Under a fee-for-service payment model, health care providers get paid by private and public payers for patient services such as physician visits, hospital stays, procedures, and tests. In an ideal world, providers would receive accurate, complete, and timely reimbursements. Unfortunately, the reality is far from ideal, where payment denials and delays are a common occurrence.

According to one study, out of $3 trillion in total claims submitted by health care organizations, an estimated 9% of charges ($262 billion), were initially denied.¹ The good news is that 90% of all denials are preventable, and two-thirds of those preventable denials can be successfully appealed.²

Hospitalists are essential in preventing denials for hospital services and should be familiar with the basics of health care reimbursement and common reasons for denials. In this article we will provide an overview of the U.S. health care payment system, revenue cycle management and types of denials, and focus on the role of physician advisors and hospitalists in preventing and combating denials.
 

Overview of the U.S. health care payment system

In 2018 alone, the U.S. spent $3.6 trillion on health care. Of those dollars, 33% went to payments for hospital care and 20% went to physician and clinical services.³ So where do the nation’s health care dollars come from?

The United States has a complex multiple-payer system that includes private insurance companies and public payers funded by the federal and state governments, such as Medicare and Medicaid. Per the National Association of Insurance Commissioners’ 2018 Market Share Reports, there are 125 private accident and health insurance companies in the U.S., with the top five – UnitedHealth, Kaiser, Anthem, Humana, and CVS – holding a cumulative market share of almost 40%.⁴

Medicare accounts for 15% of federal budget spending and provides insurance coverage to almost 60 million people who are 65 and older, have end-stage renal disease, or have been approved for Social Security disability insurance benefits.⁵ Medicare Part A covers hospital, skilled nursing facility, home health, and hospice care. For example, for inpatient stays, Medicare Part A pays hospitals a predetermined rate per discharge according to the Medicare Severity Diagnosis Related Groups (MS-DRGs), which are based on the principal and secondary diagnoses, and performed procedures.⁶

Medicare Part B covers physician services and outpatient services and supplies, including labs and durable medical equipment, which are paid based on submitted Healthcare Common Procedure Coding System (HCPCS) codes.⁷ It is important to know that hospital observation stays are considered outpatient services, and are paid by Medicare Part B. Outpatient stays often are reimbursed at a lower rate than inpatient admissions, even in cases with similar utilization of hospital resources.

Medicaid is jointly funded by the states and the federal government and offers insurance coverage to more than 75 million eligible low-income adults, children, pregnant women, elderly adults, and people with disabilities. Over 10 million people are dually eligible for both Medicare and Medicaid.⁵ Increasingly, government payers, both state and federal, are contracting with private insurance companies to deliver Medicare and Medicaid services, also known as Medicare Advantage and Managed Medicaid Plans.

According to the U.S. Department of Treasury, in the 2019 fiscal year (October 2018 to September 2019), 33% of the nation’s health care dollars came from private insurance, 21% from Medicare, 16% from Medicaid, 15% from other government programs (for example, Veteran Affairs), 10% from out-of-pocket, and 4% from other private sources.⁵

Understanding revenue cycle management and denials

Providers, such as physicians or hospitals, submit claims to insurance companies that include, among other information, patient demographics and insurance, diagnoses, MS-DRGs and/or HCPCS codes, and charges. Revenue cycle management’s goal is to receive accurate, complete, and timely reimbursement for provided patient services, which is a complex and resource-intensive process.

According to the Healthcare Financial Management Association (HFMA), revenue cycle management includes “all administrative and clinical functions that contribute to the capture, management, and collection of patient service revenue.” These functions could be broken down into four main categories:

• Claims preparation (for example, patient registration, insurance eligibility, benefit verifications, and preauthorization).
• Claims submission (for example, charge capture, medical coding based on medical record documentation and claims transmission).
• Claims management (for example, payment posting, denial management, and patient collections).
• Reporting and analysis.

Claim denial is “the refusal of an insurance company or carrier to honor a request by an individual (or his or her provider) to pay for health care services obtained from a health care professional.”⁸ Payers can deny an entire claim or provide only a partial payment. Initial denial rate is tracked at the claim level (number of claims denied/number of claims submitted) and at the dollar level (total dollar amount of claims denied/total dollar amount of claims submitted).

