Immunology

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

Q) What is known about the impact of diet on multiple sclerosis? How can I advise my patients with MS?

Multiple sclerosis (MS) is a chronic inflammatory and degenerative central nervous system disease affecting more than 2.5 million people worldwide. Today, if a Google search is performed for “diet and MS,” more than 67 million results are obtained. Many tout specific protocols as beneficial for MS but have no substantial data to support these claims. This can be confusing for patients as well as providers. How should you advise those who ask for advice on dietary modifications to help control symptoms or disease course?

First, it’s important to remember that individuals with MS have a reduced median lifespan (by about seven years), compared to healthy controls. Furthermore, patients with MS commonly have comorbid conditions—such as diabetes, obesity, and ische­mic heart disease—that increase mortality risk.^1,2 Diet and nutrition are significant factors that impact the course of these diseases.

We must also bear in mind that patients with MS experience symptoms that may impede their efforts to prepare meals. In a 2008 study of 123 MS patients (more than 50% of whom were overweight or obese), fatigue was cited as a significant factor that limited cooking and food preparation. Cognitive impairment and depression also may affect dietary intake. Interestingly, the average recorded intake for all food groups was less than that recommended in the Dietary Guidelines for Americans.³

A web-based survey conducted by the German MS Society in 2011 revealed that 42% of the 337 respondents had modified their diet due to MS. These modifications included change in intake of fatty acids; decrease or elimination of meat, sugar, and additives; and introduction of a low-carb or Paleo diet.⁴

Among an international sample of 2,087 MS patients, a significant association was found between a healthy diet and improved quality of life (both physical and mental) and reduced disability. This “healthy consumption” of fruits, vegetables, and dietary fat was also associated with a marginally decreased risk for relapse. Patients who demonstrated increased disease activity were more likely to have poor consumption of fruits, vegetables, and fats and to consume more meat and dairy products.⁵

There has also been research on specific components of dietary intake. Antioxidant-containing foods, for example, may have an anti-inflammatory effect.⁶ Vitamin B₁₂ deficiency plays a role in immunomodulatory effect, as well as formation of the myelin sheath, although its role (and the effect of biotin supplementation) in MS disease progression requires further study.⁷ Also ongoing is research into various calorie-restriction protocols, altering both timing and amount of caloric intake, since some data suggest this strategy reduces leptin, a satiety hormone that increases inflammation and has been shown to promote more aggressive MS in a mouse model.⁸

In the meantime, what can we conclude about diet and MS? A recent review determined that, although there is insufficient data to support one specific diet, there is sufficient evidence to recommend consumption of fish, foods lower in fat, whole grains, vitamin D, and supplemental omega fatty acids.⁵

It is important to discuss diet with our MS patients. In the German survey, 82% of patients felt that diet was important, yet only 10% had asked a provider for nutritional advice.⁴ In another study, patients indicated that food labels were their top source for nutrition information; only 20% sought advice from a nutritionist.³ We need to ask our MS patients if they are following a particular diet and be prepared to discuss potentially beneficial dietary choices with them—and offer referral to a nutritionist to those who require additional direction and support.—SP

Stacey Panasci, MSPAS, PA-C
Springfield Neurology Associates, LLC
Massachusetts

CE/CME No: CR-1709

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand and identify the low- and high-risk human papillomavirus (HPV) types that can lead to benign and malignant manifestations.
• Know the recommended age range and dosing schedule for individuals who can and should receive the vaccination.
• Recognize important barriers to HPV vaccination in the health care setting.
• Understand how to promote HPV vaccination to parents/caregivers and patients.
• Find resources and educational material from national organizations that recommend and support HPV vaccination.

FACULTY
Tyler Cole practices at Coastal Community Health Services in Brunswick, Georgia, and is a clinical instructor in the DNP-APRN program at the Medical University of South Carolina (MUSC). Marie C. Thomas is a registered nurse on a surgical oncology unit at MUSC and will receive her DNP-FNP from MUSC in December 2017. Katlyn Straup practices at Roper St. Francis Healthcare and Southern Care Hospice in Charleston, South Carolina; she is also a clinical associate faculty member in the MUSC College of Nursing. Ashlyn Savage is an Associate Professor of Obstetrics and Gynecology at MUSC College of Nursing and is certified by the American Board of Obstetrics and Gynecology.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through August 31, 2018.

Article begins on next page >>

Although human papillomavirus (HPV) vaccine is a safe and effective means of preventing most HPV-related cancers, HPV vaccination rates lag well behind those of other vaccines recommended for children and adolescents. Understanding the barriers to HPV vaccine acceptance and effective strategies for overcoming them will improve vaccine uptake and completion in adolescents.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States.^1,2 HPV causes approximately 30,700 new cancer cases in the US annually.³ It is the primary cause of cervical cancer, which resulted in more than 4,000 deaths in the US in 2016.⁴ HPV is also associated with some vaginal, vulvar, penile, anal, and oropharyngeal cancers and causes anogenital warts.³

Although HPV vaccines are available to protect against infection with the HPV types that lead to these sequelae, HPV vaccination rates remain low compared with other routinely administered vaccines.⁵ Reasons for these lower rates include vaccine cost, lack of patient and provider education, providers’ failure to recommend, stigmas related to sexual behavior, and misconceptions about the vaccine, such as concerns about harm.⁵ This article discusses these barriers to better educate providers about the HPV vaccine and encourage them to assist in increasing vaccination rates.

EPIDEMIOLOGY

Approximately 79 million Americans are currently infected with HPV, and 14 million new cases are reported each year.² In the US, the prevalence of HPV is highest among sexually active adolescents and young adults, especially those ages 20 to 24.² Of the more than 150 types of HPV that have been identified, 40 infect the genital area. HPV genital infections are mainly spread through sexual intercourse but can also be spread through oral-to-genital contact.²

The genital HPV types are categorized as low-risk and high-risk based on their association with cervical cancer.² High-risk types 16 and 18 are the most troublesome, accounting for 63% of all HPV-associated cancers, with HPV 16 posing the highest risk for cancer.³ High-risk types HPV 31, 33, 45, 52, and 58 account for another 10% of these cancers.³ Low-risk types, such as HPV 6 and 11, can cause low-grade cervical intraepithelial lesions, and HPV 6 and 11 account for more than 90% of genital warts.²

Most HPV infections, whether with high- or low-risk types, do not cause symptoms and resolve spontaneously in about two years.² Persistent high-risk HPV infection is necessary for the development of cervical cancer precursor lesions—and therefore, once the infection has cleared, the risk for cancer ­declines.²

HPV VACCINES

Three HPV vaccines are licensed for use in the US: bivalent (Cervarix), quadrivalent (Gardasil), and 9-valent (Gardasil 9) vaccines (see Table 1).^2,6,7 The bivalent, Cervarix, has recently been removed from the US market due to a decrease in product demand.^6,8

To ensure optimal protection, the vaccines must be administered in a series of scheduled doses over six to 12 months. The Advisory Committee on Immunization Practices (ACIP) recently updated their recommendations to include a two- or three-dose series based on age (see Table 2).⁷

HPV vaccines are recommended for males and females between the ages of 9 and 26 years, but the ACIP and the American College of Obstetricians and Gynecologists (ACOG) strongly promote a targeted age range for vaccination between 11 and 12 years for both genders.^6,7 Earlier vaccination is preferred because clinical data show a more rapid antibody response at a younger age, and because the vaccines are more effective if administered before an individual is exposed to or infected with HPV (ie, before the start of sexual activity).^6,7

LOW VACCINATION RATES

HPV vaccination rates in the US are significantly lower than rates for other regularly administered vaccines; furthermore, they do not meet the Healthy People 2020 national goal of 80% for all vaccines.⁹ Immunization rates for most childhood vaccines range from 80% to 90%, but in 2015 only 28.1% of males and 41.9% of females ages 13 to 17 had completed the entire HPV vaccine series.^9-11

The total HPV vaccination rates for male and female adolescents combined were 56.1% for one dose or more, 45.4% for two or more doses, and 34.9% for all three doses.⁹ In comparison, coverage rates for the meningococcal and Tdap (tetanus, diphtheria, and pertussis) immunizations, also recommended at the same age range as the HPV vaccine, were 81.3% and 86.4%, respectively.⁹

In addition to variation by gender and age, factors such as race, insurance coverage, and socioeconomic status influence vaccination rates.¹¹ For the HPV vaccine specifically, Hispanic, non-Hispanic black, and American Indian/Alaska Native adolescents have higher rates of receiving each of the vaccine doses and higher rates of completing the vaccine series, compared to non-Hispanic white adolescents.⁹ Adolescents with Medicaid insurance and those living below the federal poverty level have better HPV vaccination coverage compared with adolescents with commercial insurance plans or those living at or above the poverty level.^9,11

The HPV vaccine series completion rates in 2015 for males and females ages 13 to 17 living below the poverty level were 31.0% and 44.4%, respectively, compared to 27.4% and 41.3% for those living at or above the poverty level.⁹ One reason for increased rates among those living in lower-income households may be their eligibility for vaccinations at no cost through the Vaccines for Children (VFC) program, a federal program that provides vaccines to children who might otherwise forgo vaccination because of inability to pay.⁹

BARRIERS TO VACCINATION

Impediments that prevent adolescents and young adults from receiving the HPV vaccine exist throughout the vaccination process, with providers, parents, and the medical system itself contributing to low rates. Barriers to vaccination include fear and misconceptions, costs and socioeconomic status, lack of understanding and education, and logistic obstacles to completing the full series.⁵ Understanding these barriers, as well as discussing methods to overcome them, is key to increasing HPV vaccination rates and preventing the spread of this cancer-causing infection.

Health care provider barriers

Even though accredited national institutions and committees such as the CDC, ACIP, and ACOG strongly recommend vaccination based on current evidence, some health care providers still do not recommend the HPV vaccine to parents and patients.^2,6,7,11 Lack of provider recommendation and the resulting lack of parental awareness of the vaccine account for many adolescents not receiving the vaccination.^10,12

Providers do not recommend the vaccine for a number of reasons. Some have limited knowledge or conflicting ideas about the specific disease protection of the HPV vaccine, while others are hesitant to administer the vaccine before the onset of sexual activity, because they feel the suggested age for vaccination (11 to 12 years) is too young.^10,11 Still other providers report difficulty approaching parents who they perceive as having concerns about the vaccine’s association with a sexually transmitted infection or believing that it might promote sexual activity.¹⁰

Some professionals simply claim that they forget to address the HPV vaccine at health visits, or that they propose it as optional and up to the parent’s discretion.^5,10 Many providers do recommend and administer the initial dose of the vaccine, but have difficulties ensuring that patients complete the full multidose series.¹³ Evidence has shown that a strong provider recommen­dation is one of the most important incentives for parents and patients to accept ­vaccination.¹⁴

Parental and caregiver barriers

Lack of knowledge about the HPV vaccine and lack of recommendation from providers are two top reasons parents and caregivers cite for not vaccinating their children.^5,10,14,15 In a national survey, almost all parents whose daughters completed the full vaccination series reported being counseled by their provider on the appropriate age for vaccination and the timeline of the series.¹⁴

Fears and apprehensions about side effects, especially with newer vaccines, can prevent some parents from having their children vaccinated.¹⁵ Although there is some stigma related to the vaccine’s association with the sexually transmitted HPV, this is a much less significant barrier than lack of provider recommendation or knowledge about the vaccine.^5,11

Health care system barriers

Both providers and parents agree that system-level issues such as access, follow-up, and cost are barriers to initiating or completing the vaccination series.^11,13 Many adolescents have few opportunities to receive the vaccine because they do not have a primary care provider.¹¹ For those with access to primary care, visits are often problem-focused and frequently do not include a review of immunization history.¹³ Health care professionals also report challenges with scheduling follow-up visits for the second and third doses to complete the series within the recommended timeframe.¹³

Cost, insurance coverage, and reimbursement pose additional hurdles for both providers and patients, with some providers citing concerns about the cost of stocking the vaccine.¹⁶ Providers, both family practice providers and gynecologists, agree that reimbursement for administering the HPV vaccine in office poses a barrier when recommending the vaccine to patients.¹⁷ Lack of insurance coverage and type of insurance also pose barriers, with Medicaid patients more often completing the full series compared to those with private or no insurance, because Medicaid covers the cost of vaccination for men up to age 19.^9,18 A national survey of males ages 9 to 17 found that the percentage of HPV vaccine initiation was double for those with public insurance compared to those with private insurance.¹⁹ Changes at the system-level, such as participation in the VFC program, in coordination with better provider recommendation should help increase HPV vaccination rates.^9,11

STRATEGIES TO IMPROVE ­VACCINATION RATES

Many strategies for increasing HPV vaccination acceptance, decreasing barriers to access, and improving compliance with vaccine completion have been reported in the literature, with some strategies achieving more success than others. This section discusses interventions and strategies designed to help overcome provider-, parent-, and system-related barriers that have been shown to be effective (see Table 3).

Evidence supports a number of provider-level strategies to increase HPV vaccination rates (see Table 3). An improvement in vaccination acceptance was observed when providers promoted the vaccine as a safe, effective way to prevent cancer, rather than as a means to prevent a sexually transmitted infection.^10,11,20

Some primary care providers found that encouraging the HPV vaccine at the same time as the meningococcal and Tdap vaccinations, which are also recommended at age 11 to 12 years, increased vaccination rates as well.^13,20 Another successful strategy is reviewing vaccination history at every visit, whether the visit is for an acute event or an annual well exam.^10,13,20 These tactics are most useful when providers practice them consistently, which may require them to change or adapt their way of practice.

