The Journal of Family Practice

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

THE CASE

A 71-year-old woman came to our clinic with a left subconjunctival hemorrhage. She had a history of atrial flutter and had received a liver transplant approximately 10 years ago. The patient reported having a procedure 2 weeks before her visit with us to remove a basal cell carcinoma on her lower left eyelid, but had no recent changes in vision or physical damage to the eye.

In the past year, she had been started on dabigatran 150 mg twice daily after developing symptomatic atrial fibrillation. Our patient had also been receiving tacrolimus 3 mg twice daily since her transplant. Other medications she was taking included hydroxychloroquine 200 mg/d for rheumatoid arthritis, propafenone 225 mg twice daily for atrial fibrillation, valsartan 80 mg/d for hypertension, and ranitidine 150 mg/d for reflux.

Venipuncture coagulation tests showed a partial thromboplastin time (PTT) of 75.1 seconds, a prothrombin time (PT) of 46.1 seconds, and an elevated international normalized ratio (INR) of 4.5 (normal range: 0.8-1.2). Point-of-care INR results were not obtained.

A complete blood count (CBC) was unremarkable with the exception of a low platelet count and high red blood cell distribution width (RDW). Our patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both within normal limits.

Kidney function tests told another story. The patient’s serum creatinine (SCr) and blood urea nitrogen (BUN) levels were elevated (1.54 mg/dL and 29 mg/dL, respectively) and her creatinine clearance (CrCl; 30.2 mL/min) suggested moderate to severe renal dysfunction.

The patient’s CHADS₂ score was calculated as 1, suggesting she had a low-to-moderate risk of stroke.

THE DIAGNOSIS

Our patient had a left subconjunctival hemorrhage and an elevated venipuncture INR. Based on her renal dysfunction, we suspected that her elevated INR was likely due to an excessive dose of dabigatran, as well as an interaction between dabigatran and tacrolimus.

DISCUSSION

Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. An important advantage of dabigatran compared to warfarin is that the fixed-dose regimen does not require routine anticoagulation monitoring. In cases where anticoagulation monitoring is needed, PTT is the preferred method.¹

While PT and INR have generally not been shown to accurately reflect the degree of anticoagulation with dabigatran at therapeutic doses, there have been in vitro reports of elevated INRs with supratherapeutic dabigatran levels.^2,3 At a typical peak therapeutic dabigatran concentration of approximately 184 ng/mL, the INR generally ranged from 1.1 to 1.7.² However, at a dabigatran concentration of 1000 ng/mL, the INR was elevated to 4.5,^2,3 which is the same venipuncture INR recorded in our patient. While there have been published reports of falsely elevated point-of-care INR results compared to corresponding venipuncture INR results in patients taking dabigatran,^4,5 a literature review found only a case of an elevated venipuncture INR in an end-stage renal disease patient receiving hemodialysis.⁶

Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction.

In the case noted above, as well as our patient, an accumulation of dabigatran due to the patient’s renal dysfunction likely resulted in high plasma concentrations and therefore an elevated venipuncture INR. The elimination half-life for dabigatran is approximately 14 hours in patients with normal renal function; in a patient with severe renal impairment, the half-life can be up to 28 hours.⁷ Our patient’s CrCl at the time of presentation was 30.2 mL/min, which indicated moderate to severe renal dysfunction. Based on dabigatran prescribing recommendations, a dose adjustment to 75 mg bid might be appropriate.¹ (Our patient was taking 150 mg bid.)

We do not believe our patient’s elevated INR was due to her liver transplant because there were no clinical signs of liver dysfunction. A more likely contributing factor was a drug interaction with tacrolimus. Dabigatran is a moderate affinity P-glycoprotein (P-gp) substrate and tacrolimus is both a P-gp substrate and inhibitor. While an interaction between tacrolimus and dabigatran has not been studied directly, concurrent use of any P-gp inhibitor and dabigatran is contraindicated in patients with severe renal dysfunction (CrCl: 15-30 mL/min).¹ For these theoretical interactions, the Drug Interaction Probability Scale (DIPS) has been developed.⁸ In our patient’s case, the calculated DIPS score of 5 suggests a probable interaction, likely due to P-gp inhibition. The other medications our patient was taking did not have this interaction and were unlikely to contribute to the elevated INR and subconjunctival hemorrhage.