Denials are classified as hard versus soft, and clinical versus technical or administrative:

• Hard denials result in lost revenue unless successfully appealed (for example, lack of medical necessity).
• Soft denials do not require appeal and may be paid if a provider corrects the claim or submits additional information (for example, missing or inaccurate patient information, and missing medical records).
• Clinical denials are based on medical necessity, including level of care determination (for example, inpatient versus outpatient) and length of stay. They can be concurrent and retrospective and typically start as soft denials.
• Technical or administrative denials are based on reasons other than clinical (for example, failure to preauthorize care or lack of benefits).

According to the Advisory Board’s 2017 survey of hospitals and health care systems, 50% of initial denials were technical/demographic errors, 20% medical necessity, 16% eligibility, and 14% authorization. Forty seven percent of those denials came from commercial payers, 33% from Medicare/Medicare Advantage, 17% from Medicaid, and 3% from other payers.⁹

Determination of medical necessity may vary by payer. As an example, let’s look at inpatient admissions. According to the Medicare Two-Midnight Rule, inpatient admission is appropriate “if the admitting practitioner expects the beneficiary to require medically necessary hospital care spanning two or more midnights, and such reasonable expectation is supported by the medical record documentation.”¹⁰

Medicare guidelines acknowledge that a physician’s decision to admit a patient is based on complex medical factors including, but not limited to:

• The beneficiary history and comorbidities, and the severity of signs and symptoms (also known as Severity of Illness or SI).
• Current medical needs (also known as Intensity of Service or IS).
• The risk of an adverse event.

Generally, private payers do not follow the Two-Midnight Rule, and instead utilize evidence-based MCG guidelines,¹¹ InterQual® criteria¹² or internal criteria to determine if an inpatient admission is “medically necessary.” Hospital utilization review nurses often use MCG and/or InterQual® to aid admission status decisions and may request secondary review by a physician if medical necessity for an inpatient admission is not clear-cut.
 

The role of physician advisors

Considering the rising financial pressure and growing complexity of private and public payers’ rules and regulations, many hospitals turned to physician advisors to help prevent and reduce denials. Typically, physician advisors perform concurrent secondary reviews to help determine the most appropriate level of care, participate in peer-to-peer discussions with payers, and write formal appeals to overturn clinical denials.

“Physician advisors are generally not in the business of critiquing clinical practice, instead they review whether the chart documentation supports initial and continued hospitalization,” said Charles Locke, MD, senior physician advisor at the Johns Hopkins Hospital and president of the American College of Physician Advisors (ACPA). “However, physician advisors should seek additional information and provide feedback in those cases where the documentation does not support medical necessity for hospitalization.”

Many physician advisors are current or former hospitalists. Chris Shearer, MD, chief medical officer for remote advisory at Sound Physicians Advisory Services, says that “hospitalists are the natural physician advisors as they have a working knowledge of what patients need to be inpatients and which are less sick and likely to be discharged quickly.”

The role of physician advisors extends beyond reviews to include physician engagement and education. Physician advisors are a critical link between physicians, utilization review nurses, case managers, and clinical documentation integrity (CDI) and revenue cycle teams, and are increasingly involved in hospital-wide denial prevention efforts.

Physician advisors are invaluable in identifying and validating root causes for clinical denials and generating potential solutions, as they bring to the table:

• Clinical expertise.
• Understanding of clinical workflows.
• Knowledge of the most current public and private payers’ regulations.
• Insight into hospital-specific clinical documentation opportunities (for example, by diagnosis, procedure, service line, and provider).
• Understanding of payers’ reasons for clinical denials through peer-to-peer discussions

The role of hospitalists in preventing clinical denials

I asked three experienced physician advisors – Dr. Locke, Dr. Shearer, and Deepak Pahuja, MD, chief medical officer at Aerolib Healthcare Solutions – what hospitalists can do to prevent clinical denials. The experts had the following five recommendations:

1. “THINK IN INK.”

The best tool in combating denials is well-documented clinical judgment that outlines:

• WHY the patient requires hospitalization, based on severity of presenting signs and symptoms, comorbidities, and risk of complications.
• WHAT the plan of care is, including diagnostic tests and/or interventions.
• HOW LONG you anticipate the patient will be in the hospital, including potential implications of social determinants (for example homelessness, active drug use) on discharge planning.