Provider-based trainings that educate and prepare them to consistently recommend the vaccine have demonstrated success in increasing HPV vaccination uptake.^21,22 The CDC’s Assessment/Feedback/Incentive/eXchange (AFIX) quality improvement program to increase vaccination rates, which includes Web-based or in-­person consults, has been shown to increase HPV vaccination rates.^20-23 The Assessment phase of the AFIX program determines a practice’s current immunization practices and rates, while the Feedback portion provides strategies for increasing vaccination rates.²³ A study by Perkins and colleagues utilized AFIX strategies, specifically for the HPV vaccine, such as focusing provider education on HPV-related cancers and vaccine efficacy, as well as preparing providers to discuss and answer questions through basic motivational interviewing tactics.²⁰

The CDC also offers PowerPoint presentations, flyers, posters, videos, and other informational resources to guide and educate providers, parents, and patients about the HPV vaccine.²⁴ Educational resources, such as pamphlets, flyers, or fact sheets given to parents and patients, have been shown to improve intent to vaccinate as well as awareness of the vaccine.^25-27

Although Fu and colleagues in a systematic review concluded that there was insufficient data to support a specific educational intervention for widespread use, the authors did recommend utilizing educational pieces and adapting them to specific populations.²⁵ These simple interventions help increase awareness and can be implemented with other interventions in health care offices by providers and other staff.

System-level interventions

The use of systems that track patients for necessary vaccines and remind providers, parents, and patients about vaccine appointments have increased vaccination rates.^13,28 Facility-based interventions, such as electronic medical records (EMR) that track patients for scheduled vaccines and remind providers when patients are due for vaccinations, will help increase provider recommendations and completion of the entire vaccination series.¹³

The National Vaccine Advisory Committee (NVAC) suggests that provider offices implement reminder-recall systems and provide educational material for parents and patients to increase vaccination rates.²⁹ One specific study using both educational material and text-message reminders for parents found that these interventions significantly increased vaccination rates.³⁰ Health care facilities could also incorporate reminder letters mailed to patients and parents to promote vaccine initiation and completion.³¹ The evidence supports the use of reminder alerts and EMR tracking systems to increase rates, but more research is warranted to determine the most cost-effective approach.

National programs, committees, and organizations have provided recommendations for overcoming system-related barriers to HPV vaccination, such as access and cost.^29,32 The NVAC recommends incorporating alternative venues for vaccination delivery, such as pharmacies, schools, and health clinics, to increase availability to the adolescent population, especially to those who do not have primary care providers.²⁹ One study that addressed parental opinions of vaccination administration in schools found that the majority of parents were in favor of this type of program.³³ Although these recommendations seem promising and are accepted by parents, logistical barriers such as reimbursement to the pharmacies, schools, and clinics and accurate documentation of the doses received need to be addressed.²⁹ The NVAC recommends continued evaluation and efforts to develop these programs in the future.²⁹

In addition to school-based interventions, providing home visits for vaccination and implementing standing orders are other suggestions to overcome access and cost barriers for vaccinations, including HPV.³² Standing orders allow for individuals to receive a vaccine by a health care professional in an approved institution, where allowed by state law.³² This provides easier access to vaccinations, especially for those who do not see a primary care provider.

Although some of the system-level interventions mentioned in this article are outside the realm of what providers can do in the office, understanding and advocating for these advancements will promote vaccine uptake.

CONCLUSION

Lack of provider recommendation, coupled with poor or no parental knowledge about the HPV vaccine, are significant factors affecting vaccination uptake. Evidence supports the use of multifaceted interventions that promote and support provider recommendation and parent/patient education. Studies of interventions that incorporated educational resources and alert systems for both providers and patients or their caregivers have shown these strategies to be effective in increasing vaccination uptake and completion.

In addition to recommending the HPV vaccine, providers must educate parents/caregivers and patients about it, particularly by presenting the vaccine as a means of cancer prevention. Primary care facilities should implement reminder plans and provide educational literature to promote vaccine uptake. Although the interventions highlighted here have increased HPV vaccination rates, further research is warranted to evaluate more effective strategies for overcoming barriers and to determine which strategies are most cost-effective.

CE/CME No: CR-1709

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand and identify the low- and high-risk human papillomavirus (HPV) types that can lead to benign and malignant manifestations.
• Know the recommended age range and dosing schedule for individuals who can and should receive the vaccination.
• Recognize important barriers to HPV vaccination in the health care setting.
• Understand how to promote HPV vaccination to parents/caregivers and patients.
• Find resources and educational material from national organizations that recommend and support HPV vaccination.

FACULTY
Tyler Cole practices at Coastal Community Health Services in Brunswick, Georgia, and is a clinical instructor in the DNP-APRN program at the Medical University of South Carolina (MUSC). Marie C. Thomas is a registered nurse on a surgical oncology unit at MUSC and will receive her DNP-FNP from MUSC in December 2017. Katlyn Straup practices at Roper St. Francis Healthcare and Southern Care Hospice in Charleston, South Carolina; she is also a clinical associate faculty member in the MUSC College of Nursing. Ashlyn Savage is an Associate Professor of Obstetrics and Gynecology at MUSC College of Nursing and is certified by the American Board of Obstetrics and Gynecology.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through August 31, 2018.

Article begins on next page >>

Although human papillomavirus (HPV) vaccine is a safe and effective means of preventing most HPV-related cancers, HPV vaccination rates lag well behind those of other vaccines recommended for children and adolescents. Understanding the barriers to HPV vaccine acceptance and effective strategies for overcoming them will improve vaccine uptake and completion in adolescents.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States.^1,2 HPV causes approximately 30,700 new cancer cases in the US annually.³ It is the primary cause of cervical cancer, which resulted in more than 4,000 deaths in the US in 2016.⁴ HPV is also associated with some vaginal, vulvar, penile, anal, and oropharyngeal cancers and causes anogenital warts.³

Although HPV vaccines are available to protect against infection with the HPV types that lead to these sequelae, HPV vaccination rates remain low compared with other routinely administered vaccines.⁵ Reasons for these lower rates include vaccine cost, lack of patient and provider education, providers’ failure to recommend, stigmas related to sexual behavior, and misconceptions about the vaccine, such as concerns about harm.⁵ This article discusses these barriers to better educate providers about the HPV vaccine and encourage them to assist in increasing vaccination rates.

EPIDEMIOLOGY

Approximately 79 million Americans are currently infected with HPV, and 14 million new cases are reported each year.² In the US, the prevalence of HPV is highest among sexually active adolescents and young adults, especially those ages 20 to 24.² Of the more than 150 types of HPV that have been identified, 40 infect the genital area. HPV genital infections are mainly spread through sexual intercourse but can also be spread through oral-to-genital contact.²

The genital HPV types are categorized as low-risk and high-risk based on their association with cervical cancer.² High-risk types 16 and 18 are the most troublesome, accounting for 63% of all HPV-associated cancers, with HPV 16 posing the highest risk for cancer.³ High-risk types HPV 31, 33, 45, 52, and 58 account for another 10% of these cancers.³ Low-risk types, such as HPV 6 and 11, can cause low-grade cervical intraepithelial lesions, and HPV 6 and 11 account for more than 90% of genital warts.²

Most HPV infections, whether with high- or low-risk types, do not cause symptoms and resolve spontaneously in about two years.² Persistent high-risk HPV infection is necessary for the development of cervical cancer precursor lesions—and therefore, once the infection has cleared, the risk for cancer ­declines.²

HPV VACCINES

Three HPV vaccines are licensed for use in the US: bivalent (Cervarix), quadrivalent (Gardasil), and 9-valent (Gardasil 9) vaccines (see Table 1).^2,6,7 The bivalent, Cervarix, has recently been removed from the US market due to a decrease in product demand.^6,8

To ensure optimal protection, the vaccines must be administered in a series of scheduled doses over six to 12 months. The Advisory Committee on Immunization Practices (ACIP) recently updated their recommendations to include a two- or three-dose series based on age (see Table 2).⁷

HPV vaccines are recommended for males and females between the ages of 9 and 26 years, but the ACIP and the American College of Obstetricians and Gynecologists (ACOG) strongly promote a targeted age range for vaccination between 11 and 12 years for both genders.^6,7 Earlier vaccination is preferred because clinical data show a more rapid antibody response at a younger age, and because the vaccines are more effective if administered before an individual is exposed to or infected with HPV (ie, before the start of sexual activity).^6,7

LOW VACCINATION RATES

HPV vaccination rates in the US are significantly lower than rates for other regularly administered vaccines; furthermore, they do not meet the Healthy People 2020 national goal of 80% for all vaccines.⁹ Immunization rates for most childhood vaccines range from 80% to 90%, but in 2015 only 28.1% of males and 41.9% of females ages 13 to 17 had completed the entire HPV vaccine series.^9-11

The total HPV vaccination rates for male and female adolescents combined were 56.1% for one dose or more, 45.4% for two or more doses, and 34.9% for all three doses.⁹ In comparison, coverage rates for the meningococcal and Tdap (tetanus, diphtheria, and pertussis) immunizations, also recommended at the same age range as the HPV vaccine, were 81.3% and 86.4%, respectively.⁹

In addition to variation by gender and age, factors such as race, insurance coverage, and socioeconomic status influence vaccination rates.¹¹ For the HPV vaccine specifically, Hispanic, non-Hispanic black, and American Indian/Alaska Native adolescents have higher rates of receiving each of the vaccine doses and higher rates of completing the vaccine series, compared to non-Hispanic white adolescents.⁹ Adolescents with Medicaid insurance and those living below the federal poverty level have better HPV vaccination coverage compared with adolescents with commercial insurance plans or those living at or above the poverty level.^9,11

The HPV vaccine series completion rates in 2015 for males and females ages 13 to 17 living below the poverty level were 31.0% and 44.4%, respectively, compared to 27.4% and 41.3% for those living at or above the poverty level.⁹ One reason for increased rates among those living in lower-income households may be their eligibility for vaccinations at no cost through the Vaccines for Children (VFC) program, a federal program that provides vaccines to children who might otherwise forgo vaccination because of inability to pay.⁹

BARRIERS TO VACCINATION

Impediments that prevent adolescents and young adults from receiving the HPV vaccine exist throughout the vaccination process, with providers, parents, and the medical system itself contributing to low rates. Barriers to vaccination include fear and misconceptions, costs and socioeconomic status, lack of understanding and education, and logistic obstacles to completing the full series.⁵ Understanding these barriers, as well as discussing methods to overcome them, is key to increasing HPV vaccination rates and preventing the spread of this cancer-causing infection.

Health care provider barriers

Even though accredited national institutions and committees such as the CDC, ACIP, and ACOG strongly recommend vaccination based on current evidence, some health care providers still do not recommend the HPV vaccine to parents and patients.^2,6,7,11 Lack of provider recommendation and the resulting lack of parental awareness of the vaccine account for many adolescents not receiving the vaccination.^10,12

Providers do not recommend the vaccine for a number of reasons. Some have limited knowledge or conflicting ideas about the specific disease protection of the HPV vaccine, while others are hesitant to administer the vaccine before the onset of sexual activity, because they feel the suggested age for vaccination (11 to 12 years) is too young.^10,11 Still other providers report difficulty approaching parents who they perceive as having concerns about the vaccine’s association with a sexually transmitted infection or believing that it might promote sexual activity.¹⁰

Some professionals simply claim that they forget to address the HPV vaccine at health visits, or that they propose it as optional and up to the parent’s discretion.^5,10 Many providers do recommend and administer the initial dose of the vaccine, but have difficulties ensuring that patients complete the full multidose series.¹³ Evidence has shown that a strong provider recommen­dation is one of the most important incentives for parents and patients to accept ­vaccination.¹⁴

Parental and caregiver barriers

Lack of knowledge about the HPV vaccine and lack of recommendation from providers are two top reasons parents and caregivers cite for not vaccinating their children.^5,10,14,15 In a national survey, almost all parents whose daughters completed the full vaccination series reported being counseled by their provider on the appropriate age for vaccination and the timeline of the series.¹⁴

Fears and apprehensions about side effects, especially with newer vaccines, can prevent some parents from having their children vaccinated.¹⁵ Although there is some stigma related to the vaccine’s association with the sexually transmitted HPV, this is a much less significant barrier than lack of provider recommendation or knowledge about the vaccine.^5,11

Health care system barriers

Both providers and parents agree that system-level issues such as access, follow-up, and cost are barriers to initiating or completing the vaccination series.^11,13 Many adolescents have few opportunities to receive the vaccine because they do not have a primary care provider.¹¹ For those with access to primary care, visits are often problem-focused and frequently do not include a review of immunization history.¹³ Health care professionals also report challenges with scheduling follow-up visits for the second and third doses to complete the series within the recommended timeframe.¹³

Cost, insurance coverage, and reimbursement pose additional hurdles for both providers and patients, with some providers citing concerns about the cost of stocking the vaccine.¹⁶ Providers, both family practice providers and gynecologists, agree that reimbursement for administering the HPV vaccine in office poses a barrier when recommending the vaccine to patients.¹⁷ Lack of insurance coverage and type of insurance also pose barriers, with Medicaid patients more often completing the full series compared to those with private or no insurance, because Medicaid covers the cost of vaccination for men up to age 19.^9,18 A national survey of males ages 9 to 17 found that the percentage of HPV vaccine initiation was double for those with public insurance compared to those with private insurance.¹⁹ Changes at the system-level, such as participation in the VFC program, in coordination with better provider recommendation should help increase HPV vaccination rates.^9,11

STRATEGIES TO IMPROVE ­VACCINATION RATES

Many strategies for increasing HPV vaccination acceptance, decreasing barriers to access, and improving compliance with vaccine completion have been reported in the literature, with some strategies achieving more success than others. This section discusses interventions and strategies designed to help overcome provider-, parent-, and system-related barriers that have been shown to be effective (see Table 3).

