Robert Oh, MD, MPH, FAAFP

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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[5]:286-287,295).

Penny E, a 48-year-old woman with a history of asthma, presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. PE is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration. It returns at 700 ng/mL. Should you order CT pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2/1000 individuals and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

A diagnostic algorithm that includes the Wells criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insuf­ficient time in busy emergency departments, ad­herence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used, despite an absolute reduction of 11.6% in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients older than 50).⁷

Three items of the original Wells criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPA. Decreasing CTPA would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ A total of 151 patients met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA). Investigators managed the remaining 3465 study patients according to the YEARS algorithm, which calls for obtaining a D-dimer concentration in all patients and assessing for the 3 items in the YEARS clinical decision rule: clinical signs of deep vein thrombosis; hemoptysis; and whether PE was the most likely diagnosis.

PE was considered excluded if a patient had a D-dimer concentration < 1000 ng/mL and no positive YEARS items or if the patient had a D-dimer concentration < 500 ng/mL and 1 or more YEARS items. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells diagnostic algorithm had been implemented.

[polldaddy:10428150]

Continue to: Of the 1743 patients...

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000-ng/mL threshold. Of the 423 who had a D-dimer ≥ 1000 ng/mL, 55 had PE confirmed by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of them had PE confirmed by CTPA.

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%), with 6 patients (0.20%) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43%, which is similar to the 0.34% reported in a previous meta-analysis of the Wells rule algorithm.¹³ Overall, fatal PE occurred in 0.3% of patients in the YEARS cohort vs 0.6% in a meta-analysis of studies using standard algorithms.¹⁴

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells algorithm, for an absolute difference of 13% and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference) when compared with using the Wells rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria do not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of the YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% in CTPA.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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[5]:286-287,295).

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).

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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.

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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.

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

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.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (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 cause of ambulatory care visits, accounting for almost 120 million, or 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 protects against ARTIs, but only 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 of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin 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; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

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-hydroxyvitamin 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 vitamin 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 of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin 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, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification 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.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (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 cause of ambulatory care visits, accounting for almost 120 million, or 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 protects against ARTIs, but only 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 of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin 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; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

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-hydroxyvitamin 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 vitamin 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 of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin 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, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification 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.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (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 cause of ambulatory care visits, accounting for almost 120 million, or 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 protects against ARTIs, but only 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 of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin 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; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

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-hydroxyvitamin 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 vitamin 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 of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin 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, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification 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.