2. MASTER THE TWO-MIDNIGHT RULE.

If you expect that a Medicare Part A patient will require two or more midnights in the hospital, document it in the history and physical along with supporting clinical reasoning and sign an inpatient order. If the patient is discharged prior to the second midnight, document the reason in the progress notes and the discharge summary (for example, death, transfer to another hospital, departure against medical advice, faster than expected clinical improvement, or election of hospice in lieu of continued treatment in the hospital). Remember that Medicare Advantage plans may not follow the Two-Midnight rule and instead may use MCG guidelines, InterQual®, or internal criteria.

3. KNOW “SLAM DUNK” MCG CRITERIA FOR TOP DIAGNOSES.

Most large private payers utilize MCG guidelines to determine medical necessity for hospital admissions. Those guidelines are complex and change every year, and it is not required for hospitalists to know them all. However, it might help to remember a few key inpatient admission criteria for the top 5 to 10 diagnoses, such as:

• First episode of heart failure without prior history.
• Upper gastrointestinal bleeding with liver cirrhosis, syncope, or orthostatic hypotension.
• Pneumonia with documented hypoxia, outpatient treatment failure, pneumonia severity index (PSI) class 4 or 5, or CURB-65 score of 3 or greater.
• Cellulitis with outpatient treatment failure or high-risk comorbid conditions (cirrhosis, symptomatic heart failure, immunosuppression, or HbA1c greater than 10%).

4. EACH DAY, DEFEND WHY THE PATIENT NEEDS TO BE IN THE HOSPITAL.

Don’t let your progress notes be swallowed by a “copy-forward” monster and instead provide daily updates, such as:

• Up-to-date clinical status and response to interventions (for example, oxygenation or pain level).
• Updated plan of care: current interventions, additional diagnostic workup, or changes to the intensity of care (for example, increased intravenous pain medication dose or frequency).
• Why the patient cannot be safely discharged to a lower level of care (for example, a skilled nursing facility or home).

5. WORK WITH YOUR UTILIZATION REVIEW NURSES AND PHYSICIAN ADVISORS.

In the end, the two most powerful tools in combating clinical denials for hospital services are good medicine and clear documentation. Armed with an understanding of health care reimbursement and denial prevention, hospitalists can help their hospitals prevent unnecessary clinical denials and receive the reimbursements they deserve.”
 

Dr. Farah is a hospitalist, physician advisor, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. LaPointe J. $262B of Total Hospital Charges in 2016 Initially Claim Denials. RevCycle Intelligence. 2017 June 26.

2. The Advisory Board. An ounce of prevention pays off: 90% of denials are preventable. 2014 Dec 11. [www.advisory.com/research/revenue-cycle-advancement-center/at-the-margins/2014/12/denials-management]

3. Centers for Medicare & Medicaid Services, Office of the Actuary, National Health Statistics Group. The Nation’s Health Dollar: Where It Came From, Where It Went. [www.cms.gov/files/document/nations-health-dollar-where-it-came-where-it-went.pdf]

4. National Association of Insurance Commissioners. 2018 Market Share Reports. [www.naic.org/prod_serv/MSR-HB-19.pdf]

5. Centers for Medicare & Medicaid Services. Transforming the Healthcare System through Competition and Innovation. 2019 Nov. [www.cms.gov/files/document/cms-financial-report-fiscal-year-2019.pdf]

6. Centers for Medicare & Medicaid Services. MS-DRG Classifications and Software. 2020 Oct. [www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/MS-DRG-Classifications-and-Software]

7. Centers for Medicare & Medicaid Services. HCPCS Coding Questions. 2020 Feb. [www.cms.gov/Medicare/Coding/MedHCPCSGenInfo/HCPCS_Coding_Questions]

8. Healthinsurance.org. Health insurance and Obamacare terms. [www.healthinsurance.org/glossary/denial-of-claim/]

9. The Advisory Board. Latest Trends in Hospital Revenue Cycle Performance. 2017. [mahamweb.org/images/meeting/112817/maham_2017__latest_trends_in_hospital_rev_cycle_performance_abc.pdf]

10. Centers for Medicare & Medicaid Services. Medicare Program Integrity Manual. Chapter 6: Medicare Contractor Medical Review Guidelines for Specific Services. 2020 July. [www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/pim83c06.pdf]

11. MCG Health. Industry-Leading Evidence-Based Care Guidelines. [www.mcg.com/care-guidelines/care-guidelines/]

12. Change Healthcare. What Is InterQual? [www.changehealthcare.com/solutions/clinical-decision-support/interqual]

Under a fee-for-service payment model, health care providers get paid by private and public payers for patient services such as physician visits, hospital stays, procedures, and tests. In an ideal world, providers would receive accurate, complete, and timely reimbursements. Unfortunately, the reality is far from ideal, where payment denials and delays are a common occurrence.

