Cannabis use disorder in the context of medical marijuana

Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.³¹ Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.³¹ Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.

Continue to: A recent study...

A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.³² Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.³²

A paucity of pediatric data

Cannabis smoke carries many of the same carcinogens found in tobacco smoke.

The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.

The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.³³ The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.³⁴

Recognized risk: Not supporting medical Cannabis

At press time, the CDC issued a statement on respiratory illnesses reported after use of e-cigarette products. To learn more, go to www.cdc.gov/media/releases/2019/s0830-statement-e-cigarette.html.

As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:

Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.³⁵

Continue to: Limiting patients to other medications

Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.³⁶

 Resigning patients to obtain Cannabis from an illegal source.  This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:

• Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.³⁷
• Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.³⁸

CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; [email protected].

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

It is estimated that there are 1.1 million people in the United States living with HIV and that 15% of those people do not know they have HIV. Although the number of new cases reported each year is decreasing, there were still 38,281 new diagnoses in 2017. New cases might be decreasing overall, but the incidence of HIV is rising in some groups including people aged 25-29 years old and American Indian/Alaska Native and Asian populations. In addition, HIV disproportionately affects men who have sex with men, black/African American populations, and Hispanic/Latino populations, according to the USPSTF statement.

Given the prevalence of HIV and rising new cases in certain groups, it is thought that preexposure prophylaxis (PrEP) is being underutilized. The CDC reported that, in 2015, 1.2 million people were candidates for PrEP, but in 2017, only 100,282 people were using PrEP. The USPSTF performed a meta-analysis of 12 RCTs comparing rates of HIV infection in groups treated with PrEP versus those treated with placebo or no treatment and found a risk ratio of 0.46 (95% confidence interval, 0.33-0.66) and absolute risk reduction of –2% (95% CI, –2.8% to –1.2%) after 4 months and 4 years.

With this epidemiologic data and the meta-analysis, the USPSTF offered the following recommendations.
 

Screening

In order to decrease the rates of transmission and incidence of HIV infection, we must appropriately identify those who would be good candidates for PrEP. That begins with taking a complete and thorough sexual and injection drug use history in a manner that does not make patients feel stigmatized or discriminated against. The USPSTF recommends screening for HIV infection in patients aged 15-65 years old, in younger and older patients who have increased risk factors, and all pregnant patients. PrEP is not an appropriate choice in those who have HIV because it can lead to drug resistance.

When screening for HIV and considering starting PrEP, it is recommended that clinicians also test for kidney function, hepatitis B and C, other STIs, and pregnancy. The USPSTF suggests that the following groups be considered for PrEP given the increased risk of HIV infection:

• Men who have sex with men, are sexually active, and have one of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during receptive or insertive anal sex, or infection with syphilis, gonorrhea, or chlamydia in the past 6 months.
• Heterosexual men or women who are sexually active with one or more of these additional characteristics: a serodiscordant sex partner, inconsistent use of condoms during sex with a partner whose HIV status is unknown and who is at high risk, and infection with syphilis or gonorrhea in the past 6 months.
• Patients who inject drugs with one or more of the following characteristics: shared use of drug injection equipment and risk of sexual acquisition (as in the categories above).

The USPSTF also notes that those who engage in transactional sex (for money, drugs, or housing) and transgender patients are at an increased risk of HIV infection.

Treatment

The only FDA approved treatment for the prevention HIV infection is once daily oral combined tenofovir disoproxil fumarate and emtricitabine; however, some studies have found that tenofovir disproxil fumarate monotherapy is also effective. Considering these trials, the CDC has suggested that tenofovir disoproxil fumarate monotherapy can be used as an alternative for men and women at high risk and those who inject drugs.

Tenofovir disoproxil fumarate/emtricitabine can also be used in pregnant patients, however the USPSTF notes that no PrEP trials included pregnant women. Additionally, tenofovir disoproxil fumarate/emtricitabine can be used in adolescents who weigh more than 35 kg. It is unknown how much time it takes to achieve protection against HIV infection after starting PrEP, and there is no clear timeline for how long patients should be on PrEP. Patients may discontinue medication because of preference, decreased risk of HIV exposure, or side effects.