Evidence supports a number of provider-level strategies to increase HPV vaccination rates (see Table 3). An improvement in vaccination acceptance was observed when providers promoted the vaccine as a safe, effective way to prevent cancer, rather than as a means to prevent a sexually transmitted infection.^10,11,20

Some primary care providers found that encouraging the HPV vaccine at the same time as the meningococcal and Tdap vaccinations, which are also recommended at age 11 to 12 years, increased vaccination rates as well.^13,20 Another successful strategy is reviewing vaccination history at every visit, whether the visit is for an acute event or an annual well exam.^10,13,20 These tactics are most useful when providers practice them consistently, which may require them to change or adapt their way of practice.

Provider-based trainings that educate and prepare them to consistently recommend the vaccine have demonstrated success in increasing HPV vaccination uptake.^21,22 The CDC’s Assessment/Feedback/Incentive/eXchange (AFIX) quality improvement program to increase vaccination rates, which includes Web-based or in-­person consults, has been shown to increase HPV vaccination rates.^20-23 The Assessment phase of the AFIX program determines a practice’s current immunization practices and rates, while the Feedback portion provides strategies for increasing vaccination rates.²³ A study by Perkins and colleagues utilized AFIX strategies, specifically for the HPV vaccine, such as focusing provider education on HPV-related cancers and vaccine efficacy, as well as preparing providers to discuss and answer questions through basic motivational interviewing tactics.²⁰

The CDC also offers PowerPoint presentations, flyers, posters, videos, and other informational resources to guide and educate providers, parents, and patients about the HPV vaccine.²⁴ Educational resources, such as pamphlets, flyers, or fact sheets given to parents and patients, have been shown to improve intent to vaccinate as well as awareness of the vaccine.^25-27

Although Fu and colleagues in a systematic review concluded that there was insufficient data to support a specific educational intervention for widespread use, the authors did recommend utilizing educational pieces and adapting them to specific populations.²⁵ These simple interventions help increase awareness and can be implemented with other interventions in health care offices by providers and other staff.

System-level interventions

The use of systems that track patients for necessary vaccines and remind providers, parents, and patients about vaccine appointments have increased vaccination rates.^13,28 Facility-based interventions, such as electronic medical records (EMR) that track patients for scheduled vaccines and remind providers when patients are due for vaccinations, will help increase provider recommendations and completion of the entire vaccination series.¹³

The National Vaccine Advisory Committee (NVAC) suggests that provider offices implement reminder-recall systems and provide educational material for parents and patients to increase vaccination rates.²⁹ One specific study using both educational material and text-message reminders for parents found that these interventions significantly increased vaccination rates.³⁰ Health care facilities could also incorporate reminder letters mailed to patients and parents to promote vaccine initiation and completion.³¹ The evidence supports the use of reminder alerts and EMR tracking systems to increase rates, but more research is warranted to determine the most cost-effective approach.

National programs, committees, and organizations have provided recommendations for overcoming system-related barriers to HPV vaccination, such as access and cost.^29,32 The NVAC recommends incorporating alternative venues for vaccination delivery, such as pharmacies, schools, and health clinics, to increase availability to the adolescent population, especially to those who do not have primary care providers.²⁹ One study that addressed parental opinions of vaccination administration in schools found that the majority of parents were in favor of this type of program.³³ Although these recommendations seem promising and are accepted by parents, logistical barriers such as reimbursement to the pharmacies, schools, and clinics and accurate documentation of the doses received need to be addressed.²⁹ The NVAC recommends continued evaluation and efforts to develop these programs in the future.²⁹

In addition to school-based interventions, providing home visits for vaccination and implementing standing orders are other suggestions to overcome access and cost barriers for vaccinations, including HPV.³² Standing orders allow for individuals to receive a vaccine by a health care professional in an approved institution, where allowed by state law.³² This provides easier access to vaccinations, especially for those who do not see a primary care provider.

Although some of the system-level interventions mentioned in this article are outside the realm of what providers can do in the office, understanding and advocating for these advancements will promote vaccine uptake.

CONCLUSION

Lack of provider recommendation, coupled with poor or no parental knowledge about the HPV vaccine, are significant factors affecting vaccination uptake. Evidence supports the use of multifaceted interventions that promote and support provider recommendation and parent/patient education. Studies of interventions that incorporated educational resources and alert systems for both providers and patients or their caregivers have shown these strategies to be effective in increasing vaccination uptake and completion.

In addition to recommending the HPV vaccine, providers must educate parents/caregivers and patients about it, particularly by presenting the vaccine as a means of cancer prevention. Primary care facilities should implement reminder plans and provide educational literature to promote vaccine uptake. Although the interventions highlighted here have increased HPV vaccination rates, further research is warranted to evaluate more effective strategies for overcoming barriers and to determine which strategies are most cost-effective.

CE/CME No: CR-1709

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Understand and identify the low- and high-risk human papillomavirus (HPV) types that can lead to benign and malignant manifestations.
• Know the recommended age range and dosing schedule for individuals who can and should receive the vaccination.
• Recognize important barriers to HPV vaccination in the health care setting.
• Understand how to promote HPV vaccination to parents/caregivers and patients.
• Find resources and educational material from national organizations that recommend and support HPV vaccination.

FACULTY
Tyler Cole practices at Coastal Community Health Services in Brunswick, Georgia, and is a clinical instructor in the DNP-APRN program at the Medical University of South Carolina (MUSC). Marie C. Thomas is a registered nurse on a surgical oncology unit at MUSC and will receive her DNP-FNP from MUSC in December 2017. Katlyn Straup practices at Roper St. Francis Healthcare and Southern Care Hospice in Charleston, South Carolina; she is also a clinical associate faculty member in the MUSC College of Nursing. Ashlyn Savage is an Associate Professor of Obstetrics and Gynecology at MUSC College of Nursing and is certified by the American Board of Obstetrics and Gynecology.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid through August 31, 2018.

Article begins on next page >>

Although human papillomavirus (HPV) vaccine is a safe and effective means of preventing most HPV-related cancers, HPV vaccination rates lag well behind those of other vaccines recommended for children and adolescents. Understanding the barriers to HPV vaccine acceptance and effective strategies for overcoming them will improve vaccine uptake and completion in adolescents.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States.^1,2 HPV causes approximately 30,700 new cancer cases in the US annually.³ It is the primary cause of cervical cancer, which resulted in more than 4,000 deaths in the US in 2016.⁴ HPV is also associated with some vaginal, vulvar, penile, anal, and oropharyngeal cancers and causes anogenital warts.³

Although HPV vaccines are available to protect against infection with the HPV types that lead to these sequelae, HPV vaccination rates remain low compared with other routinely administered vaccines.⁵ Reasons for these lower rates include vaccine cost, lack of patient and provider education, providers’ failure to recommend, stigmas related to sexual behavior, and misconceptions about the vaccine, such as concerns about harm.⁵ This article discusses these barriers to better educate providers about the HPV vaccine and encourage them to assist in increasing vaccination rates.

EPIDEMIOLOGY

Approximately 79 million Americans are currently infected with HPV, and 14 million new cases are reported each year.² In the US, the prevalence of HPV is highest among sexually active adolescents and young adults, especially those ages 20 to 24.² Of the more than 150 types of HPV that have been identified, 40 infect the genital area. HPV genital infections are mainly spread through sexual intercourse but can also be spread through oral-to-genital contact.²

The genital HPV types are categorized as low-risk and high-risk based on their association with cervical cancer.² High-risk types 16 and 18 are the most troublesome, accounting for 63% of all HPV-associated cancers, with HPV 16 posing the highest risk for cancer.³ High-risk types HPV 31, 33, 45, 52, and 58 account for another 10% of these cancers.³ Low-risk types, such as HPV 6 and 11, can cause low-grade cervical intraepithelial lesions, and HPV 6 and 11 account for more than 90% of genital warts.²

Most HPV infections, whether with high- or low-risk types, do not cause symptoms and resolve spontaneously in about two years.² Persistent high-risk HPV infection is necessary for the development of cervical cancer precursor lesions—and therefore, once the infection has cleared, the risk for cancer ­declines.²

HPV VACCINES

Three HPV vaccines are licensed for use in the US: bivalent (Cervarix), quadrivalent (Gardasil), and 9-valent (Gardasil 9) vaccines (see Table 1).^2,6,7 The bivalent, Cervarix, has recently been removed from the US market due to a decrease in product demand.^6,8

To ensure optimal protection, the vaccines must be administered in a series of scheduled doses over six to 12 months. The Advisory Committee on Immunization Practices (ACIP) recently updated their recommendations to include a two- or three-dose series based on age (see Table 2).⁷

HPV vaccines are recommended for males and females between the ages of 9 and 26 years, but the ACIP and the American College of Obstetricians and Gynecologists (ACOG) strongly promote a targeted age range for vaccination between 11 and 12 years for both genders.^6,7 Earlier vaccination is preferred because clinical data show a more rapid antibody response at a younger age, and because the vaccines are more effective if administered before an individual is exposed to or infected with HPV (ie, before the start of sexual activity).^6,7

LOW VACCINATION RATES

HPV vaccination rates in the US are significantly lower than rates for other regularly administered vaccines; furthermore, they do not meet the Healthy People 2020 national goal of 80% for all vaccines.⁹ Immunization rates for most childhood vaccines range from 80% to 90%, but in 2015 only 28.1% of males and 41.9% of females ages 13 to 17 had completed the entire HPV vaccine series.^9-11

The total HPV vaccination rates for male and female adolescents combined were 56.1% for one dose or more, 45.4% for two or more doses, and 34.9% for all three doses.⁹ In comparison, coverage rates for the meningococcal and Tdap (tetanus, diphtheria, and pertussis) immunizations, also recommended at the same age range as the HPV vaccine, were 81.3% and 86.4%, respectively.⁹

In addition to variation by gender and age, factors such as race, insurance coverage, and socioeconomic status influence vaccination rates.¹¹ For the HPV vaccine specifically, Hispanic, non-Hispanic black, and American Indian/Alaska Native adolescents have higher rates of receiving each of the vaccine doses and higher rates of completing the vaccine series, compared to non-Hispanic white adolescents.⁹ Adolescents with Medicaid insurance and those living below the federal poverty level have better HPV vaccination coverage compared with adolescents with commercial insurance plans or those living at or above the poverty level.^9,11

The HPV vaccine series completion rates in 2015 for males and females ages 13 to 17 living below the poverty level were 31.0% and 44.4%, respectively, compared to 27.4% and 41.3% for those living at or above the poverty level.⁹ One reason for increased rates among those living in lower-income households may be their eligibility for vaccinations at no cost through the Vaccines for Children (VFC) program, a federal program that provides vaccines to children who might otherwise forgo vaccination because of inability to pay.⁹

BARRIERS TO VACCINATION

Impediments that prevent adolescents and young adults from receiving the HPV vaccine exist throughout the vaccination process, with providers, parents, and the medical system itself contributing to low rates. Barriers to vaccination include fear and misconceptions, costs and socioeconomic status, lack of understanding and education, and logistic obstacles to completing the full series.⁵ Understanding these barriers, as well as discussing methods to overcome them, is key to increasing HPV vaccination rates and preventing the spread of this cancer-causing infection.

Health care provider barriers

Even though accredited national institutions and committees such as the CDC, ACIP, and ACOG strongly recommend vaccination based on current evidence, some health care providers still do not recommend the HPV vaccine to parents and patients.^2,6,7,11 Lack of provider recommendation and the resulting lack of parental awareness of the vaccine account for many adolescents not receiving the vaccination.^10,12

Providers do not recommend the vaccine for a number of reasons. Some have limited knowledge or conflicting ideas about the specific disease protection of the HPV vaccine, while others are hesitant to administer the vaccine before the onset of sexual activity, because they feel the suggested age for vaccination (11 to 12 years) is too young.^10,11 Still other providers report difficulty approaching parents who they perceive as having concerns about the vaccine’s association with a sexually transmitted infection or believing that it might promote sexual activity.¹⁰

Some professionals simply claim that they forget to address the HPV vaccine at health visits, or that they propose it as optional and up to the parent’s discretion.^5,10 Many providers do recommend and administer the initial dose of the vaccine, but have difficulties ensuring that patients complete the full multidose series.¹³ Evidence has shown that a strong provider recommen­dation is one of the most important incentives for parents and patients to accept ­vaccination.¹⁴

Parental and caregiver barriers

Lack of knowledge about the HPV vaccine and lack of recommendation from providers are two top reasons parents and caregivers cite for not vaccinating their children.^5,10,14,15 In a national survey, almost all parents whose daughters completed the full vaccination series reported being counseled by their provider on the appropriate age for vaccination and the timeline of the series.¹⁴

Fears and apprehensions about side effects, especially with newer vaccines, can prevent some parents from having their children vaccinated.¹⁵ Although there is some stigma related to the vaccine’s association with the sexually transmitted HPV, this is a much less significant barrier than lack of provider recommendation or knowledge about the vaccine.^5,11

Health care system barriers

Both providers and parents agree that system-level issues such as access, follow-up, and cost are barriers to initiating or completing the vaccination series.^11,13 Many adolescents have few opportunities to receive the vaccine because they do not have a primary care provider.¹¹ For those with access to primary care, visits are often problem-focused and frequently do not include a review of immunization history.¹³ Health care professionals also report challenges with scheduling follow-up visits for the second and third doses to complete the series within the recommended timeframe.¹³

Cost, insurance coverage, and reimbursement pose additional hurdles for both providers and patients, with some providers citing concerns about the cost of stocking the vaccine.¹⁶ Providers, both family practice providers and gynecologists, agree that reimbursement for administering the HPV vaccine in office poses a barrier when recommending the vaccine to patients.¹⁷ Lack of insurance coverage and type of insurance also pose barriers, with Medicaid patients more often completing the full series compared to those with private or no insurance, because Medicaid covers the cost of vaccination for men up to age 19.^9,18 A national survey of males ages 9 to 17 found that the percentage of HPV vaccine initiation was double for those with public insurance compared to those with private insurance.¹⁹ Changes at the system-level, such as participation in the VFC program, in coordination with better provider recommendation should help increase HPV vaccination rates.^9,11

STRATEGIES TO IMPROVE ­VACCINATION RATES

Many strategies for increasing HPV vaccination acceptance, decreasing barriers to access, and improving compliance with vaccine completion have been reported in the literature, with some strategies achieving more success than others. This section discusses interventions and strategies designed to help overcome provider-, parent-, and system-related barriers that have been shown to be effective (see Table 3).