According to one study, out of $3 trillion in total claims submitted by health care organizations, an estimated 9% of charges ($262 billion), were initially denied.¹ The good news is that 90% of all denials are preventable, and two-thirds of those preventable denials can be successfully appealed.²

Hospitalists are essential in preventing denials for hospital services and should be familiar with the basics of health care reimbursement and common reasons for denials. In this article we will provide an overview of the U.S. health care payment system, revenue cycle management and types of denials, and focus on the role of physician advisors and hospitalists in preventing and combating denials.
 

Overview of the U.S. health care payment system

In 2018 alone, the U.S. spent $3.6 trillion on health care. Of those dollars, 33% went to payments for hospital care and 20% went to physician and clinical services.³ So where do the nation’s health care dollars come from?

The United States has a complex multiple-payer system that includes private insurance companies and public payers funded by the federal and state governments, such as Medicare and Medicaid. Per the National Association of Insurance Commissioners’ 2018 Market Share Reports, there are 125 private accident and health insurance companies in the U.S., with the top five – UnitedHealth, Kaiser, Anthem, Humana, and CVS – holding a cumulative market share of almost 40%.⁴

Medicare accounts for 15% of federal budget spending and provides insurance coverage to almost 60 million people who are 65 and older, have end-stage renal disease, or have been approved for Social Security disability insurance benefits.⁵ Medicare Part A covers hospital, skilled nursing facility, home health, and hospice care. For example, for inpatient stays, Medicare Part A pays hospitals a predetermined rate per discharge according to the Medicare Severity Diagnosis Related Groups (MS-DRGs), which are based on the principal and secondary diagnoses, and performed procedures.⁶

Medicare Part B covers physician services and outpatient services and supplies, including labs and durable medical equipment, which are paid based on submitted Healthcare Common Procedure Coding System (HCPCS) codes.⁷ It is important to know that hospital observation stays are considered outpatient services, and are paid by Medicare Part B. Outpatient stays often are reimbursed at a lower rate than inpatient admissions, even in cases with similar utilization of hospital resources.

Medicaid is jointly funded by the states and the federal government and offers insurance coverage to more than 75 million eligible low-income adults, children, pregnant women, elderly adults, and people with disabilities. Over 10 million people are dually eligible for both Medicare and Medicaid.⁵ Increasingly, government payers, both state and federal, are contracting with private insurance companies to deliver Medicare and Medicaid services, also known as Medicare Advantage and Managed Medicaid Plans.

According to the U.S. Department of Treasury, in the 2019 fiscal year (October 2018 to September 2019), 33% of the nation’s health care dollars came from private insurance, 21% from Medicare, 16% from Medicaid, 15% from other government programs (for example, Veteran Affairs), 10% from out-of-pocket, and 4% from other private sources.⁵

Understanding revenue cycle management and denials

Providers, such as physicians or hospitals, submit claims to insurance companies that include, among other information, patient demographics and insurance, diagnoses, MS-DRGs and/or HCPCS codes, and charges. Revenue cycle management’s goal is to receive accurate, complete, and timely reimbursement for provided patient services, which is a complex and resource-intensive process.

According to the Healthcare Financial Management Association (HFMA), revenue cycle management includes “all administrative and clinical functions that contribute to the capture, management, and collection of patient service revenue.” These functions could be broken down into four main categories:

• Claims preparation (for example, patient registration, insurance eligibility, benefit verifications, and preauthorization).
• Claims submission (for example, charge capture, medical coding based on medical record documentation and claims transmission).
• Claims management (for example, payment posting, denial management, and patient collections).
• Reporting and analysis.