Our patient was instructed to stop taking dabigatran and return in 3 days for additional lab tests. At her follow-up visit, the lab results were PTT, 34.3 seconds; PT, 11.6 seconds; and venipuncture INR, 1.1. Her CBC was unremarkable and unchanged. Shortly after the follow-up visit, our patient was assessed by her cardiologist. Due to her renal dysfunction, risk of bleeding, and relatively low CHADS₂ score, the cardiologist decided to discontinue dabigatran and start her on aspirin.

THE TAKEAWAY

Dabigatran may cause elevated INR levels in patients with renal dysfunction and/or those taking other medications that could interact with dabigatran. Concurrent use of any P-gp inhibitor (such as tacrolimus) and dabigatran is contraindicated in patients with severe renal dysfunction. Despite the lack of required routine laboratory monitoring, renal function and drug interactions associated with dabigatran therapy should be monitored closely.

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; prockwel@med.umich.edu.

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; prockwel@med.umich.edu.

Vaccines have been proven effective in preventing disease and are one of the most cost-effective and successful public health initiatives of the 20th century. Nevertheless, adult vaccination rates in the United States for vaccine-preventable diseases are low for most routinely recommended vaccines.¹ In 2013 alone, there were an estimated 3700 deaths in the United States (95% of which were adults) from pneumococcal infections—a vaccine-preventable disorder.²

Consider the threat posed by the flu. Annually, most people who die of influenza and its complications are adults, with estimates ranging from a low of 3000 to a high of 49,000 based on Centers for Disease Control and Prevention (CDC) data from the 1976-1977 flu season to the 2006-2007 season.³ Vaccination during the 2013-2014 season resulted in an estimated 7.2 million fewer cases of influenza, 90,000 fewer hospitalizations, and 3.1 million fewer medically attended cases than would have been expected without vaccination.⁴ If vaccination levels had reached the Healthy People 2020 target of 70%, an additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations might have been averted.⁴

How are we doing with other vaccines? Based on the 2013 National Health Interview Survey, the CDC assessed vaccination coverage among adults ages ≥19 years for selected vaccines: pneumococcal vaccine, tetanus toxoid-containing vaccines (tetanus and diphtheria vaccine [Td] or tetanus and diphtheria with acellular pertussis vaccine [Tdap]), and vaccines for hepatitis A, hepatitis B, herpes zoster, and human papillomavirus (HPV). (With the exception of influenza vaccination, which is recommended annually for all adults, other vaccinations are directed at specific populations based on age, health conditions, behavioral risk factors, occupation, or travel conditions.)

Overall, coverage rates for hepatitis A and B, pneumococcal, Td, and human papillomavirus (HPV) for all adults did not improve from 2012 to 2013; rates increased only modestly for Tdap among adults ≥19 years, for herpes zoster among adults ≥60 years, and for HPV among men ages 19 to 26. Furthermore, racial and ethnic gaps in coverage are seen in all vaccines, and these gaps widened since 2012 for Tdap, herpes zoster, and HPV vaccination.¹

Commonly cited barriers to improved vaccine uptake in adults include lack of regular assessment of vaccine status; lack of physician and other health care provider knowledge on current vaccine recommendations; cost; insufficient stocking of some vaccines; financial disincentives for vaccination in the primary care setting; limited use of electronic records, tools, and immunization registries; missed opportunities; and patient hesitancy and vaccine refusal.⁵

Removing barriers to immunization. Several recommendations on ways to improve adult vaccination rates are made by many federal organizations as well as by The Community Preventive Services Task Force (Task Force), an independent, nonfederal, unpaid panel of public health and prevention experts. The Task Force—which makes recommendations based on systematic reviews of the evidence of effectiveness, the applicability of the evidence, economic evaluations, and barriers to implementation of interventions⁶—advocates a 3-pronged approach to improve adult vaccination rates: 1) enhance access to vaccination services; 2) increase community demand for vaccinations; and 3) incorporate physician- or system-based interventions into practice.⁷

Using your state’s immunization information system can help ensure accurate tracking of patients’ immunization status.