Evidence supports a number of provider-level strategies to increase HPV vaccination rates (see Table 3). An improvement in vaccination acceptance was observed when providers promoted the vaccine as a safe, effective way to prevent cancer, rather than as a means to prevent a sexually transmitted infection.^10,11,20

Some primary care providers found that encouraging the HPV vaccine at the same time as the meningococcal and Tdap vaccinations, which are also recommended at age 11 to 12 years, increased vaccination rates as well.^13,20 Another successful strategy is reviewing vaccination history at every visit, whether the visit is for an acute event or an annual well exam.^10,13,20 These tactics are most useful when providers practice them consistently, which may require them to change or adapt their way of practice.

Provider-based trainings that educate and prepare them to consistently recommend the vaccine have demonstrated success in increasing HPV vaccination uptake.^21,22 The CDC’s Assessment/Feedback/Incentive/eXchange (AFIX) quality improvement program to increase vaccination rates, which includes Web-based or in-­person consults, has been shown to increase HPV vaccination rates.^20-23 The Assessment phase of the AFIX program determines a practice’s current immunization practices and rates, while the Feedback portion provides strategies for increasing vaccination rates.²³ A study by Perkins and colleagues utilized AFIX strategies, specifically for the HPV vaccine, such as focusing provider education on HPV-related cancers and vaccine efficacy, as well as preparing providers to discuss and answer questions through basic motivational interviewing tactics.²⁰

The CDC also offers PowerPoint presentations, flyers, posters, videos, and other informational resources to guide and educate providers, parents, and patients about the HPV vaccine.²⁴ Educational resources, such as pamphlets, flyers, or fact sheets given to parents and patients, have been shown to improve intent to vaccinate as well as awareness of the vaccine.^25-27

Although Fu and colleagues in a systematic review concluded that there was insufficient data to support a specific educational intervention for widespread use, the authors did recommend utilizing educational pieces and adapting them to specific populations.²⁵ These simple interventions help increase awareness and can be implemented with other interventions in health care offices by providers and other staff.

System-level interventions

The use of systems that track patients for necessary vaccines and remind providers, parents, and patients about vaccine appointments have increased vaccination rates.^13,28 Facility-based interventions, such as electronic medical records (EMR) that track patients for scheduled vaccines and remind providers when patients are due for vaccinations, will help increase provider recommendations and completion of the entire vaccination series.¹³

The National Vaccine Advisory Committee (NVAC) suggests that provider offices implement reminder-recall systems and provide educational material for parents and patients to increase vaccination rates.²⁹ One specific study using both educational material and text-message reminders for parents found that these interventions significantly increased vaccination rates.³⁰ Health care facilities could also incorporate reminder letters mailed to patients and parents to promote vaccine initiation and completion.³¹ The evidence supports the use of reminder alerts and EMR tracking systems to increase rates, but more research is warranted to determine the most cost-effective approach.

National programs, committees, and organizations have provided recommendations for overcoming system-related barriers to HPV vaccination, such as access and cost.^29,32 The NVAC recommends incorporating alternative venues for vaccination delivery, such as pharmacies, schools, and health clinics, to increase availability to the adolescent population, especially to those who do not have primary care providers.²⁹ One study that addressed parental opinions of vaccination administration in schools found that the majority of parents were in favor of this type of program.³³ Although these recommendations seem promising and are accepted by parents, logistical barriers such as reimbursement to the pharmacies, schools, and clinics and accurate documentation of the doses received need to be addressed.²⁹ The NVAC recommends continued evaluation and efforts to develop these programs in the future.²⁹

In addition to school-based interventions, providing home visits for vaccination and implementing standing orders are other suggestions to overcome access and cost barriers for vaccinations, including HPV.³² Standing orders allow for individuals to receive a vaccine by a health care professional in an approved institution, where allowed by state law.³² This provides easier access to vaccinations, especially for those who do not see a primary care provider.

Although some of the system-level interventions mentioned in this article are outside the realm of what providers can do in the office, understanding and advocating for these advancements will promote vaccine uptake.

CONCLUSION

Lack of provider recommendation, coupled with poor or no parental knowledge about the HPV vaccine, are significant factors affecting vaccination uptake. Evidence supports the use of multifaceted interventions that promote and support provider recommendation and parent/patient education. Studies of interventions that incorporated educational resources and alert systems for both providers and patients or their caregivers have shown these strategies to be effective in increasing vaccination uptake and completion.

In addition to recommending the HPV vaccine, providers must educate parents/caregivers and patients about it, particularly by presenting the vaccine as a means of cancer prevention. Primary care facilities should implement reminder plans and provide educational literature to promote vaccine uptake. Although the interventions highlighted here have increased HPV vaccination rates, further research is warranted to evaluate more effective strategies for overcoming barriers and to determine which strategies are most cost-effective.

A black 37-year-old man has gradually lost 100 lb (45 kg) over the past 2 years, and reports progressive fatigue and malaise as well. He has not noted swollen lymph nodes, fever, or night sweats. He denies dyspnea, cough, or chest pain. He has no skin rashes, and no dry or red eyes or visual changes. He reports no flank pain, dysuria, frank hematuria, foamy urine, decline in urine output, or difficulty voiding.

He has no history of significant medical conditions. He does not drink, smoke, or use recreational drugs. He is not taking any prescription medications and has not been using nonsteroidal anti-inflammatory drugs (NSAIDs) or combination analgesics. He does not have a family history of kidney disease.

Physical examination. He appears relaxed and comfortable. He does not have nasal polyps or signs of pharyngeal inflammation. He has no apparent lymphadenopathy. His breath sounds are normal without rales or wheezes. Cardiac examination reveals a regular rhythm, with no rub or murmurs. The abdomen is soft and nontender with no flank pain or groin tenderness. The skin is intact with no rash or nodules.

• Temperature 98.4ºF (36.9ºC)
• Blood pressure 125/70 mm Hg
• Heart rate 102 beats per minute
• Respiratory rate 19 per minute
• Oxygen saturation 99% while breathing room air
• Weight 194 lb (88 kg)
• Body mass index 28 kg/m².

Laboratory testing (Table 1) reveals severe renal insufficiency with anemia:

• Serum creatinine 9 mg/dL (reference range 0.5–1.2)
• Estimated glomerular filtration rate (eGFR) 8 mL/min/1.73m² (using the Modification of Diet in Renal Disease Study equation).

His serum calcium level is normal, but his serum phosphorus is 5.3 mg/dL (reference range 2.5–4.6), and his parathyroid hormone level is 317 pg/mL (12–88), consistent with hyperparathyroidism secondary to chronic kidney disease. His 25-hydroxyvitamin D level is less than 13 ng/mL (30–80), and angiotensin-converting enzyme (ACE) is 129 U/L (9–67 U/L). His urinary calcium level is less than 3.0 mg/dL.

Urinalysis:

• Urine protein 100 mg/dL (0–20)
• No urine crystals
• 3 to 5 coarse granular urine casts per high-power field
• No hematuria or pyuria.

Renal ultrasonography shows normal kidneys with no hydronephrosis.

Renal biopsy study demonstrates noncaseating granulomatous interstitial nephritis (Figure 1).

GRANULOMATOUS INTERSTITIAL NEPHRITIS

1. Based on the information above, what is the most likely cause of this patient’s kidney disease?

• Medication
• Granulomatosis with polyangiitis
• Sarcoidosis
• Infection

Granulomatous interstitial nephritis is a histologic diagnosis that is present in up to 1% of renal biopsies. It has been associated with medications, infections, sarcoidosis, crystal deposits, paraproteinemia, and granulomatosis with polyangiitis and also is seen in an idiopathic form.

Medicines implicated include anticonvulsants, antibiotics, NSAIDs, allopurinol, and diuretics.

Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases of renal transplant.¹ Granulomas are usually not found on kidney biopsy in granulomatosis with polyangiitis, and that diagnosis is usually made by the presence of antiproteinase 3 antibodies.²

Sarcoidosis is the most likely diagnosis in this patient after excluding implicated medications, infection, and vasculitis and confirming the presence of granulomatous interstitial nephritis on renal biopsy.

SARCOIDOSIS: A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem inflammatory disease of unknown cause, characterized by noncaseating epithelioid granulomas. It can involve any organ but most commonly the thoracic and peripheral lymph nodes.^3,4 Involvement of the eyes and skin is also relatively common.

Extrapulmonary involvement occurs in more than 30% of cases of sarcoidosis, almost always with concomitant thoracic involvement.^5,6 Isolated extrathoracic sarcoidosis is unusual, found in only 2% of patients in a sarcoidosis case-control study.⁵

Current theory suggests that sarcoidosis develops from a cell-mediated immune response triggered by one or more unidentified antigens in people with a genetic predisposition.⁷

Sarcoidosis affects men and women of all ages, most often adults ages 20 to 40; but more recently, it has increased in US adults over age 55.⁸ The condition is more prevalent in Northern Europe and Japan, and in blacks in the United States.⁷

2. What is the likelihood of finding clinically apparent renal involvement in a patient with sarcoidosis?

• Greater than 70%
• Greater than 50%
• Up to 50%
• Less than 10%

The prevalence of renal involvement in sarcoidosis is hard to determine due to differences in study design and patient populations included in the available reports, and because renal involvement may be silent for many years. Recent studies have reported impaired renal function in 0.7% to 9.7% of cases: eg, a case-control study of 736 patients reported clinically apparent renal involvement in 0.7% of patients,⁵ and in a series of 818 patients, the incidence was 1%.⁹ In earlier studies, depending on the diagnostic criteria, the incidence ranged from 1.1% to 9.7%.¹⁰

The prevalence of renal involvement may also be underestimated because it can be asymp­tomatic, and the number of granulomas may be so few that they are absent in a small biopsy specimen. A higher prevalence of renal involvement in sarcoidosis is reported from autopsy studies, although many cases remained clinically silent. These studies have reported renal noncaseating granulomas in 7% to 23% of sarcoidosis patients.^11–13

PRESENTATION OF RENAL SARCOIDOSIS

3. What is the most common presentation in isolated renal sarcoidosis?

• Sterile pyuria
• Elevated urine eosinophils
• Renal insufficiency
• Painless hematuria

Renal manifestations of sarcoidosis include hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and impaired renal function.¹⁴ Renal involvement can occur during the course of existing sarcoidosis, at the time of first presentation, or even as the sole presentation of the disease.^1,11,15 In patients with isolated renal sarcoidosis, the most common presentation is renal insufficiency.^15,16

Two main pathways for nephron insult that have been validated are granulomatous infiltration of the renal interstitium and disordered calcium homeostasis.^11,17 Though extremely rare, various types of glomerular disease, renal tubular defects, and renal vascular involvement such as renal artery granulomatous angiitis have been documented.¹⁸

Hypercalcemia in sarcoidosis

Sarcoidosis is known to cause hypercalcemia by increasing calcium absorption secondary to 1,25-dihydroxyvitamin D production from granulomas. Our patient’s case is unusual, as renal failure was the sole extrapulmonary manifestation of sarcoidosis without hypercalcemia.

In sarcoidosis, extrarenal production of 1-alpha-hydroxylase by activated macrophages inappropriately increases levels of 1,25-dihydroxyvitamin D (calcitriol). Subsequently, serum calcium levels are increased. Unlike its renal equivalent, granulomatous 1-alpha-hydroxylase evades the normal negative feedback of hypercalcemia, so that increased calcitriol levels are sustained, leading to hypercalcemia, often accompanied by hypercalciuria.¹⁹

Disruption of calcium homeostasis affects renal function through several mechanisms. Hypercalcemia promotes vasoconstriction of the afferent arteriole, leading to a reduction in the GFR. Intracellular calcium overload can contribute to acute tubular necrosis and intratubular precipitation of calcium, leading to tubular obstruction. Hypercalciuria predisposes to nephrolithiasis and obstructive uropathy. Chronic hypercalcemia and hypercalciuria, if untreated, cause progressive interstitial inflammation and deposition of calcium in the kidney parenchyma and tubules, resulting in nephrocalcinosis. In some cases, nephrocalcinosis leads to chronic kidney injury and renal dysfunction.