Side effects include renal adverse events (serum creatinine rise), gastrointestinal adverse events (mostly nausea), and bone loss and increased fracture risk, although none were statistically significant when PrEP and placebo groups were compared. The USPSTF’s recommendations note that the effectiveness of PrEP is dependent on medication adherence.

While PrEP is an important part of preventing HIV, it is always important to counsel patients on other ways to reduce risk. The USPSTF notes that consistent condom use reduces the risk of HIV infection by around 80% in addition to reducing the risk of other STIs. All trials studied by the USPSTF for these recommendations included counseling on behavior, adherence, and condom use.
 

Bottom Line

It is estimated that 1.1 million Americans are living with HIV and 15% are unaware that they are positive for HIV. Overall cases of new HIV diagnoses are down, but they are rising in some groups. PrEP is an effective medication for reducing the risk of HIV infection, but is currently underutilized. Every patient should be screened for high-risk sexual behavior and drug use with a thorough history. Patients aged 15-65 years should be screened for HIV. If patients are negative for HIV, but participate in high-risk sexual behaviors and drug injection, they should be offered PrEP along with counseling on, medication adherence, condom use, and reduction of high-risk behaviors.
 

Dr. Skolnik is professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Sprogell is a second-year resident in the Family Medicine Residency Program at Abington Jefferson Health

Reference

Owens DK et al. “Preexposure prophylaxis for the prevention of HIV infection: US Preventive Services Task Force recommendation statement.” JAMA. 2019 Jun 11;321(22):2203-13.

Survivors of the 2013-2016 Ebola epidemic in West Africa had lingering health effects of the disease. These patients had a much greater mortality in the first year after discharge, compared with the general population. Among those survivors who died, the majority appear to have expired because of renal failure, according to the results of an assessment the by the Guinean national survivors’ monitoring program.

CDC/Athalia Christie

The Surveillance Active en Ceinture obtained data on 1,130 (89%) of survivors of Ebola virus disease who were discharged from Ebola treatment units in Guinea. Compared with the general Guinean population, survivors of Ebola virus showed a five times increased risk of mortality within a year of follow-up after discharge, according to a survey of patients’ medical records and patients’ relatives, reported researchers Mory Keita, MD, and colleagues.

After 1 year, the difference in mortality between Ebola survivors and the general population had disappeared, according to the study published online in the Lancet Infectious Diseases.

A total of 59 deaths were reported among the discharged survivors available for follow-up. Renal failure was the assumed cause in 37 (63%) of these patients based on a description of reported anuria. The exact date of death was unknown for 43 of the 59 deaths. Of the 16 initial survivors for whom an exact date of death was available, 5 died within a month of discharge from Ebola treatment units, an additional 3 died within 3 months of discharge, 4 died 3-12 months after discharge, and 4 died more than a year after discharge (up to 21 months).

Age and area of residence (urban vs. nonurban area) were independently and significantly associated with mortality, with patients of older age (55 years or greater) and those from nonurban areas being at greater risk. Patient sex was not associated with survival.

Those survivors who were hospitalized for 12 days or more had more than double the risk of death than did those hospitalized less than 12 days, which was a statistically significant association.

“Survivors’ monitoring programs should be strengthened and should not focus exclusively on testing of bodily fluids,” the authors advised. “Furthermore, our study provides preliminary evidence that survivors hospitalized for longer than 12 days with Ebola virus disease could be at particularly high risk of mortality and should be specifically targeted, and perhaps also evidence that renal function should be monitored,” Dr. Keita and colleagues concluded.

The study was funded by the World Health Organization, International Medical Corps, and the Guinean Red Cross. The authors reported that they had no conflicts

[email protected]

SOURCE: Keita M et al. Lancet Infect Dis 2019 Sept 4. doi: 10.1016/S1473-3099(19)30313-5.

Survivors of the 2013-2016 Ebola epidemic in West Africa had lingering health effects of the disease. These patients had a much greater mortality in the first year after discharge, compared with the general population. Among those survivors who died, the majority appear to have expired because of renal failure, according to the results of an assessment the by the Guinean national survivors’ monitoring program.