The CDC and other groups such as the National Vaccine Advisory Committee (NVAC) recommend that every routine adult office visit include a vaccination needs assessment, recommendation, and offer of vaccination.⁸ Additionally, the Task Force recommends 3 means of enhancing adult access to vaccination services: make home visits, reduce patient costs, and offer vaccination programs in the community.⁷

This article describes a number of simple steps physicians can take to increase the likelihood that adults will get their vaccines and reviews the literature on using new media such as smartphones and other Internet-based tools to improve immunization coverage.⁹

Increasing community demands for vaccinations

Physicians and other healthcare providers can increase community demand for vaccinations by improving their own knowledge on the subject, recommending vaccination to patients, and increasing their community and political involvement to strengthen or change laws to better support immunization uptake.

To increase awareness and education, keep abreast of the Advisory Committee on Immunization Practices (ACIP) recommendations and guidelines, which are updated annually and reported on in this journal’s Practice Alert column. Consider taking advantage of free immunization apps that are available from the CDC (“CDC Vaccine Schedules” http://www.cdc.gov/vaccines/schedules/hcp/schedule-app.html), the Society of Teachers of Family Medicine (STFM; “Shots Immunizations” http://www.immunizationed.org/Shots-Mobile-App), and the American College of Physicians (“ACP Immunization Advisor” http://immunization.acponline.org/app/).

Take steps to put guidelines into practice. Despite wide promulgation, clinical practice guidelines alone have had limited effect on changing physician behavior and improving patient outcomes. Interactive techniques are more effective than guidelines and didactic presentations alone at changing physician care and patient outcomes. Such techniques include audit/feedback (the reporting of an individual clinician’s vaccination rates compared with desired or target rates, for example), academic detailing/outreach, and reminders by way of electronic or other alerts.^10,11

Promote immunization to patients. Physicians are highly influential in determining a patient’s decision to vaccinate, and it is well documented that a strong recommendation about the importance of immunizations makes a difference to patients.^12,13

What you say and how you say it matters. A halfhearted recommendation for vaccination may result in the patient remaining unvaccinated.¹⁴ For example, “If you want, you can get your pneumonia shot today” is much less persuasive than, “I recommend you get your pneumonia vaccine today to prevent a potentially serious disease that affects thousands of adults each year.” Most adults believe that vaccines are important and are likely to get them if recommended by their health care professionals.¹⁵

At the time of a visit, chart reminders—electronic or paper—can keep the need for immunization visible amid competing priorities.

The CDC recommends that physicians encourage patients to make an informed decision about vaccination by sharing critical information highlighting the importance of vaccinations and reminding patients what vaccines protect against while addressing their concerns (www.cdc.gov/vaccines/adultstandards). Free educational materials for patients can be found at www.cdc.gov/vaccines/AdultPatientEd.

Draw on community resources. Laws and policies that require vaccinations as a prerequisite for attending childcare, school, or college increase coverage. Community and faith-based organizations are likely to play an important role in reducing racial and ethnic disparities in adult immunizations because they can deliver education that is culturally sensitive and tailored to specific subpopulations.^16,17 Physicians and other health care providers can get involved with community and faith-based groups and local and federal legislative efforts to improve immunization rates.