HISTOLOGIC FEATURES

4. What is the characteristic histologic feature of renal sarcoidosis?

• Membranous glomerulonephritis
• Mesangioproliferative glomerulonephritis
• Minimal change disease
• Granulomatous interstitial nephritis
• Immunoglobulin (Ig) A nephropathy

Granulomatous interstitial nephritis is the most typical histologic feature of renal sarcoidosis.^4,20–22 However, interstitial nephritis without granulomas is found in up to one-third of patients with sarcoid interstitial nephritis.^15,23

Patients with sarcoid granulomatous interstitial nephritis usually present with elevated serum creatinine with or without mild proteinuria (< 1 g/24 hours).^1,15,16 Advanced renal failure (stage 4 or 5 chronic kidney disease) is relatively common at the time of presentation.^1,15,16 In the 2 largest case series of renal sarcoidosis to date, the mean presenting serum creatinine levels were 3.0 and 4.8 mg/dL.^11,15 The most common clinical syndrome associated with sarcoidosis and granulomatous interstitial nephritis is chronic kidney disease with a decline in renal function, which if untreated can occur over weeks to months.²¹ Acute renal failure as an initial presentation is also well documented.^15,24

Even though glomerular involvement in sarcoidosis is rare, different kinds of glomerulonephritis have been reported, including membranous glomerulonephritis, mesangio­proliferative glomerulonephritis, IgA nephropathy, minimal change disease, focal segmental sclerosis, and crescentic glomerulonephritis.²⁵

DIAGNOSIS OF RENAL SARCOIDOSIS

5. How is renal sarcoidosis diagnosed?

• By exclusion
• Complete urine analysis and renal function assessment
• Renal biopsy
• Computed tomography
• Renal ultrasonography

The diagnosis of renal sarcoidosis is one of exclusion. Sarcoidosis must be considered in the differential diagnosis of renal failure of unknown origin, especially if disordered calcium homeostasis is also present. If clinically suspected, diagnosis usually requires pathohistologic demonstration of typical granulomatous lesions in the kidneys or in one or more organ systems.²⁶

In cases of sarcoidosis with granulomatous interstitial nephritis with isolated renal failure as a presenting feature, other causes of granulomatous interstitial nephritis must be ruled out. A number of drug reactions are associated with interstitial nephritis, most commonly with antibiotics, NSAIDs, and diuretics. Although granulomatous interstitial nephritis may develop as a reaction to some drugs, most cases of drug-induced interstitial nephritis do not involve granulomatous interstitial nephritis.

Other causes of granulomatous interstitial infiltrates include granulomatous infection by mycobacteria, fungi, or Brucella; foreign-body reaction such as cholesterol atheroemboli; heroin; lymphoma; or autoimmune disease such as tubulointerstitial nephritis with uveitis syndrome, granulomatosis with polyangiitis, or Crohn disease.^27,28 The absence of characteristic kidney biopsy findings does not exclude the diagnosis because renal sarcoidosis can be focal and easily missed on biopsy.²⁹

Urinary manifestations of renal sarcoidosis are usually not specific. In renal sarcoidosis with interstitial nephritis with or without granulomas, proteinuria is mild or absent, usually less than 1.0 g/day.^11,15,16 Urine studies may show a “bland” sediment (ie, without red or white blood cells) or may show sterile pyuria or microscopic hematuria. In glomerular disease, more overt proteinuria or the presence of red blood cell casts is more typical.

Hypercalciuria, nephrocalcinosis, and nephrolithiasis are nonspecific abnormalities that may be present in patients with sarcoidosis. In this regard, an elevated urine calcium level may support the diagnosis of renal sarcoidosis.

Computed tomography and renal ultrasonography may aid in diagnosis by detecting nephrocalcinosis or nephrolithiasis.

The serum ACE level is elevated in 55% to 60% of patients with sarcoidosis, but it may also be elevated in other granulomatous diseases or in chronic kidney disease from various causes.⁵ Therefore, considering its nonspecificity, the serum ACE level has a limited role in the diagnosis of sarcoidosis.³⁰ Using the ACE level as a marker for disease activity and response to treatment remains controversial because levels do not correlate with disease activity.^5,11

6. Which is a first-line therapy for renal sarcoidosis?

• Corticosteroids
• Azathioprine
• Mycophenolate mofetil
• Infliximab
• Adalimumab

Treatment of impaired calcium homeostasis in sarcoidosis includes hydration; reducing intake of calcium, vitamin D, and oxalate; and limiting sun exposure.^11,31 For more significant hypercalcemia (eg, serum calcium levels > 11 mg/dL) or nephrolithiasis, corticosteroid therapy is the first choice and should be implemented at the first sign of renal involvement. Corticosteroids inhibit the activity of 1-alpha-hydroxylase in macrophages, thereby reducing the production of 1,25-dihydroxyvitamin D.

Chloroquine and hydroxychloroquine have been mentioned in the literature as alternatives to corticosteroids.³² But the effect of these agents is less predictable and is slower than treatment with corticosteroids. Ketoconazole has no effect on granuloma formation but corrects hypercalcemia by inhibiting calcitriol production, and can be used as an adjunct for treating hypercalcemia and hypercalciuria.

Corticosteroids are the mainstay of treatment for renal sarcoidosis, including granulomatous interstitial nephritis and interstitial nephritis without granulomas. Most patients experience significant improvement in renal function. However, full recovery is rare, likely as a result of long-standing disease with some degree of already established irreversible renal injury.¹⁶

Corticosteroid dosage

There is no standard dosing protocol, but patients with impaired renal function due to biopsy-proven renal sarcoidosis should receive prednisone 0.5 to 1 mg/kg/day, depending on the severity of the disease, in a single dose every morning.

The optimal dosing and duration of maintenance therapy are unknown. Based on studies to date, the initial dosing should be maintained for 4 weeks, after which it can be tapered by 5 mg each week down to a maintenance dosage of 5 to 10 mg/day.⁴

Patients with a poor response after 4 weeks tend to have a worse renal outcome and are more susceptible to relapse.¹⁵ Fortunately, relapse often responds to increased corticosteroid doses.^11,15 In the case of relapse, the dose should be increased to the lowest effective dose and continued for 4 weeks, then tapered more gradually.

A total of 24 months of treatment seems necessary to be effective and to prevent relapse.¹⁵ Some authors have proposed a lifelong maintenance dose for patients with frequent relapses, and some propose it for all patients.⁴

Other agents

Tumor necrosis factor (TNF)-blocking agents. Considering the critical role TNF plays in granuloma formation, anti-TNF-alpha agents are useful in steroid-resistant sarcoidosis.³³ A thorough workup is necessary before starting these agents because of the increased risk of serious infection, including reactivation of latent tuberculosis. Of the current TNF-blocking agents, infliximab is most often used in renal sarcoidosis.³⁴ Experience with adalimumab is more limited, though promising results indicate it could be an alternative for patients who do not tolerate infliximab.³⁵

Azathioprine, mycophenolate mofetil, or methotrexate may also be used as a second-line agent if treatment with corticosteroids is not tolerated or does not control the disease. The evidence in support of these agents is limited. In small series, they have allowed sustainable control of renal function while reducing the steroid dose. Currently, these agents are used for patients resistant to corticosteroid therapy, who would otherwise need prolonged high-dose corticosteroid treatment, or who have corticosteroid intolerance; they allow a more effective steroid taper and maintenance of stable renal function.^15,36

The data supporting a standardized treatment of renal sarcoidosis are limited. For steroid intolerance or resistance, cytotoxic drugs and selected anti-TNF-alpha agents, as mentioned above, have shown promise in improving or stabilizing serum creatinine levels. Further exploration is required as to which agent or combination is better at limiting the disease process with fewer adverse effects.

Our patient was initially treated with corticosteroids and was ultimately weaned to a maintenance dose of 5 mg/day. He was followed as an outpatient and was started on mycophenolate mofetil in place of higher steroid doses. His renal function stabilized, but he was lost to follow-up after 2 years.

KEY POINTS

• Sarcoidosis is a multisystem granulomatous disease that most commonly involves the lungs, skin, and reticuloendothelial system.
• Renal involvement in sarcoidosis is likely underestimated due to its often clinically silent nature and the possibility of missing typical granulomatous lesions in a small or less-than-optimal biopsy sample.
• Manifestations of renal sarcoidosis include disrupted calcium homeostasis, nephrocalcinosis, nephrolithiasis, and renal failure.
• Because the clinical and histopathologic manifestations of renal sarcoidosis are nonspecific, the diagnosis is one of exclusion. In patients with renal failure or with hypercalcemia or hypercalciuria of unknown cause, renal sarcoidosis should be included in the differential diagnosis. Patients with chronic sarcoidosis should also be screened for renal impairment.
• Granulomatous interstitial nephritis is the classic histologic finding of renal sarcoidosis. Nonetheless, up to one-third of patients have interstitial nephritis without granulomas.
• Corticosteroids are the mainstay of treatment for renal sarcoidosis. An initial dose of oral prednisone 0.5 to 1 mg/kg/day should be maintained for 4 weeks and then gradually tapered to 5 to 10 mg/day for a total of 24 months. Some patients require lifelong therapy.
• Several immunosuppressive and cytotoxic agents may be used in cases of corticosteroid intolerance or to aid in effective taper of corticosteroids.

A black 37-year-old man has gradually lost 100 lb (45 kg) over the past 2 years, and reports progressive fatigue and malaise as well. He has not noted swollen lymph nodes, fever, or night sweats. He denies dyspnea, cough, or chest pain. He has no skin rashes, and no dry or red eyes or visual changes. He reports no flank pain, dysuria, frank hematuria, foamy urine, decline in urine output, or difficulty voiding.

He has no history of significant medical conditions. He does not drink, smoke, or use recreational drugs. He is not taking any prescription medications and has not been using nonsteroidal anti-inflammatory drugs (NSAIDs) or combination analgesics. He does not have a family history of kidney disease.

Physical examination. He appears relaxed and comfortable. He does not have nasal polyps or signs of pharyngeal inflammation. He has no apparent lymphadenopathy. His breath sounds are normal without rales or wheezes. Cardiac examination reveals a regular rhythm, with no rub or murmurs. The abdomen is soft and nontender with no flank pain or groin tenderness. The skin is intact with no rash or nodules.

• Temperature 98.4ºF (36.9ºC)
• Blood pressure 125/70 mm Hg
• Heart rate 102 beats per minute
• Respiratory rate 19 per minute
• Oxygen saturation 99% while breathing room air
• Weight 194 lb (88 kg)
• Body mass index 28 kg/m².

Laboratory testing (Table 1) reveals severe renal insufficiency with anemia:

• Serum creatinine 9 mg/dL (reference range 0.5–1.2)
• Estimated glomerular filtration rate (eGFR) 8 mL/min/1.73m² (using the Modification of Diet in Renal Disease Study equation).

His serum calcium level is normal, but his serum phosphorus is 5.3 mg/dL (reference range 2.5–4.6), and his parathyroid hormone level is 317 pg/mL (12–88), consistent with hyperparathyroidism secondary to chronic kidney disease. His 25-hydroxyvitamin D level is less than 13 ng/mL (30–80), and angiotensin-converting enzyme (ACE) is 129 U/L (9–67 U/L). His urinary calcium level is less than 3.0 mg/dL.

Urinalysis:

• Urine protein 100 mg/dL (0–20)
• No urine crystals
• 3 to 5 coarse granular urine casts per high-power field
• No hematuria or pyuria.

Renal ultrasonography shows normal kidneys with no hydronephrosis.

Renal biopsy study demonstrates noncaseating granulomatous interstitial nephritis (Figure 1).

GRANULOMATOUS INTERSTITIAL NEPHRITIS

1. Based on the information above, what is the most likely cause of this patient’s kidney disease?

• Medication
• Granulomatosis with polyangiitis
• Sarcoidosis
• Infection

Granulomatous interstitial nephritis is a histologic diagnosis that is present in up to 1% of renal biopsies. It has been associated with medications, infections, sarcoidosis, crystal deposits, paraproteinemia, and granulomatosis with polyangiitis and also is seen in an idiopathic form.

Medicines implicated include anticonvulsants, antibiotics, NSAIDs, allopurinol, and diuretics.

Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases of renal transplant.¹ Granulomas are usually not found on kidney biopsy in granulomatosis with polyangiitis, and that diagnosis is usually made by the presence of antiproteinase 3 antibodies.²

Sarcoidosis is the most likely diagnosis in this patient after excluding implicated medications, infection, and vasculitis and confirming the presence of granulomatous interstitial nephritis on renal biopsy.

SARCOIDOSIS: A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem inflammatory disease of unknown cause, characterized by noncaseating epithelioid granulomas. It can involve any organ but most commonly the thoracic and peripheral lymph nodes.^3,4 Involvement of the eyes and skin is also relatively common.