CDC/Athalia Christie

The Surveillance Active en Ceinture obtained data on 1,130 (89%) of survivors of Ebola virus disease who were discharged from Ebola treatment units in Guinea. Compared with the general Guinean population, survivors of Ebola virus showed a five times increased risk of mortality within a year of follow-up after discharge, according to a survey of patients’ medical records and patients’ relatives, reported researchers Mory Keita, MD, and colleagues.

After 1 year, the difference in mortality between Ebola survivors and the general population had disappeared, according to the study published online in the Lancet Infectious Diseases.

A total of 59 deaths were reported among the discharged survivors available for follow-up. Renal failure was the assumed cause in 37 (63%) of these patients based on a description of reported anuria. The exact date of death was unknown for 43 of the 59 deaths. Of the 16 initial survivors for whom an exact date of death was available, 5 died within a month of discharge from Ebola treatment units, an additional 3 died within 3 months of discharge, 4 died 3-12 months after discharge, and 4 died more than a year after discharge (up to 21 months).

Age and area of residence (urban vs. nonurban area) were independently and significantly associated with mortality, with patients of older age (55 years or greater) and those from nonurban areas being at greater risk. Patient sex was not associated with survival.

Those survivors who were hospitalized for 12 days or more had more than double the risk of death than did those hospitalized less than 12 days, which was a statistically significant association.

“Survivors’ monitoring programs should be strengthened and should not focus exclusively on testing of bodily fluids,” the authors advised. “Furthermore, our study provides preliminary evidence that survivors hospitalized for longer than 12 days with Ebola virus disease could be at particularly high risk of mortality and should be specifically targeted, and perhaps also evidence that renal function should be monitored,” Dr. Keita and colleagues concluded.

The study was funded by the World Health Organization, International Medical Corps, and the Guinean Red Cross. The authors reported that they had no conflicts

[email protected]

SOURCE: Keita M et al. Lancet Infect Dis 2019 Sept 4. doi: 10.1016/S1473-3099(19)30313-5.

Survivors of the 2013-2016 Ebola epidemic in West Africa had lingering health effects of the disease. These patients had a much greater mortality in the first year after discharge, compared with the general population. Among those survivors who died, the majority appear to have expired because of renal failure, according to the results of an assessment the by the Guinean national survivors’ monitoring program.

CDC/Athalia Christie

The Surveillance Active en Ceinture obtained data on 1,130 (89%) of survivors of Ebola virus disease who were discharged from Ebola treatment units in Guinea. Compared with the general Guinean population, survivors of Ebola virus showed a five times increased risk of mortality within a year of follow-up after discharge, according to a survey of patients’ medical records and patients’ relatives, reported researchers Mory Keita, MD, and colleagues.

After 1 year, the difference in mortality between Ebola survivors and the general population had disappeared, according to the study published online in the Lancet Infectious Diseases.

A total of 59 deaths were reported among the discharged survivors available for follow-up. Renal failure was the assumed cause in 37 (63%) of these patients based on a description of reported anuria. The exact date of death was unknown for 43 of the 59 deaths. Of the 16 initial survivors for whom an exact date of death was available, 5 died within a month of discharge from Ebola treatment units, an additional 3 died within 3 months of discharge, 4 died 3-12 months after discharge, and 4 died more than a year after discharge (up to 21 months).

Age and area of residence (urban vs. nonurban area) were independently and significantly associated with mortality, with patients of older age (55 years or greater) and those from nonurban areas being at greater risk. Patient sex was not associated with survival.

Those survivors who were hospitalized for 12 days or more had more than double the risk of death than did those hospitalized less than 12 days, which was a statistically significant association.

“Survivors’ monitoring programs should be strengthened and should not focus exclusively on testing of bodily fluids,” the authors advised. “Furthermore, our study provides preliminary evidence that survivors hospitalized for longer than 12 days with Ebola virus disease could be at particularly high risk of mortality and should be specifically targeted, and perhaps also evidence that renal function should be monitored,” Dr. Keita and colleagues concluded.