Consider implementing these system-based interventions

The following 6 system-based interventions can help improve adult immunization rates:

1. Develop a practice team. The practice team, based on the Patient-Centered Medical Home (PCMH), includes physicians, midlevel providers, nurses, medical assistants, pharmacists, social workers, and other staff. The PCMH team model can facilitate a shift of responsibilities among individuals to better orient the practice toward patients’ health and preventive services.^18,19 While physicians have traditionally held all of the responsibility for patient care, including screening for disease and prevention, shifting the responsibility of vaccine screening to nurses or medical assistants can free up time for longer physician/patient interactions.¹⁸

The creation of a practice champion within the PCMH team—a physician, midlevel provider, or nurse—to oversee quality improvement for vaccine rates and work to generate support and cooperation from coworkers has also been shown to improve vaccination rates.²⁰ The vaccine champion should keep abreast of new vaccine recommendations and relay that information to the practice through regular staff meetings, announcements, and office postings. The champion can also supervise pre-visit planning for immunizations.¹⁹

2. Use electronic immunization information systems (IIS). All states except New Hampshire have an IIS.²¹ Accurate tracking of adult immunizations in a registry provides a complete record and is essential to improving adult immunization rates,²² as does the use of chart notes, computerized alerts, checklists, and other tools that remind health care providers when patients are due for vaccinations.¹⁸ NVAC recommends that all physicians use their state IIS and create a process in their practice to include its use.

3. Incorporate physician feedback. Many health care systems and payers are using benchmarking and incentives to provide physician feedback on vaccination performance.²³ Using achievable benchmarks enhances the effectiveness of physician performance feedback.²⁴ The Task Force conducted a systematic review of the evidence on the effectiveness of health care provider assessment and feedback for increasing coverage rates and found that this strategy remains an effective means to increase vaccination rates.²⁵

4. Use reminders/alerts. Even though you may intend to routinely recommend immunizations, remembering to do so at the time of each visit can be difficult when there are so many other issues to address. Reminders at the time of the visit can help. Some electronic records have reminder prompts, or “best practice alerts” (BPAs), programmed into their systems.²⁶ These BPAs will prompt for needed immunizations whether the patient is being seen for a well, acute, or routine follow-up visit. These reminder/recall activities can be greatly simplified by participation in a population-based IIS.

Practices that don’t have an electronic health record can still improve vaccination rates by conveying the reminder with a brightly colored paper form attached to the front of a patient’s chart during the check-in process. One recent study showed that this approach increased rates of influenza vaccination in an urban practice by 12 percentage points.²⁷

Furthermore, simply reminding patients to vaccinate increases the vaccination rate.²⁸ Patient reminder/recall systems using telephone calls or mailings (phone calls are more effective than mailings) improve both childhood and adult vaccinations in all medical settings. More intensive systems using multiple reminders appear to be more effective than single reminders, and while costly, the benefits of increasing preventive visits/services and vaccine uptake help offset this cost.²⁸

5. Implement standing orders. Standing orders—which allow nurses and other appropriately trained health care personnel to assess immunization status and administer vaccinations according to protocol—help improve immunization rates.²⁹ ACIP advises that standing order programs be used in long-term care facilities under the supervision of a medical director to ensure the administration of recommended vaccinations for adults, and in inpatient and outpatient facilities. Because of the societal burden of influenza and pneumococcal disease, implementation of standing orders programs to improve adult vaccination coverage for these diseases is considered a national public health priority.³⁰

6. Develop an encouraging communication style. Studies show that how one communicates with patients is just as important as what one communicates. Certain communication styles and techniques may be more or less effective when discussing vaccination needs with some patients, especially those with vaccine hesitancy or low confidence in vaccine safety or effectiveness. For example, styles that are “directing” are usually unhelpful in addressing concerns about vaccination. These styles typically use information and persuasion to achieve change and may be perceived as confrontational. This approach can lead to cues being missed, jargon being used, and vaccine safety being overstated.

Styles shown to be helpful are those that elicit patient concerns, ask permission to discuss, acknowledge/listen/empathize, determine readiness to change, inform about benefits and risks, and give appropriate resources. These helpful forms of communication are more of a “May I help you?” style vs a “This is what you should do” style of communication.³¹

Telling a patient that vaccines are safe and, “You are silly not to get yours” is not as effective as saying, “What are your concerns about vaccines? Let’s talk about them.”

Assure patients that recommendations are based on the best interest of their health and on the best available science. Listen to a patient’s concerns and acknowledge them in a nonconfrontational manner, allowing patients to express their concerns and thereby increase their willingness to listen.³² Saying that there is “absolutely no need to worry—vaccines are safe and you are silly not to get yours” is not as effective as saying, “What are your concerns regarding vaccines? Let’s talk about them.”