Extrapulmonary involvement occurs in more than 30% of cases of sarcoidosis, almost always with concomitant thoracic involvement.^5,6 Isolated extrathoracic sarcoidosis is unusual, found in only 2% of patients in a sarcoidosis case-control study.⁵

Current theory suggests that sarcoidosis develops from a cell-mediated immune response triggered by one or more unidentified antigens in people with a genetic predisposition.⁷

Sarcoidosis affects men and women of all ages, most often adults ages 20 to 40; but more recently, it has increased in US adults over age 55.⁸ The condition is more prevalent in Northern Europe and Japan, and in blacks in the United States.⁷

2. What is the likelihood of finding clinically apparent renal involvement in a patient with sarcoidosis?

• Greater than 70%
• Greater than 50%
• Up to 50%
• Less than 10%

The prevalence of renal involvement in sarcoidosis is hard to determine due to differences in study design and patient populations included in the available reports, and because renal involvement may be silent for many years. Recent studies have reported impaired renal function in 0.7% to 9.7% of cases: eg, a case-control study of 736 patients reported clinically apparent renal involvement in 0.7% of patients,⁵ and in a series of 818 patients, the incidence was 1%.⁹ In earlier studies, depending on the diagnostic criteria, the incidence ranged from 1.1% to 9.7%.¹⁰

The prevalence of renal involvement may also be underestimated because it can be asymp­tomatic, and the number of granulomas may be so few that they are absent in a small biopsy specimen. A higher prevalence of renal involvement in sarcoidosis is reported from autopsy studies, although many cases remained clinically silent. These studies have reported renal noncaseating granulomas in 7% to 23% of sarcoidosis patients.^11–13

PRESENTATION OF RENAL SARCOIDOSIS

3. What is the most common presentation in isolated renal sarcoidosis?

• Sterile pyuria
• Elevated urine eosinophils
• Renal insufficiency
• Painless hematuria

Renal manifestations of sarcoidosis include hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and impaired renal function.¹⁴ Renal involvement can occur during the course of existing sarcoidosis, at the time of first presentation, or even as the sole presentation of the disease.^1,11,15 In patients with isolated renal sarcoidosis, the most common presentation is renal insufficiency.^15,16

Two main pathways for nephron insult that have been validated are granulomatous infiltration of the renal interstitium and disordered calcium homeostasis.^11,17 Though extremely rare, various types of glomerular disease, renal tubular defects, and renal vascular involvement such as renal artery granulomatous angiitis have been documented.¹⁸

Hypercalcemia in sarcoidosis

Sarcoidosis is known to cause hypercalcemia by increasing calcium absorption secondary to 1,25-dihydroxyvitamin D production from granulomas. Our patient’s case is unusual, as renal failure was the sole extrapulmonary manifestation of sarcoidosis without hypercalcemia.

In sarcoidosis, extrarenal production of 1-alpha-hydroxylase by activated macrophages inappropriately increases levels of 1,25-dihydroxyvitamin D (calcitriol). Subsequently, serum calcium levels are increased. Unlike its renal equivalent, granulomatous 1-alpha-hydroxylase evades the normal negative feedback of hypercalcemia, so that increased calcitriol levels are sustained, leading to hypercalcemia, often accompanied by hypercalciuria.¹⁹

Disruption of calcium homeostasis affects renal function through several mechanisms. Hypercalcemia promotes vasoconstriction of the afferent arteriole, leading to a reduction in the GFR. Intracellular calcium overload can contribute to acute tubular necrosis and intratubular precipitation of calcium, leading to tubular obstruction. Hypercalciuria predisposes to nephrolithiasis and obstructive uropathy. Chronic hypercalcemia and hypercalciuria, if untreated, cause progressive interstitial inflammation and deposition of calcium in the kidney parenchyma and tubules, resulting in nephrocalcinosis. In some cases, nephrocalcinosis leads to chronic kidney injury and renal dysfunction.

HISTOLOGIC FEATURES

4. What is the characteristic histologic feature of renal sarcoidosis?

• Membranous glomerulonephritis
• Mesangioproliferative glomerulonephritis
• Minimal change disease
• Granulomatous interstitial nephritis
• Immunoglobulin (Ig) A nephropathy

Granulomatous interstitial nephritis is the most typical histologic feature of renal sarcoidosis.^4,20–22 However, interstitial nephritis without granulomas is found in up to one-third of patients with sarcoid interstitial nephritis.^15,23

Patients with sarcoid granulomatous interstitial nephritis usually present with elevated serum creatinine with or without mild proteinuria (< 1 g/24 hours).^1,15,16 Advanced renal failure (stage 4 or 5 chronic kidney disease) is relatively common at the time of presentation.^1,15,16 In the 2 largest case series of renal sarcoidosis to date, the mean presenting serum creatinine levels were 3.0 and 4.8 mg/dL.^11,15 The most common clinical syndrome associated with sarcoidosis and granulomatous interstitial nephritis is chronic kidney disease with a decline in renal function, which if untreated can occur over weeks to months.²¹ Acute renal failure as an initial presentation is also well documented.^15,24

Even though glomerular involvement in sarcoidosis is rare, different kinds of glomerulonephritis have been reported, including membranous glomerulonephritis, mesangio­proliferative glomerulonephritis, IgA nephropathy, minimal change disease, focal segmental sclerosis, and crescentic glomerulonephritis.²⁵

DIAGNOSIS OF RENAL SARCOIDOSIS

5. How is renal sarcoidosis diagnosed?

• By exclusion
• Complete urine analysis and renal function assessment
• Renal biopsy
• Computed tomography
• Renal ultrasonography

The diagnosis of renal sarcoidosis is one of exclusion. Sarcoidosis must be considered in the differential diagnosis of renal failure of unknown origin, especially if disordered calcium homeostasis is also present. If clinically suspected, diagnosis usually requires pathohistologic demonstration of typical granulomatous lesions in the kidneys or in one or more organ systems.²⁶

In cases of sarcoidosis with granulomatous interstitial nephritis with isolated renal failure as a presenting feature, other causes of granulomatous interstitial nephritis must be ruled out. A number of drug reactions are associated with interstitial nephritis, most commonly with antibiotics, NSAIDs, and diuretics. Although granulomatous interstitial nephritis may develop as a reaction to some drugs, most cases of drug-induced interstitial nephritis do not involve granulomatous interstitial nephritis.

Other causes of granulomatous interstitial infiltrates include granulomatous infection by mycobacteria, fungi, or Brucella; foreign-body reaction such as cholesterol atheroemboli; heroin; lymphoma; or autoimmune disease such as tubulointerstitial nephritis with uveitis syndrome, granulomatosis with polyangiitis, or Crohn disease.^27,28 The absence of characteristic kidney biopsy findings does not exclude the diagnosis because renal sarcoidosis can be focal and easily missed on biopsy.²⁹

Urinary manifestations of renal sarcoidosis are usually not specific. In renal sarcoidosis with interstitial nephritis with or without granulomas, proteinuria is mild or absent, usually less than 1.0 g/day.^11,15,16 Urine studies may show a “bland” sediment (ie, without red or white blood cells) or may show sterile pyuria or microscopic hematuria. In glomerular disease, more overt proteinuria or the presence of red blood cell casts is more typical.

Hypercalciuria, nephrocalcinosis, and nephrolithiasis are nonspecific abnormalities that may be present in patients with sarcoidosis. In this regard, an elevated urine calcium level may support the diagnosis of renal sarcoidosis.

Computed tomography and renal ultrasonography may aid in diagnosis by detecting nephrocalcinosis or nephrolithiasis.

The serum ACE level is elevated in 55% to 60% of patients with sarcoidosis, but it may also be elevated in other granulomatous diseases or in chronic kidney disease from various causes.⁵ Therefore, considering its nonspecificity, the serum ACE level has a limited role in the diagnosis of sarcoidosis.³⁰ Using the ACE level as a marker for disease activity and response to treatment remains controversial because levels do not correlate with disease activity.^5,11

6. Which is a first-line therapy for renal sarcoidosis?

• Corticosteroids
• Azathioprine
• Mycophenolate mofetil
• Infliximab
• Adalimumab

Treatment of impaired calcium homeostasis in sarcoidosis includes hydration; reducing intake of calcium, vitamin D, and oxalate; and limiting sun exposure.^11,31 For more significant hypercalcemia (eg, serum calcium levels > 11 mg/dL) or nephrolithiasis, corticosteroid therapy is the first choice and should be implemented at the first sign of renal involvement. Corticosteroids inhibit the activity of 1-alpha-hydroxylase in macrophages, thereby reducing the production of 1,25-dihydroxyvitamin D.

Chloroquine and hydroxychloroquine have been mentioned in the literature as alternatives to corticosteroids.³² But the effect of these agents is less predictable and is slower than treatment with corticosteroids. Ketoconazole has no effect on granuloma formation but corrects hypercalcemia by inhibiting calcitriol production, and can be used as an adjunct for treating hypercalcemia and hypercalciuria.

Corticosteroids are the mainstay of treatment for renal sarcoidosis, including granulomatous interstitial nephritis and interstitial nephritis without granulomas. Most patients experience significant improvement in renal function. However, full recovery is rare, likely as a result of long-standing disease with some degree of already established irreversible renal injury.¹⁶

Corticosteroid dosage

There is no standard dosing protocol, but patients with impaired renal function due to biopsy-proven renal sarcoidosis should receive prednisone 0.5 to 1 mg/kg/day, depending on the severity of the disease, in a single dose every morning.

The optimal dosing and duration of maintenance therapy are unknown. Based on studies to date, the initial dosing should be maintained for 4 weeks, after which it can be tapered by 5 mg each week down to a maintenance dosage of 5 to 10 mg/day.⁴

Patients with a poor response after 4 weeks tend to have a worse renal outcome and are more susceptible to relapse.¹⁵ Fortunately, relapse often responds to increased corticosteroid doses.^11,15 In the case of relapse, the dose should be increased to the lowest effective dose and continued for 4 weeks, then tapered more gradually.

A total of 24 months of treatment seems necessary to be effective and to prevent relapse.¹⁵ Some authors have proposed a lifelong maintenance dose for patients with frequent relapses, and some propose it for all patients.⁴

Other agents

Tumor necrosis factor (TNF)-blocking agents. Considering the critical role TNF plays in granuloma formation, anti-TNF-alpha agents are useful in steroid-resistant sarcoidosis.³³ A thorough workup is necessary before starting these agents because of the increased risk of serious infection, including reactivation of latent tuberculosis. Of the current TNF-blocking agents, infliximab is most often used in renal sarcoidosis.³⁴ Experience with adalimumab is more limited, though promising results indicate it could be an alternative for patients who do not tolerate infliximab.³⁵

Azathioprine, mycophenolate mofetil, or methotrexate may also be used as a second-line agent if treatment with corticosteroids is not tolerated or does not control the disease. The evidence in support of these agents is limited. In small series, they have allowed sustainable control of renal function while reducing the steroid dose. Currently, these agents are used for patients resistant to corticosteroid therapy, who would otherwise need prolonged high-dose corticosteroid treatment, or who have corticosteroid intolerance; they allow a more effective steroid taper and maintenance of stable renal function.^15,36

The data supporting a standardized treatment of renal sarcoidosis are limited. For steroid intolerance or resistance, cytotoxic drugs and selected anti-TNF-alpha agents, as mentioned above, have shown promise in improving or stabilizing serum creatinine levels. Further exploration is required as to which agent or combination is better at limiting the disease process with fewer adverse effects.

Our patient was initially treated with corticosteroids and was ultimately weaned to a maintenance dose of 5 mg/day. He was followed as an outpatient and was started on mycophenolate mofetil in place of higher steroid doses. His renal function stabilized, but he was lost to follow-up after 2 years.

KEY POINTS

• Sarcoidosis is a multisystem granulomatous disease that most commonly involves the lungs, skin, and reticuloendothelial system.
• Renal involvement in sarcoidosis is likely underestimated due to its often clinically silent nature and the possibility of missing typical granulomatous lesions in a small or less-than-optimal biopsy sample.
• Manifestations of renal sarcoidosis include disrupted calcium homeostasis, nephrocalcinosis, nephrolithiasis, and renal failure.
• Because the clinical and histopathologic manifestations of renal sarcoidosis are nonspecific, the diagnosis is one of exclusion. In patients with renal failure or with hypercalcemia or hypercalciuria of unknown cause, renal sarcoidosis should be included in the differential diagnosis. Patients with chronic sarcoidosis should also be screened for renal impairment.
• Granulomatous interstitial nephritis is the classic histologic finding of renal sarcoidosis. Nonetheless, up to one-third of patients have interstitial nephritis without granulomas.
• Corticosteroids are the mainstay of treatment for renal sarcoidosis. An initial dose of oral prednisone 0.5 to 1 mg/kg/day should be maintained for 4 weeks and then gradually tapered to 5 to 10 mg/day for a total of 24 months. Some patients require lifelong therapy.
• Several immunosuppressive and cytotoxic agents may be used in cases of corticosteroid intolerance or to aid in effective taper of corticosteroids.

A black 37-year-old man has gradually lost 100 lb (45 kg) over the past 2 years, and reports progressive fatigue and malaise as well. He has not noted swollen lymph nodes, fever, or night sweats. He denies dyspnea, cough, or chest pain. He has no skin rashes, and no dry or red eyes or visual changes. He reports no flank pain, dysuria, frank hematuria, foamy urine, decline in urine output, or difficulty voiding.

He has no history of significant medical conditions. He does not drink, smoke, or use recreational drugs. He is not taking any prescription medications and has not been using nonsteroidal anti-inflammatory drugs (NSAIDs) or combination analgesics. He does not have a family history of kidney disease.

Physical examination. He appears relaxed and comfortable. He does not have nasal polyps or signs of pharyngeal inflammation. He has no apparent lymphadenopathy. His breath sounds are normal without rales or wheezes. Cardiac examination reveals a regular rhythm, with no rub or murmurs. The abdomen is soft and nontender with no flank pain or groin tenderness. The skin is intact with no rash or nodules.

• Temperature 98.4ºF (36.9ºC)
• Blood pressure 125/70 mm Hg
• Heart rate 102 beats per minute
• Respiratory rate 19 per minute
• Oxygen saturation 99% while breathing room air
• Weight 194 lb (88 kg)
• Body mass index 28 kg/m².