Claim denial is “the refusal of an insurance company or carrier to honor a request by an individual (or his or her provider) to pay for health care services obtained from a health care professional.”⁸ Payers can deny an entire claim or provide only a partial payment. Initial denial rate is tracked at the claim level (number of claims denied/number of claims submitted) and at the dollar level (total dollar amount of claims denied/total dollar amount of claims submitted).

Denials are classified as hard versus soft, and clinical versus technical or administrative:

• Hard denials result in lost revenue unless successfully appealed (for example, lack of medical necessity).
• Soft denials do not require appeal and may be paid if a provider corrects the claim or submits additional information (for example, missing or inaccurate patient information, and missing medical records).
• Clinical denials are based on medical necessity, including level of care determination (for example, inpatient versus outpatient) and length of stay. They can be concurrent and retrospective and typically start as soft denials.
• Technical or administrative denials are based on reasons other than clinical (for example, failure to preauthorize care or lack of benefits).

According to the Advisory Board’s 2017 survey of hospitals and health care systems, 50% of initial denials were technical/demographic errors, 20% medical necessity, 16% eligibility, and 14% authorization. Forty seven percent of those denials came from commercial payers, 33% from Medicare/Medicare Advantage, 17% from Medicaid, and 3% from other payers.⁹

Determination of medical necessity may vary by payer. As an example, let’s look at inpatient admissions. According to the Medicare Two-Midnight Rule, inpatient admission is appropriate “if the admitting practitioner expects the beneficiary to require medically necessary hospital care spanning two or more midnights, and such reasonable expectation is supported by the medical record documentation.”¹⁰

Medicare guidelines acknowledge that a physician’s decision to admit a patient is based on complex medical factors including, but not limited to:

• The beneficiary history and comorbidities, and the severity of signs and symptoms (also known as Severity of Illness or SI).
• Current medical needs (also known as Intensity of Service or IS).
• The risk of an adverse event.

Generally, private payers do not follow the Two-Midnight Rule, and instead utilize evidence-based MCG guidelines,¹¹ InterQual® criteria¹² or internal criteria to determine if an inpatient admission is “medically necessary.” Hospital utilization review nurses often use MCG and/or InterQual® to aid admission status decisions and may request secondary review by a physician if medical necessity for an inpatient admission is not clear-cut.
 

The role of physician advisors

Considering the rising financial pressure and growing complexity of private and public payers’ rules and regulations, many hospitals turned to physician advisors to help prevent and reduce denials. Typically, physician advisors perform concurrent secondary reviews to help determine the most appropriate level of care, participate in peer-to-peer discussions with payers, and write formal appeals to overturn clinical denials.

“Physician advisors are generally not in the business of critiquing clinical practice, instead they review whether the chart documentation supports initial and continued hospitalization,” said Charles Locke, MD, senior physician advisor at the Johns Hopkins Hospital and president of the American College of Physician Advisors (ACPA). “However, physician advisors should seek additional information and provide feedback in those cases where the documentation does not support medical necessity for hospitalization.”

Many physician advisors are current or former hospitalists. Chris Shearer, MD, chief medical officer for remote advisory at Sound Physicians Advisory Services, says that “hospitalists are the natural physician advisors as they have a working knowledge of what patients need to be inpatients and which are less sick and likely to be discharged quickly.”

The role of physician advisors extends beyond reviews to include physician engagement and education. Physician advisors are a critical link between physicians, utilization review nurses, case managers, and clinical documentation integrity (CDI) and revenue cycle teams, and are increasingly involved in hospital-wide denial prevention efforts.

Physician advisors are invaluable in identifying and validating root causes for clinical denials and generating potential solutions, as they bring to the table:

• Clinical expertise.
• Understanding of clinical workflows.
• Knowledge of the most current public and private payers’ regulations.
• Insight into hospital-specific clinical documentation opportunities (for example, by diagnosis, procedure, service line, and provider).
• Understanding of payers’ reasons for clinical denials through peer-to-peer discussions

The role of hospitalists in preventing clinical denials

I asked three experienced physician advisors – Dr. Locke, Dr. Shearer, and Deepak Pahuja, MD, chief medical officer at Aerolib Healthcare Solutions – what hospitalists can do to prevent clinical denials. The experts had the following five recommendations:

1. “THINK IN INK.”