For the vaccine-hesitant group, building trust is essential through a respectful, nonjudgmental approach that aims to elicit and address specific concerns. For those who refuse vaccines, keep the consultation brief, keep the door open for further discussion, and provide appropriate resources if the patient wants them.³³

Increase use of new media

Mass communication through smartphones and other Internet-based tools such as Facebook and Twitter brings a new dimension to health care, allowing patients and health professionals to communicate about health issues and possibly improve health outcomes.³⁴ The number of people using social media increased by almost 570% worldwide between 2000 and 2012 and surpassed 2.75 billion in 2013.³⁵

Sixty-one percent of adults in the United States look online for health information.³⁶ In a survey conducted in September 2014, the Pew Research Center found that Facebook is the most popular social media site in the United States. Seventy-one percent of online-knowledgeable adults use Facebook, and multiplatform use is on the rise: 52% of adult Internet users now use 2 or more social media sites, a significant increase from 2013, when it stood at 42%. (Other platforms such as Twitter, Instagram, Pinterest, and LinkedIn saw significant increases over the past year in the proportion of online adults who use them).³⁷

One RCT showed that patient access to a personalized Web-based portal increased influenza vaccination rates.

Health information provided by social media can answer medical questions and concerns and enhance health promotion and education.³⁵ A recent review of 98 research studies provided evidence that social media can create a space to share, comment, and discuss health information.³⁴ Compared with traditional communication methods, the widespread availability of social media makes health information more accessible, broadening access to various population groups, regardless of age, education, race, ethnicity, and locale.

New media platforms are proving effective. The first systematic assessment of available evidence on the use of new media to increase vaccine uptake and immunization coverage (a review of 7 randomized controlled trials [RCTs], 5 non-RCTs, 3 cross-sectional studies, one case-control study and 3 operational research studies published between 2000-2013) found that text messaging, accessing immunization campaign Web sites, using patient-held Web-based portals, computerized reminders, and standing orders increased immunization coverage rates.³⁵ However, evidence was insufficient in this regard on the value of social networks, email communication, and smartphone applications.

One RCT showed that having access to a personalized Web-based portal where patients could manage health records as well as interact with both health care providers and other members of the community through social forums and messaging tools increased influenza vaccination rates.³⁵

CORRESPONDENCE
Pamela G. Rockwell, DO, Department of Family Medicine, University of Michigan, 24 Frank Lloyd Wright Drive, P.O. Box 431, Ann Arbor, MI 48106-0795; prockwel@med.umich.edu.

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

CASE › James A, age 68, presents to his family physician (FP) with anorexia, nausea, and vague upper abdominal pain that he’s had for 2 weeks. Mr. A has diabetes and hypertension, both of which are well controlled by medications. He also consumes more than 4 alcoholic beverages daily.

On examination, the FP notes icterus and tenderness in the right hypochondrium. Liver function testing reveals elevated liver enzyme levels: aspartate aminotransferase (AST), 864 IU/L (normal range: 10-40 IU/L); alanine aminotransferase (ALT), 1012 IU/L (normal range: 7-56 IU/L); serum bilirubin, 4.8 mg/dL (normal range: 0.3-1.9 mg/dL); and alkaline phosphatase (ALP), 200 IU/L (normal range: 44-147 IU/L). Mr. A’s coagulation profile is slightly abnormal. He is provisionally diagnosed with acute hepatitis. The FP sends blood samples to the lab to assess for viral markers, and starts symptomatic management.

If Mr. A were your patient, how would you proceed?

In the United States, drug-induced liver injury (DILI) is the most common cause of acute liver failure.^1,2 It can occur due to ingestion of any therapeutic drug, herbal product, or xenobiotic. Further complicating matters is the fact that it has an unpredictable and heterogeneous course, ranging from an asymptomatic rise in liver enzymes to acute liver failure. This article describes the risk factors, common causative agents, tools for early diagnosis, and effective management of DILI.