The study was funded by the World Health Organization, International Medical Corps, and the Guinean Red Cross. The authors reported that they had no conflicts

[email protected]

SOURCE: Keita M et al. Lancet Infect Dis 2019 Sept 4. doi: 10.1016/S1473-3099(19)30313-5.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

Fleas of the order Siphonaptera are insects that feed on the blood of a mammalian host. They have no wings but jump to near 150 times their body lengths to reach potential hosts.¹ An epidemiologic survey performed in 2016 demonstrated that 96% of fleas in the United States are cat fleas (Ctenocephalides felis).² The bites often present as pruritic, nonfollicular-based, excoriated papules; papular urticaria; or vesiculobullous lesions distributed across the lower legs. Antihistamines and topical steroids may be helpful for symptomatic relief, but flea eradication is key.

Identification

Ctenocephalides fleas, including the common cat flea and the dog flea, have a characteristic pronotal comb that resembles a mane of hair (Figure 1) and genal comb that resembles a mustache. Compared to the dog flea (Ctenocephalides canis), cat fleas have a flatter head and fewer hair-bearing notches on the dorsal hind tibia (the dog flea has 8 notches and the cat flea has 6 notches)(Figure 2).

Flea Prevention and Eradication

Effective management of flea bites requires avoidance of infested areas and eradication of fleas from the home and pets. Home treatment should be performed by a qualified specialist and a veterinarian should treat the pet, but the dermatologist must be knowledgeable about treatment options. Flea pupae can lie dormant between floorboards for extended periods of time and hatch rapidly when new tenants enter a house or apartment. Insecticidal dusts and spray formulations frequently are used to treat infested homes. It also is important to reduce flea egg numbers by vacuuming carpets and areas where pets sleep.³ Rodents often introduce fleas to households and pets, so eliminating them from the area may play an important role in flea control. Consulting with a veterinarian is important, as treatment directed at pets is critical to control flea populations. Oral agents, including fluralaner, afoxolaner, sarolaner, and spinosad, can reduce flea populations on animals by as much as 99.3% after 7 days.^4,5 Fast-acting pulicidal agents, such as the combination of dinotefuran and fipronil, demonstrate curative activity as soon as 3 hours after treatment, which also may prevent reinfestation for as long as 6 weeks after treatment.⁶

Vector-Borne Disease

Fleas living on animals in close contact with humans, such as cats and dogs, can transmit zoonotic pathogens. Around 12,000 outpatients and 500 inpatients are diagnosed with cat scratch disease, a form of bartonellosis, annually. Ctenocephalides felis transmits Bartonella henselae from cat-to-cat and often cat-to-human through infected flea feces, causing a primary inoculation lesion and lymphadenitis. Of 3011 primary care providers surveyed from 2014 to 2015, 37.2% had treated at least 1 patient with cat scratch disease, yet knowledge gaps remain regarding the proper treatment and preventative measures for the disease.⁷ Current recommendations for the treatment of lymphadenitis caused by B henselae include a 5-day course of oral azithromycin.⁸ The preferred dosing regimen in adults is 500 mg on day 1 and 250 mg on days 2 through 5. Pediatric patients weighing less than 45.5 kg should receive 10 mg/kg on day 1 and 5 mg/kg on days 2 through 5.⁸ Additionally, less than one-third of the primary care providers surveyed from 2014 to 2015 said they would discuss the importance of pet flea control with immunocompromised patients who own cats, despite evidence implicating fleas in disease transmission.⁷ Pet-directed topical therapy with agents such as selamectin prescribed by a qualified veterinarian can prevent transmission of B henselae in cats exposed to fleas infected with the bacteria,⁹ which supports the importance of patient education and flea control, especially in pets owned by immunocompromised patients. Patients who are immunocompromised are at increased risk for persistent or disseminated bartonellosis, including endocarditis, in addition to cat scratch disease. Although arriving at a diagnosis may be difficult, one study found that bartonellosis in 13 renal transplant recipients was best diagnosed using both serology and polymerase chain reaction via DNA extraction of tissue specimens.¹⁰ These findings may enhance diagnostic yield for similar patients when bartonellosis is suspected.