The best tool in combating denials is well-documented clinical judgment that outlines:

• WHY the patient requires hospitalization, based on severity of presenting signs and symptoms, comorbidities, and risk of complications.
• WHAT the plan of care is, including diagnostic tests and/or interventions.
• HOW LONG you anticipate the patient will be in the hospital, including potential implications of social determinants (for example homelessness, active drug use) on discharge planning.

2. MASTER THE TWO-MIDNIGHT RULE.

If you expect that a Medicare Part A patient will require two or more midnights in the hospital, document it in the history and physical along with supporting clinical reasoning and sign an inpatient order. If the patient is discharged prior to the second midnight, document the reason in the progress notes and the discharge summary (for example, death, transfer to another hospital, departure against medical advice, faster than expected clinical improvement, or election of hospice in lieu of continued treatment in the hospital). Remember that Medicare Advantage plans may not follow the Two-Midnight rule and instead may use MCG guidelines, InterQual®, or internal criteria.

3. KNOW “SLAM DUNK” MCG CRITERIA FOR TOP DIAGNOSES.

Most large private payers utilize MCG guidelines to determine medical necessity for hospital admissions. Those guidelines are complex and change every year, and it is not required for hospitalists to know them all. However, it might help to remember a few key inpatient admission criteria for the top 5 to 10 diagnoses, such as:

• First episode of heart failure without prior history.
• Upper gastrointestinal bleeding with liver cirrhosis, syncope, or orthostatic hypotension.
• Pneumonia with documented hypoxia, outpatient treatment failure, pneumonia severity index (PSI) class 4 or 5, or CURB-65 score of 3 or greater.
• Cellulitis with outpatient treatment failure or high-risk comorbid conditions (cirrhosis, symptomatic heart failure, immunosuppression, or HbA1c greater than 10%).

4. EACH DAY, DEFEND WHY THE PATIENT NEEDS TO BE IN THE HOSPITAL.

Don’t let your progress notes be swallowed by a “copy-forward” monster and instead provide daily updates, such as:

• Up-to-date clinical status and response to interventions (for example, oxygenation or pain level).
• Updated plan of care: current interventions, additional diagnostic workup, or changes to the intensity of care (for example, increased intravenous pain medication dose or frequency).
• Why the patient cannot be safely discharged to a lower level of care (for example, a skilled nursing facility or home).

5. WORK WITH YOUR UTILIZATION REVIEW NURSES AND PHYSICIAN ADVISORS.

In the end, the two most powerful tools in combating clinical denials for hospital services are good medicine and clear documentation. Armed with an understanding of health care reimbursement and denial prevention, hospitalists can help their hospitals prevent unnecessary clinical denials and receive the reimbursements they deserve.”
 

Dr. Farah is a hospitalist, physician advisor, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. LaPointe J. $262B of Total Hospital Charges in 2016 Initially Claim Denials. RevCycle Intelligence. 2017 June 26.

2. The Advisory Board. An ounce of prevention pays off: 90% of denials are preventable. 2014 Dec 11. [www.advisory.com/research/revenue-cycle-advancement-center/at-the-margins/2014/12/denials-management]

3. Centers for Medicare & Medicaid Services, Office of the Actuary, National Health Statistics Group. The Nation’s Health Dollar: Where It Came From, Where It Went. [www.cms.gov/files/document/nations-health-dollar-where-it-came-where-it-went.pdf]

4. National Association of Insurance Commissioners. 2018 Market Share Reports. [www.naic.org/prod_serv/MSR-HB-19.pdf]

5. Centers for Medicare & Medicaid Services. Transforming the Healthcare System through Competition and Innovation. 2019 Nov. [www.cms.gov/files/document/cms-financial-report-fiscal-year-2019.pdf]

6. Centers for Medicare & Medicaid Services. MS-DRG Classifications and Software. 2020 Oct. [www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/MS-DRG-Classifications-and-Software]

7. Centers for Medicare & Medicaid Services. HCPCS Coding Questions. 2020 Feb. [www.cms.gov/Medicare/Coding/MedHCPCSGenInfo/HCPCS_Coding_Questions]