Two types of risk factors for DILI

Risk factors for DILI can be classified as drug-related (eg, dose, concomitant medications, polypharmacy) or host-related (eg, age, gender, alcohol intake, concomitant infections).^3-5

Drug-related factors. Hundreds of agents can lead to liver injury. In fact, the US National Library of Medicine and the National Institute of Diabetes and Digestive and Kidney Diseases have created LiverTox (http://www.livertox.nih.gov/), an online database that provides detailed information on more than 600 such agents.⁶ Antibiotics are the most common cause of DILI, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, analgesics, antineoplastic drugs, and lipid-lowering agents.²

Among antibiotics, the specific medication most often responsible for DILI varies by geographical region. Amoxicillin/clavulanic acid is the most common causative antibiotic in the United States, whereas anti-tuberculosis agents such as isoniazid, rifampin, and pyrazinamide are the most common causative drugs in developing countries such as India, where the prevalence of tuberculosis is still high.^7,8 Herbal and dietary supplements are emerging as an important cause of DILI.^5,9,10

The use of multiple drugs further increases the risk of developing DILI.¹⁰ Drugs with a recommended daily dose of <50 mg are rarely associated with DILI.¹¹

Host-related factors. Vulnerability to DILI is influenced by a patient’s age and sex.^3,12 Very young and very old patients have an increased risk of developing DILI, and a patient’s age may make him or her particularly susceptible to the effects of certain medications.^3,12,13 For example, children are more susceptible to DILI as a result of taking valproate or aspirin, whereas older patients are more likely to experience DILI brought on by amoxicillin/clavulanic acid.¹³ The pattern of liver injury also varies by age. Younger patients present most commonly with a hepatocellular pattern of injury, whereas older patients mostly present with a cholestatic pattern of liver injury.³

Some studies have found that women have a greater risk of developing DILI than men.¹³ The presence of chronic liver diseases, alcoholism, and nonalcoholic fatty liver disease (NAFLD) increase the risk of developing DILI.¹⁴ Diabetes is an independent risk factor for DILI.³

Clinical presentation of DILI varies widely

Some degree of liver injury may occur in any patient who ingests a drug that is metabolized in the liver. The clinical presentation of a patient with DILI can vary from an asymptomatic rise in liver enzymes to acute liver failure. Unexplained transaminitis should raise the possibility of DILI, especially when the patient has started a new drug in the preceding 3 months. However, in most patients, an asymptomatic rise in liver enzymes is due to hepatic adaptation or tolerance. In such cases, liver enzyme levels tend to normalize even if the patient continues to take the drug in the same dose.¹⁵

Apart from nonspecific symptoms such as anorexia, nausea, and vomiting, a patient with DILI may exhibit right upper quadrant pain, skin rash, or itching. A patient with severe DILI might exhibit jaundice, ascites, or encephalopathy.¹⁵

A stepwise approach to evaluation

DILI is a diagnosis of exclusion.¹⁶ Guidelines from the American College of Gastroenterology (ACG) recommend a stepwise approach to evaluating a patient you suspect may have DILI (TABLE).¹⁶ First, take a detailed history regarding the onset of symptoms, time latency, and use of hepatotoxic and other drugs (dosage and duration of use). Also ask the patient about his or her use of herbal products, dietary supplements, and alcohol. Check the patient’s history for the presence of other liver diseases such as NAFLD.

Next, make sure initial laboratory testing includes liver function tests and an eosinophil count. In order to classify the pattern of liver injury as hepatocellular, cholestatic, or mixed, you’ll need to calculate the patient’s R value (ALGORITHM^16-18). This value is calculated by dividing the patient’s ALT level by the ALP, using the upper limit of the normal range (ULN) as follows: R = (ALT value ÷ ALT ULN) ÷ (ALP value ÷ ALP ULN).¹⁷ A hepatocellular pattern of liver injury is indicated by an R value >5, a cholestatic pattern is an R value <2, and a mixed pattern is suggested by an R value between 2 and 5.¹⁷

Antibiotics are the most common cause of drug-induced liver injury, followed by neuropsychiatric drugs, immunomodulatory agents, antihypertensives, and analgesics.