Flea-borne typhus is endemic to Texas and Southern California.^11,12 Evidence suggests that the pathogenic bacteria, Rickettsia typhi and Rickettsia felis, also commonly infect fleas in the Great Plains area.¹³ Opossums carry R felis, and the fleas transmit murine or endemic typhus. A retrospective case series in Texas identified 11 cases of fatal flea-borne typhus from 1985 to 2015.¹¹ More than half of the patients reported contact with animals or fleas prior to the illness. Patients with typhus may present with fever, nausea, vomiting, rash (macular, maculopapular, papular, petechial, or morbilliform), respiratory or neurologic symptoms, thrombocytopenia, and elevated hepatic liver enzymes. Unfortunately, there often is a notable delay in initiation of treatment with the appropriate class of antibiotics—tetracyclines—and such delays can prove fatal.¹¹ The current recommendation for nonpregnant adults is oral doxycycline 100 mg twice daily continued 48 hours after the patient becomes afebrile or for 7 days, whichever therapy duration is longer.¹⁴ Because of the consequences of delayed treatment, it is important for clinicians to consider a diagnosis of vector-borne illness in a febrile patient with other associated gastrointestinal, cutaneous, respiratory, or neurologic symptoms, especially if they have animal or flea exposures. Flea control and exposure awareness remains paramount in preventing and treating this illness.

Yersinia pestis causes the plague, an important re-emerging disease that causes infection through flea bites, inhalation, or ingestion.¹⁵ From 2000 to 2009, 56 cases and 7 deaths in the United States—New Mexico, Arizona, Colorado, California, and Texas—and 21,725 cases and 1612 deaths worldwide were attributed to Y pestis. Most patients present with the bubonic form of the disease, with fever and an enlarging painful femoral or inguinal lymph node due to leg flea bites.¹⁶ Other forms of disease, including septicemic and pneumonic plague, are less common but relevant, as one-third of cases in the United States present with septicemia.^15,17,18 Although molecular diagnosis and immunohistochemistry play important roles, the diagnosis of Y pestis infection often is still accomplished with culture. A 2012 survey of 392 strains from 17 countries demonstrated that Y pestis remained susceptible to the antibiotics currently used to treat the disease, including doxycycline, streptomycin, gentamicin, tetracycline, trimethoprim-sulfamethoxazole, and ciprofloxacin.¹⁹

Human infection with Dipylidium caninum, a dog tapeworm, has been reported after suspected accidental ingestion of cat fleas carrying the parasite.²⁰ Children, who may present with diarrhea or white worms in their feces, are more susceptible to the infection, perhaps due to accidental flea consumption while being licked by the pet.^20,21

Conclusion

Cat fleas may act as a pruritic nuisance for pet owners and even deliver deadly pathogens to immunocompromised patients. Providers can minimize their impact by educating patients on flea prevention and eradication as well as astutely recognizing and treating flea-borne diseases.

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

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

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

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

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]

The measles outbreak in New York City, the largest in the nation this year, has officially ended, Mayor Bill de Blasio and city health officials announced Sept. 3.

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

“Ending the measles outbreak required extensive collaboration with community organizations and Jewish leaders. They helped encourage vaccinations and achieve record immunization levels in parts of Brooklyn,” Mayor de Blasio said in a written statement. “As we head back to school this week, we just remain vigilant. To keep our children and communities safe, I urge all New Yorkers to get vaccinated. It’s the best defense we have.”

A measles outbreak is considered to be over when 42 days, or two incubation periods, have elapsed since the last affected persons in the area were no longer infectious. “That time period has now passed for the people most recently infected with measles and reported,” the city health department said in the statement.

Since the outbreak began in October of last year, 654 individuals were diagnosed with measles in the five boroughs of New York, although 72% occurred in the Williamsburg neighborhood of Brooklyn. Of those 654 cases, there have been 52 hospitalizations and 16 admissions to intensive care, according to the health department. The majority of affected people were under 18 years of age (80%), and most were either unvaccinated (73%) or incompletely vaccinated (7%).

The end of the measles outbreak also brings an end to the public health emergency that was declared on April 9 for parts of Brooklyn, the statement noted.

“Vaccination coverage has increased significantly since the emergency order, which has been supported by community-led efforts. We are grateful to the New Yorkers who shared the truth about vaccines and protected the health of their friends and neighbors through this outbreak,” city health commissioner Dr. Oxiris Barbot said in the statement.

[email protected]