8. Healthinsurance.org. Health insurance and Obamacare terms. [www.healthinsurance.org/glossary/denial-of-claim/]

9. The Advisory Board. Latest Trends in Hospital Revenue Cycle Performance. 2017. [mahamweb.org/images/meeting/112817/maham_2017__latest_trends_in_hospital_rev_cycle_performance_abc.pdf]

10. Centers for Medicare & Medicaid Services. Medicare Program Integrity Manual. Chapter 6: Medicare Contractor Medical Review Guidelines for Specific Services. 2020 July. [www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/pim83c06.pdf]

11. MCG Health. Industry-Leading Evidence-Based Care Guidelines. [www.mcg.com/care-guidelines/care-guidelines/]

12. Change Healthcare. What Is InterQual? [www.changehealthcare.com/solutions/clinical-decision-support/interqual]

Under a fee-for-service payment model, health care providers get paid by private and public payers for patient services such as physician visits, hospital stays, procedures, and tests. In an ideal world, providers would receive accurate, complete, and timely reimbursements. Unfortunately, the reality is far from ideal, where payment denials and delays are a common occurrence.

According to one study, out of $3 trillion in total claims submitted by health care organizations, an estimated 9% of charges ($262 billion), were initially denied.¹ The good news is that 90% of all denials are preventable, and two-thirds of those preventable denials can be successfully appealed.²

Hospitalists are essential in preventing denials for hospital services and should be familiar with the basics of health care reimbursement and common reasons for denials. In this article we will provide an overview of the U.S. health care payment system, revenue cycle management and types of denials, and focus on the role of physician advisors and hospitalists in preventing and combating denials.
 

Overview of the U.S. health care payment system

In 2018 alone, the U.S. spent $3.6 trillion on health care. Of those dollars, 33% went to payments for hospital care and 20% went to physician and clinical services.³ So where do the nation’s health care dollars come from?

The United States has a complex multiple-payer system that includes private insurance companies and public payers funded by the federal and state governments, such as Medicare and Medicaid. Per the National Association of Insurance Commissioners’ 2018 Market Share Reports, there are 125 private accident and health insurance companies in the U.S., with the top five – UnitedHealth, Kaiser, Anthem, Humana, and CVS – holding a cumulative market share of almost 40%.⁴

Medicare accounts for 15% of federal budget spending and provides insurance coverage to almost 60 million people who are 65 and older, have end-stage renal disease, or have been approved for Social Security disability insurance benefits.⁵ Medicare Part A covers hospital, skilled nursing facility, home health, and hospice care. For example, for inpatient stays, Medicare Part A pays hospitals a predetermined rate per discharge according to the Medicare Severity Diagnosis Related Groups (MS-DRGs), which are based on the principal and secondary diagnoses, and performed procedures.⁶

Medicare Part B covers physician services and outpatient services and supplies, including labs and durable medical equipment, which are paid based on submitted Healthcare Common Procedure Coding System (HCPCS) codes.⁷ It is important to know that hospital observation stays are considered outpatient services, and are paid by Medicare Part B. Outpatient stays often are reimbursed at a lower rate than inpatient admissions, even in cases with similar utilization of hospital resources.

Medicaid is jointly funded by the states and the federal government and offers insurance coverage to more than 75 million eligible low-income adults, children, pregnant women, elderly adults, and people with disabilities. Over 10 million people are dually eligible for both Medicare and Medicaid.⁵ Increasingly, government payers, both state and federal, are contracting with private insurance companies to deliver Medicare and Medicaid services, also known as Medicare Advantage and Managed Medicaid Plans.

According to the U.S. Department of Treasury, in the 2019 fiscal year (October 2018 to September 2019), 33% of the nation’s health care dollars came from private insurance, 21% from Medicare, 16% from Medicaid, 15% from other government programs (for example, Veteran Affairs), 10% from out-of-pocket, and 4% from other private sources.⁵

Understanding revenue cycle management and denials

Providers, such as physicians or hospitals, submit claims to insurance companies that include, among other information, patient demographics and insurance, diagnoses, MS-DRGs and/or HCPCS codes, and charges. Revenue cycle management’s goal is to receive accurate, complete, and timely reimbursement for provided patient services, which is a complex and resource-intensive process.