Quite often, the pattern of liver damage is characteristic of a particular drug or drug class. For example, DILI induced by amoxicillin/clavulanic acid typically will exhibit a cholestatic injury pattern, whereas DILI resulting from a nonsteroidal anti-inflammatory drug typically is associated with a hepatocellular injury pattern.¹⁶

Rule out other causes. Further investigations should be directed at ruling out other possible causes of liver injury. If a patient has a hepatocellular pattern of liver injury, order serological tests to rule out acute viral hepatitis (hepatitis A, B, C, and E). Such patients should also be evaluated for autoimmune hepatitis, Budd-Chiari syndrome, Wilson’s disease, and ischemic hepatitis.¹⁶ In patients with a predominant cholestatic pattern, imaging studies and other serological tests should be ordered to rule out pancreato-biliary diseases.

Once DILI is confirmed, identify offending agent, grade severity

Which medication is responsible for DILI is determined by the physician based on his or her clinical experience and judgment. Guiding points are improvement of liver function tests after stopping the suspected drug (more on that in a bit), exclusion of other possible causes of liver injury, and the results of liver biopsy. (See “Time for a biopsy?”¹⁶)

DILI severity can be graded as mild (1+) to fatal (5+).¹⁹ Mild forms of DILI are associated with increased levels of liver enzymes (AST, ALT, or ALP) without raised serum bilirubin or clinical jaundice, whereas moderately severe DILI is associated with clinical jaundice or hyperbilirubinemia (bilirubin >2 mg/dL).¹⁹ Severe forms of DILI are associated with features of hepatic failure, such as ascites, encephalopathy, and an elevated international normalized ratio (>1.5), in addition to hyperbilirubinemia or jaundice.

CASE › Mr. A’s lab results are negative for viral markers. On further questioning, he reveals that he had recovered from a sore throat 3 weeks earlier, for which he had been prescribed an unknown dose of amoxicillin/clavulanic acid. A review of Mr. A’s drug history finds that he is taking metformin, pioglitazone, telmisartan, and atorvastatin for his chronic conditions. The FP suspects DILI , and refers Mr. A to a liver specialist for further investigation.

For many patients, stopping the offending drug will be sufficient 

The first step in managing DILI is to stop the medication suspected of causing the liver injury.²⁰ Discontinuing the suspected medication may not always be necessary in patients who have only slightly elevated liver enzymes, but should be strongly considered for a patient who has a considerable increase in liver enzymes levels (ie, an AST, ALT, or serum bilirubin level more than 3 times the ULN or an ALP more than 1.5 times the ULN at any time after initiating a new drug).¹⁸ Certain drugs, such as those used to treat tuberculosis, are associated with hepatic adaptation, in which there is spontaneous resolution of the increased liver enzymes level even while the drug is continued in the same dose.

Diabetes is an independent risk factor for drug-induced liver injury.

In patients with mild to moderate DILI, stopping the offending drug typically results in normalization of liver enzyme levels.²⁰ Management of patients with moderate to severe DILI is mainly supportive; however, a patient with acute liver failure will require intensive care support.^21,22 Consider hospital admission for patients who exhibit severe symptoms, such as intractable vomiting or severe dehydration, those who experience bleeding due to coagulation failure, and those who develop hepatic encephalopathy.²¹

When more aggressive steps are needed

N-acetylcysteine (NAC) should be considered for all patients with DILI who present with acute liver failure.^12,23-25 NAC can be administered either orally or intravenously. The following 3 regimens have been well studied for patients with acetaminophen-induced liver injury:²⁶
• Oral 72-hour regimen: Loading dose of 140 mg/kg followed by 70 mg/kg every 4 hours up to 72 hours
• Intravenous 72-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 418.75 mg/kg over 67 hours
• Intravenous 21-hour regimen: Loading infusion of 150 mg/kg over one hour, followed by 50 mg/kg over 4 hours, followed by 100 mg/kg over 16 hours.