Laboratory testing (Table 1) reveals severe renal insufficiency with anemia:

• Serum creatinine 9 mg/dL (reference range 0.5–1.2)
• Estimated glomerular filtration rate (eGFR) 8 mL/min/1.73m² (using the Modification of Diet in Renal Disease Study equation).

His serum calcium level is normal, but his serum phosphorus is 5.3 mg/dL (reference range 2.5–4.6), and his parathyroid hormone level is 317 pg/mL (12–88), consistent with hyperparathyroidism secondary to chronic kidney disease. His 25-hydroxyvitamin D level is less than 13 ng/mL (30–80), and angiotensin-converting enzyme (ACE) is 129 U/L (9–67 U/L). His urinary calcium level is less than 3.0 mg/dL.

Urinalysis:

• Urine protein 100 mg/dL (0–20)
• No urine crystals
• 3 to 5 coarse granular urine casts per high-power field
• No hematuria or pyuria.

Renal ultrasonography shows normal kidneys with no hydronephrosis.

Renal biopsy study demonstrates noncaseating granulomatous interstitial nephritis (Figure 1).

GRANULOMATOUS INTERSTITIAL NEPHRITIS

1. Based on the information above, what is the most likely cause of this patient’s kidney disease?

• Medication
• Granulomatosis with polyangiitis
• Sarcoidosis
• Infection

Granulomatous interstitial nephritis is a histologic diagnosis that is present in up to 1% of renal biopsies. It has been associated with medications, infections, sarcoidosis, crystal deposits, paraproteinemia, and granulomatosis with polyangiitis and also is seen in an idiopathic form.

Medicines implicated include anticonvulsants, antibiotics, NSAIDs, allopurinol, and diuretics.

Mycobacteria and fungi are the main infective causes and seem to be the main causative factor in cases of renal transplant.¹ Granulomas are usually not found on kidney biopsy in granulomatosis with polyangiitis, and that diagnosis is usually made by the presence of antiproteinase 3 antibodies.²

Sarcoidosis is the most likely diagnosis in this patient after excluding implicated medications, infection, and vasculitis and confirming the presence of granulomatous interstitial nephritis on renal biopsy.

SARCOIDOSIS: A MULTISYSTEM DISEASE

Sarcoidosis is a multisystem inflammatory disease of unknown cause, characterized by noncaseating epithelioid granulomas. It can involve any organ but most commonly the thoracic and peripheral lymph nodes.^3,4 Involvement of the eyes and skin is also relatively common.

Extrapulmonary involvement occurs in more than 30% of cases of sarcoidosis, almost always with concomitant thoracic involvement.^5,6 Isolated extrathoracic sarcoidosis is unusual, found in only 2% of patients in a sarcoidosis case-control study.⁵

Current theory suggests that sarcoidosis develops from a cell-mediated immune response triggered by one or more unidentified antigens in people with a genetic predisposition.⁷

Sarcoidosis affects men and women of all ages, most often adults ages 20 to 40; but more recently, it has increased in US adults over age 55.⁸ The condition is more prevalent in Northern Europe and Japan, and in blacks in the United States.⁷

2. What is the likelihood of finding clinically apparent renal involvement in a patient with sarcoidosis?

• Greater than 70%
• Greater than 50%
• Up to 50%
• Less than 10%

The prevalence of renal involvement in sarcoidosis is hard to determine due to differences in study design and patient populations included in the available reports, and because renal involvement may be silent for many years. Recent studies have reported impaired renal function in 0.7% to 9.7% of cases: eg, a case-control study of 736 patients reported clinically apparent renal involvement in 0.7% of patients,⁵ and in a series of 818 patients, the incidence was 1%.⁹ In earlier studies, depending on the diagnostic criteria, the incidence ranged from 1.1% to 9.7%.¹⁰

The prevalence of renal involvement may also be underestimated because it can be asymp­tomatic, and the number of granulomas may be so few that they are absent in a small biopsy specimen. A higher prevalence of renal involvement in sarcoidosis is reported from autopsy studies, although many cases remained clinically silent. These studies have reported renal noncaseating granulomas in 7% to 23% of sarcoidosis patients.^11–13

PRESENTATION OF RENAL SARCOIDOSIS

3. What is the most common presentation in isolated renal sarcoidosis?

• Sterile pyuria
• Elevated urine eosinophils
• Renal insufficiency
• Painless hematuria

Renal manifestations of sarcoidosis include hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and impaired renal function.¹⁴ Renal involvement can occur during the course of existing sarcoidosis, at the time of first presentation, or even as the sole presentation of the disease.^1,11,15 In patients with isolated renal sarcoidosis, the most common presentation is renal insufficiency.^15,16

Two main pathways for nephron insult that have been validated are granulomatous infiltration of the renal interstitium and disordered calcium homeostasis.^11,17 Though extremely rare, various types of glomerular disease, renal tubular defects, and renal vascular involvement such as renal artery granulomatous angiitis have been documented.¹⁸

Hypercalcemia in sarcoidosis

Sarcoidosis is known to cause hypercalcemia by increasing calcium absorption secondary to 1,25-dihydroxyvitamin D production from granulomas. Our patient’s case is unusual, as renal failure was the sole extrapulmonary manifestation of sarcoidosis without hypercalcemia.

In sarcoidosis, extrarenal production of 1-alpha-hydroxylase by activated macrophages inappropriately increases levels of 1,25-dihydroxyvitamin D (calcitriol). Subsequently, serum calcium levels are increased. Unlike its renal equivalent, granulomatous 1-alpha-hydroxylase evades the normal negative feedback of hypercalcemia, so that increased calcitriol levels are sustained, leading to hypercalcemia, often accompanied by hypercalciuria.¹⁹

Disruption of calcium homeostasis affects renal function through several mechanisms. Hypercalcemia promotes vasoconstriction of the afferent arteriole, leading to a reduction in the GFR. Intracellular calcium overload can contribute to acute tubular necrosis and intratubular precipitation of calcium, leading to tubular obstruction. Hypercalciuria predisposes to nephrolithiasis and obstructive uropathy. Chronic hypercalcemia and hypercalciuria, if untreated, cause progressive interstitial inflammation and deposition of calcium in the kidney parenchyma and tubules, resulting in nephrocalcinosis. In some cases, nephrocalcinosis leads to chronic kidney injury and renal dysfunction.

HISTOLOGIC FEATURES

4. What is the characteristic histologic feature of renal sarcoidosis?

• Membranous glomerulonephritis
• Mesangioproliferative glomerulonephritis
• Minimal change disease
• Granulomatous interstitial nephritis
• Immunoglobulin (Ig) A nephropathy

Granulomatous interstitial nephritis is the most typical histologic feature of renal sarcoidosis.^4,20–22 However, interstitial nephritis without granulomas is found in up to one-third of patients with sarcoid interstitial nephritis.^15,23

Patients with sarcoid granulomatous interstitial nephritis usually present with elevated serum creatinine with or without mild proteinuria (< 1 g/24 hours).^1,15,16 Advanced renal failure (stage 4 or 5 chronic kidney disease) is relatively common at the time of presentation.^1,15,16 In the 2 largest case series of renal sarcoidosis to date, the mean presenting serum creatinine levels were 3.0 and 4.8 mg/dL.^11,15 The most common clinical syndrome associated with sarcoidosis and granulomatous interstitial nephritis is chronic kidney disease with a decline in renal function, which if untreated can occur over weeks to months.²¹ Acute renal failure as an initial presentation is also well documented.^15,24

Even though glomerular involvement in sarcoidosis is rare, different kinds of glomerulonephritis have been reported, including membranous glomerulonephritis, mesangio­proliferative glomerulonephritis, IgA nephropathy, minimal change disease, focal segmental sclerosis, and crescentic glomerulonephritis.²⁵

DIAGNOSIS OF RENAL SARCOIDOSIS

5. How is renal sarcoidosis diagnosed?

• By exclusion
• Complete urine analysis and renal function assessment
• Renal biopsy
• Computed tomography
• Renal ultrasonography

The diagnosis of renal sarcoidosis is one of exclusion. Sarcoidosis must be considered in the differential diagnosis of renal failure of unknown origin, especially if disordered calcium homeostasis is also present. If clinically suspected, diagnosis usually requires pathohistologic demonstration of typical granulomatous lesions in the kidneys or in one or more organ systems.²⁶

In cases of sarcoidosis with granulomatous interstitial nephritis with isolated renal failure as a presenting feature, other causes of granulomatous interstitial nephritis must be ruled out. A number of drug reactions are associated with interstitial nephritis, most commonly with antibiotics, NSAIDs, and diuretics. Although granulomatous interstitial nephritis may develop as a reaction to some drugs, most cases of drug-induced interstitial nephritis do not involve granulomatous interstitial nephritis.

Other causes of granulomatous interstitial infiltrates include granulomatous infection by mycobacteria, fungi, or Brucella; foreign-body reaction such as cholesterol atheroemboli; heroin; lymphoma; or autoimmune disease such as tubulointerstitial nephritis with uveitis syndrome, granulomatosis with polyangiitis, or Crohn disease.^27,28 The absence of characteristic kidney biopsy findings does not exclude the diagnosis because renal sarcoidosis can be focal and easily missed on biopsy.²⁹

Urinary manifestations of renal sarcoidosis are usually not specific. In renal sarcoidosis with interstitial nephritis with or without granulomas, proteinuria is mild or absent, usually less than 1.0 g/day.^11,15,16 Urine studies may show a “bland” sediment (ie, without red or white blood cells) or may show sterile pyuria or microscopic hematuria. In glomerular disease, more overt proteinuria or the presence of red blood cell casts is more typical.

Hypercalciuria, nephrocalcinosis, and nephrolithiasis are nonspecific abnormalities that may be present in patients with sarcoidosis. In this regard, an elevated urine calcium level may support the diagnosis of renal sarcoidosis.

Computed tomography and renal ultrasonography may aid in diagnosis by detecting nephrocalcinosis or nephrolithiasis.

The serum ACE level is elevated in 55% to 60% of patients with sarcoidosis, but it may also be elevated in other granulomatous diseases or in chronic kidney disease from various causes.⁵ Therefore, considering its nonspecificity, the serum ACE level has a limited role in the diagnosis of sarcoidosis.³⁰ Using the ACE level as a marker for disease activity and response to treatment remains controversial because levels do not correlate with disease activity.^5,11

6. Which is a first-line therapy for renal sarcoidosis?

• Corticosteroids
• Azathioprine
• Mycophenolate mofetil
• Infliximab
• Adalimumab

Treatment of impaired calcium homeostasis in sarcoidosis includes hydration; reducing intake of calcium, vitamin D, and oxalate; and limiting sun exposure.^11,31 For more significant hypercalcemia (eg, serum calcium levels > 11 mg/dL) or nephrolithiasis, corticosteroid therapy is the first choice and should be implemented at the first sign of renal involvement. Corticosteroids inhibit the activity of 1-alpha-hydroxylase in macrophages, thereby reducing the production of 1,25-dihydroxyvitamin D.

Chloroquine and hydroxychloroquine have been mentioned in the literature as alternatives to corticosteroids.³² But the effect of these agents is less predictable and is slower than treatment with corticosteroids. Ketoconazole has no effect on granuloma formation but corrects hypercalcemia by inhibiting calcitriol production, and can be used as an adjunct for treating hypercalcemia and hypercalciuria.

Corticosteroids are the mainstay of treatment for renal sarcoidosis, including granulomatous interstitial nephritis and interstitial nephritis without granulomas. Most patients experience significant improvement in renal function. However, full recovery is rare, likely as a result of long-standing disease with some degree of already established irreversible renal injury.¹⁶

Corticosteroid dosage

There is no standard dosing protocol, but patients with impaired renal function due to biopsy-proven renal sarcoidosis should receive prednisone 0.5 to 1 mg/kg/day, depending on the severity of the disease, in a single dose every morning.

The optimal dosing and duration of maintenance therapy are unknown. Based on studies to date, the initial dosing should be maintained for 4 weeks, after which it can be tapered by 5 mg each week down to a maintenance dosage of 5 to 10 mg/day.⁴

Patients with a poor response after 4 weeks tend to have a worse renal outcome and are more susceptible to relapse.¹⁵ Fortunately, relapse often responds to increased corticosteroid doses.^11,15 In the case of relapse, the dose should be increased to the lowest effective dose and continued for 4 weeks, then tapered more gradually.

A total of 24 months of treatment seems necessary to be effective and to prevent relapse.¹⁵ Some authors have proposed a lifelong maintenance dose for patients with frequent relapses, and some propose it for all patients.⁴

Other agents

Tumor necrosis factor (TNF)-blocking agents. Considering the critical role TNF plays in granuloma formation, anti-TNF-alpha agents are useful in steroid-resistant sarcoidosis.³³ A thorough workup is necessary before starting these agents because of the increased risk of serious infection, including reactivation of latent tuberculosis. Of the current TNF-blocking agents, infliximab is most often used in renal sarcoidosis.³⁴ Experience with adalimumab is more limited, though promising results indicate it could be an alternative for patients who do not tolerate infliximab.³⁵

Azathioprine, mycophenolate mofetil, or methotrexate may also be used as a second-line agent if treatment with corticosteroids is not tolerated or does not control the disease. The evidence in support of these agents is limited. In small series, they have allowed sustainable control of renal function while reducing the steroid dose. Currently, these agents are used for patients resistant to corticosteroid therapy, who would otherwise need prolonged high-dose corticosteroid treatment, or who have corticosteroid intolerance; they allow a more effective steroid taper and maintenance of stable renal function.^15,36

The data supporting a standardized treatment of renal sarcoidosis are limited. For steroid intolerance or resistance, cytotoxic drugs and selected anti-TNF-alpha agents, as mentioned above, have shown promise in improving or stabilizing serum creatinine levels. Further exploration is required as to which agent or combination is better at limiting the disease process with fewer adverse effects.