Of these regimens, the 72-hour IV regimen has been found to be more effective than the 21-hour regimen for patients with acetaminophen-induced liver toxicity.²⁶ A study of NAC administered as continuous infusion for 72 hours in patients with acute liver failure found that the transplant-free survival rate was 40% for NAC in comparison with 27% for placebo.²⁶

L-carnitine can be used to treat valproate-induced hepatotoxicity. In a case-control study of 92 patients with severe, symptomatic, valproate-induced hepatotoxicity, nearly half of 42 patients treated with L-carnitine survived, but only 10% of 50 patients treated solely with aggressive supportive care survived.²⁷ Greater benefit has been found for IV vs oral L-carnitine.^27,28

Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg, may be helpful for DILI patients with a cholestatic pattern of liver injury.

Other therapies. Steroids have no defined role in management of DILI except in autoimmune-type DILI. Other drugs, such as silymarin and antioxidants, have been used to treat other forms of hepatic toxicities and might be beneficial for patients with DILI.^29,30

Liver transplantation may be necessary to prevent death due to acute liver failure in patients with severe DILI. Various criteria, including Kings College criteria,³¹ can be used to select which patients may best benefit from liver transplantation.

For most patients, hospitalization will not be necessary

Generally, patients with DILI have a good prognosis.^20,30 About 70% of patients with DILI do not require hospitalization, and approximately 90% recover without reaching the threshold of acute liver failure. However, patients with acute liver failure have a poor prognosis; 40% will require liver transplantation.^16,20

A patient with a hepatocellular pattern of liver injury should receive serological tests to rule out acute viral hepatitis.

Traditionally, patients with a cholestatic pattern of liver injury have been considered to have a better prognosis than those with a hepatocellular pattern of liver injury. Patients whose DILI is the result of a hypersensitivity reaction to a drug also have a good prognosis. This may be because features such as skin rash prompt early diagnosis and discontinuation of the offending drugs.⁷

CASE › A liver specialist evaluates Mr. A and concludes that his liver injury was caused by his long-term heavy alcohol consumption and exacerbated by the amoxicillin/clavulanic acid he had recently been prescribed. After 2 days, Mr. A develops drowsiness and is admitted to the hospital for further management. He is managed in the intensive care unit under supervision of a gastroenterologist. A NAC infusion is started at a loading dose of 150 mg/kg to manage acute liver failure. Unfortunately, however, Mr. A succumbs to his illness.

CORRESPONDENCE
Piyush Ranjan, MD, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India 110029; drpiyushaiims@gmail.com.

Patients with undiagnosed and untreated obstructive sleep apnea (OSA) are at increased risk for excessive daytime sleepiness, as well as cardiovascular and cerebrovascular complications. This review describes how best to address the symptoms and complications that make OSA a public health concern. To read the full article, go to Clinician Reviews: http://www.clinicianreviews.com/cecme/cecme-activities/article/obstructive-sleep-apnea-evaluation-management/b511b960cab855040da9165a39ab5eb8.html?tx_ttnews%5BsViewPointer%5D=1.

Patients with undiagnosed and untreated obstructive sleep apnea (OSA) are at increased risk for excessive daytime sleepiness, as well as cardiovascular and cerebrovascular complications. This review describes how best to address the symptoms and complications that make OSA a public health concern. To read the full article, go to Clinician Reviews: http://www.clinicianreviews.com/cecme/cecme-activities/article/obstructive-sleep-apnea-evaluation-management/b511b960cab855040da9165a39ab5eb8.html?tx_ttnews%5BsViewPointer%5D=1.

Patients with undiagnosed and untreated obstructive sleep apnea (OSA) are at increased risk for excessive daytime sleepiness, as well as cardiovascular and cerebrovascular complications. This review describes how best to address the symptoms and complications that make OSA a public health concern. To read the full article, go to Clinician Reviews: http://www.clinicianreviews.com/cecme/cecme-activities/article/obstructive-sleep-apnea-evaluation-management/b511b960cab855040da9165a39ab5eb8.html?tx_ttnews%5BsViewPointer%5D=1.