Our patient was initially treated with corticosteroids and was ultimately weaned to a maintenance dose of 5 mg/day. He was followed as an outpatient and was started on mycophenolate mofetil in place of higher steroid doses. His renal function stabilized, but he was lost to follow-up after 2 years.

KEY POINTS

• Sarcoidosis is a multisystem granulomatous disease that most commonly involves the lungs, skin, and reticuloendothelial system.
• Renal involvement in sarcoidosis is likely underestimated due to its often clinically silent nature and the possibility of missing typical granulomatous lesions in a small or less-than-optimal biopsy sample.
• Manifestations of renal sarcoidosis include disrupted calcium homeostasis, nephrocalcinosis, nephrolithiasis, and renal failure.
• Because the clinical and histopathologic manifestations of renal sarcoidosis are nonspecific, the diagnosis is one of exclusion. In patients with renal failure or with hypercalcemia or hypercalciuria of unknown cause, renal sarcoidosis should be included in the differential diagnosis. Patients with chronic sarcoidosis should also be screened for renal impairment.
• Granulomatous interstitial nephritis is the classic histologic finding of renal sarcoidosis. Nonetheless, up to one-third of patients have interstitial nephritis without granulomas.
• Corticosteroids are the mainstay of treatment for renal sarcoidosis. An initial dose of oral prednisone 0.5 to 1 mg/kg/day should be maintained for 4 weeks and then gradually tapered to 5 to 10 mg/day for a total of 24 months. Some patients require lifelong therapy.
• Several immunosuppressive and cytotoxic agents may be used in cases of corticosteroid intolerance or to aid in effective taper of corticosteroids.

Children are not receiving optimal antibiotics because of misdiagnosed penicillin allergies, according to David Vyles, DO, and his associates at the Medical College of Wisconsin, Milwaukee.

Because there is no process to safely and rapidly diagnose true penicillin allergy in a critical care setting, pediatric providers are reluctant to prescribe penicillin to children with a reported allergy. In this study, a three-tier penicillin testing process was used to evaluate the accuracy of a parent-reported penicillin allergy questionnaire in identifying children likely to be at low risk for penicillin allergy in an ED setting.

Fuse/thinkstockphotos.com

[email protected]

Children are not receiving optimal antibiotics because of misdiagnosed penicillin allergies, according to David Vyles, DO, and his associates at the Medical College of Wisconsin, Milwaukee.

Because there is no process to safely and rapidly diagnose true penicillin allergy in a critical care setting, pediatric providers are reluctant to prescribe penicillin to children with a reported allergy. In this study, a three-tier penicillin testing process was used to evaluate the accuracy of a parent-reported penicillin allergy questionnaire in identifying children likely to be at low risk for penicillin allergy in an ED setting.

Fuse/thinkstockphotos.com

[email protected]

Children are not receiving optimal antibiotics because of misdiagnosed penicillin allergies, according to David Vyles, DO, and his associates at the Medical College of Wisconsin, Milwaukee.

Because there is no process to safely and rapidly diagnose true penicillin allergy in a critical care setting, pediatric providers are reluctant to prescribe penicillin to children with a reported allergy. In this study, a three-tier penicillin testing process was used to evaluate the accuracy of a parent-reported penicillin allergy questionnaire in identifying children likely to be at low risk for penicillin allergy in an ED setting.

Fuse/thinkstockphotos.com

[email protected]

MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.

These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.

MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.

These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.

MADRID – Rheumatologists all over the world are beginning to find that the new class of anticancer immune checkpoint inhibitor therapies have the potential to elicit symptoms of rheumatoid arthritis (RA) and other rheumatic diseases in patients with no previous history of them, and two reports from the European Congress of Rheumatology provide typical examples.

These immune checkpoint inhibitor (ICI) agents, which include ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda), target regulatory pathways in T cells to boost antitumor immune responses, leading to improved survival for many cancer patients, but the induction of rheumatic disease can sometimes lead to the suspension of the agents, according to investigators.

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

IN THIS ARTICLE

• Diagnosis
• Treatment/management
• Physcial signs suggestive of CVID in patients with appropriate history
• Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹ Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷ About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

PATIENT EDUCATION

Scrupulous hand hygiene, careful avoidance of infectious exposures, watchful food handling and preparation, and lifestyle choices that support good general health are key elements of self-care for patients who have CVID. Preventive measures serve this population well by helping to reduce some of the complications of this serious disease.

Patients with CVID should understand keys aspects regarding its diagnosis, treatment, and prognosis. Specifically, they should know that people who have CVID are born missing some of the body’s immune defenses, which increases their risk for infection, especially of the sinuses, lungs, and gut. Sometimes it takes years to make this diagnosis, because it is a rare cause of common symptoms.

The patient was referred to immunology, and a diagnosis of CVID was made. She was successfully treated with subcutaneous IgG replacement therapy. She died due to overwhelming sepsis after an episode of pneumonia at age 84.

CONCLUSION

The secret to prompt detection of CVID is adding it to the differential diagnosis of recurrent infections. Timely recognition and appropriate referral prevent serious complications, since successful treatment options are available.

Special thanks to Doug Bartelt, DNP, APNP, NP-C.

Coadministration of meningococcal serogroup B (4CMenB) and serogroup C (MenC CRM) vaccines in infants was noninferior to administration of MenC CRM alone against MenC, and it demonstrated adequate immune response to MenB, according to Marco Aurelio P. Safadi, MD, of Santa Casa de São Paulo (Brazil) School of Medical Sciences, and his associates.

Of 117 healthy infants who received 4CMenB concomitantly with MenC CRM and 111 who received MenC CRM alone, 99%-100% of infants had serum bactericidal antibody assay using human complement (hSBA) titres 1:8 or greater against MenC after the second vaccination of the primary series (3 months, 5 months, and 12 months of age), and 100% of infants reached these titres after the booster vaccination.

Courtesy CDC

Steve Mann/Thinkstock

Coadministration of meningococcal serogroup B (4CMenB) and serogroup C (MenC CRM) vaccines in infants was noninferior to administration of MenC CRM alone against MenC, and it demonstrated adequate immune response to MenB, according to Marco Aurelio P. Safadi, MD, of Santa Casa de São Paulo (Brazil) School of Medical Sciences, and his associates.

Of 117 healthy infants who received 4CMenB concomitantly with MenC CRM and 111 who received MenC CRM alone, 99%-100% of infants had serum bactericidal antibody assay using human complement (hSBA) titres 1:8 or greater against MenC after the second vaccination of the primary series (3 months, 5 months, and 12 months of age), and 100% of infants reached these titres after the booster vaccination.

Courtesy CDC

Steve Mann/Thinkstock

Coadministration of meningococcal serogroup B (4CMenB) and serogroup C (MenC CRM) vaccines in infants was noninferior to administration of MenC CRM alone against MenC, and it demonstrated adequate immune response to MenB, according to Marco Aurelio P. Safadi, MD, of Santa Casa de São Paulo (Brazil) School of Medical Sciences, and his associates.

Of 117 healthy infants who received 4CMenB concomitantly with MenC CRM and 111 who received MenC CRM alone, 99%-100% of infants had serum bactericidal antibody assay using human complement (hSBA) titres 1:8 or greater against MenC after the second vaccination of the primary series (3 months, 5 months, and 12 months of age), and 100% of infants reached these titres after the booster vaccination.

Courtesy CDC

Steve Mann/Thinkstock

Increased levels of the human leukocyte antigen-A*31:01 allele appear to be associated with lamotrigine-induced severe cutaneous adverse reactions (SCAR) in Korean patients , reported Byung-Keun Kim, MD, of Seoul National University and associates.

In a study of 18 Korean patients with lamotrigine-induced SCAR, a control group of Korean lamotrigine-tolerant patients, and a control group of the general Korean population, the frequency of the HLA-A*31:01 allele was significantly higher in the lamotrigine-induced SCAR patients than in the lamotrigine-tolerant patients (odds ratio, 11.43; P = .0037) or the other control group (OR, 7.27; P = .00034).

High levels of the HLA-A*31:01 allele also have been reported in Korean patients with carbamazepine-induced SCAR, suggesting an association with the HLA allele and drug-induced SCAR that is specific to ethnicity.

That idea is supported by reports that the HLA-B*15:02 allele is a well-known risk allele of carbamazepine-induced SCAR in Han Chinese and Southeast Asians and that other HLA alleles have been significantly associated with SCAR only with patients of European ancestry or only with patients of Mestizo Mexican ancestry, Dr. Kim and associates said.

The SCAR in this study were Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic syndrome, also known as DRESS.

Read more in the Annals of Allergy, Asthma & Immunology (2017 May;118[5]:629-30).

[email protected]

Increased levels of the human leukocyte antigen-A*31:01 allele appear to be associated with lamotrigine-induced severe cutaneous adverse reactions (SCAR) in Korean patients , reported Byung-Keun Kim, MD, of Seoul National University and associates.

In a study of 18 Korean patients with lamotrigine-induced SCAR, a control group of Korean lamotrigine-tolerant patients, and a control group of the general Korean population, the frequency of the HLA-A*31:01 allele was significantly higher in the lamotrigine-induced SCAR patients than in the lamotrigine-tolerant patients (odds ratio, 11.43; P = .0037) or the other control group (OR, 7.27; P = .00034).

High levels of the HLA-A*31:01 allele also have been reported in Korean patients with carbamazepine-induced SCAR, suggesting an association with the HLA allele and drug-induced SCAR that is specific to ethnicity.

That idea is supported by reports that the HLA-B*15:02 allele is a well-known risk allele of carbamazepine-induced SCAR in Han Chinese and Southeast Asians and that other HLA alleles have been significantly associated with SCAR only with patients of European ancestry or only with patients of Mestizo Mexican ancestry, Dr. Kim and associates said.

The SCAR in this study were Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic syndrome, also known as DRESS.

Read more in the Annals of Allergy, Asthma & Immunology (2017 May;118[5]:629-30).

[email protected]

Increased levels of the human leukocyte antigen-A*31:01 allele appear to be associated with lamotrigine-induced severe cutaneous adverse reactions (SCAR) in Korean patients , reported Byung-Keun Kim, MD, of Seoul National University and associates.

In a study of 18 Korean patients with lamotrigine-induced SCAR, a control group of Korean lamotrigine-tolerant patients, and a control group of the general Korean population, the frequency of the HLA-A*31:01 allele was significantly higher in the lamotrigine-induced SCAR patients than in the lamotrigine-tolerant patients (odds ratio, 11.43; P = .0037) or the other control group (OR, 7.27; P = .00034).

High levels of the HLA-A*31:01 allele also have been reported in Korean patients with carbamazepine-induced SCAR, suggesting an association with the HLA allele and drug-induced SCAR that is specific to ethnicity.

That idea is supported by reports that the HLA-B*15:02 allele is a well-known risk allele of carbamazepine-induced SCAR in Han Chinese and Southeast Asians and that other HLA alleles have been significantly associated with SCAR only with patients of European ancestry or only with patients of Mestizo Mexican ancestry, Dr. Kim and associates said.

The SCAR in this study were Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic syndrome, also known as DRESS.

Read more in the Annals of Allergy, Asthma & Immunology (2017 May;118[5]:629-30).

[email protected]

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

[email protected]

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

[email protected]

Aluminum hydroxide–adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) were noninferior to standard inactivated poliovirus vaccine (IPV) in a large trial in the Dominican Republic, said Luis Rivera, MD, of the Hospital Maternidad Nuestra Señora de la Altagracia, Santo Domingo, Dominican Republic, and his associates.

If these findings are replicated in phase III trials and regulatory approval follows, such vaccines could be low-cost replacements for standard IPV and oral poliovirus vaccines in low-resource countries, the study authors suggested.

designer491/Thinkstock

[email protected]

Adalimumab (ADA) as a first-line anti–tumor necrosis factor therapy induced and maintained clinical remission in children with Crohn’s disease, said Víctor Manuel Navas-López, MD, PhD, of the Hospital Materno Infantil, Málaga, Spain, and his associates.

Infliximab is the usual first-line anti–tumor necrosis factor treatment given to children with Crohn’s disease, with ADA used in patients who don’t respond or who develop tolerance to infliximab.

Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

[email protected]

Adalimumab (ADA) as a first-line anti–tumor necrosis factor therapy induced and maintained clinical remission in children with Crohn’s disease, said Víctor Manuel Navas-López, MD, PhD, of the Hospital Materno Infantil, Málaga, Spain, and his associates.

Infliximab is the usual first-line anti–tumor necrosis factor treatment given to children with Crohn’s disease, with ADA used in patients who don’t respond or who develop tolerance to infliximab.

Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

[email protected]

Adalimumab (ADA) as a first-line anti–tumor necrosis factor therapy induced and maintained clinical remission in children with Crohn’s disease, said Víctor Manuel Navas-López, MD, PhD, of the Hospital Materno Infantil, Málaga, Spain, and his associates.

Infliximab is the usual first-line anti–tumor necrosis factor treatment given to children with Crohn’s disease, with ADA used in patients who don’t respond or who develop tolerance to infliximab.

Nephron/Wikimedia Commons/CC BY-SA 3.0/No changes

[email protected]