According to the Healthcare Financial Management Association (HFMA), revenue cycle management includes “all administrative and clinical functions that contribute to the capture, management, and collection of patient service revenue.” These functions could be broken down into four main categories:

• Claims preparation (for example, patient registration, insurance eligibility, benefit verifications, and preauthorization).
• Claims submission (for example, charge capture, medical coding based on medical record documentation and claims transmission).
• Claims management (for example, payment posting, denial management, and patient collections).
• Reporting and analysis.

Claim denial is “the refusal of an insurance company or carrier to honor a request by an individual (or his or her provider) to pay for health care services obtained from a health care professional.”⁸ Payers can deny an entire claim or provide only a partial payment. Initial denial rate is tracked at the claim level (number of claims denied/number of claims submitted) and at the dollar level (total dollar amount of claims denied/total dollar amount of claims submitted).

Denials are classified as hard versus soft, and clinical versus technical or administrative:

• Hard denials result in lost revenue unless successfully appealed (for example, lack of medical necessity).
• Soft denials do not require appeal and may be paid if a provider corrects the claim or submits additional information (for example, missing or inaccurate patient information, and missing medical records).
• Clinical denials are based on medical necessity, including level of care determination (for example, inpatient versus outpatient) and length of stay. They can be concurrent and retrospective and typically start as soft denials.
• Technical or administrative denials are based on reasons other than clinical (for example, failure to preauthorize care or lack of benefits).

According to the Advisory Board’s 2017 survey of hospitals and health care systems, 50% of initial denials were technical/demographic errors, 20% medical necessity, 16% eligibility, and 14% authorization. Forty seven percent of those denials came from commercial payers, 33% from Medicare/Medicare Advantage, 17% from Medicaid, and 3% from other payers.⁹

Determination of medical necessity may vary by payer. As an example, let’s look at inpatient admissions. According to the Medicare Two-Midnight Rule, inpatient admission is appropriate “if the admitting practitioner expects the beneficiary to require medically necessary hospital care spanning two or more midnights, and such reasonable expectation is supported by the medical record documentation.”¹⁰

Medicare guidelines acknowledge that a physician’s decision to admit a patient is based on complex medical factors including, but not limited to:

• The beneficiary history and comorbidities, and the severity of signs and symptoms (also known as Severity of Illness or SI).
• Current medical needs (also known as Intensity of Service or IS).
• The risk of an adverse event.

Generally, private payers do not follow the Two-Midnight Rule, and instead utilize evidence-based MCG guidelines,¹¹ InterQual® criteria¹² or internal criteria to determine if an inpatient admission is “medically necessary.” Hospital utilization review nurses often use MCG and/or InterQual® to aid admission status decisions and may request secondary review by a physician if medical necessity for an inpatient admission is not clear-cut.
 

The role of physician advisors

Considering the rising financial pressure and growing complexity of private and public payers’ rules and regulations, many hospitals turned to physician advisors to help prevent and reduce denials. Typically, physician advisors perform concurrent secondary reviews to help determine the most appropriate level of care, participate in peer-to-peer discussions with payers, and write formal appeals to overturn clinical denials.

“Physician advisors are generally not in the business of critiquing clinical practice, instead they review whether the chart documentation supports initial and continued hospitalization,” said Charles Locke, MD, senior physician advisor at the Johns Hopkins Hospital and president of the American College of Physician Advisors (ACPA). “However, physician advisors should seek additional information and provide feedback in those cases where the documentation does not support medical necessity for hospitalization.”

Many physician advisors are current or former hospitalists. Chris Shearer, MD, chief medical officer for remote advisory at Sound Physicians Advisory Services, says that “hospitalists are the natural physician advisors as they have a working knowledge of what patients need to be inpatients and which are less sick and likely to be discharged quickly.”

The role of physician advisors extends beyond reviews to include physician engagement and education. Physician advisors are a critical link between physicians, utilization review nurses, case managers, and clinical documentation integrity (CDI) and revenue cycle teams, and are increasingly involved in hospital-wide denial prevention efforts.

Physician advisors are invaluable in identifying and validating root causes for clinical denials and generating potential solutions, as they bring to the table:

• Clinical expertise.
• Understanding of clinical workflows.
• Knowledge of the most current public and private payers’ regulations.
• Insight into hospital-specific clinical documentation opportunities (for example, by diagnosis, procedure, service line, and provider).
• Understanding of payers’ reasons for clinical denials through peer-to-peer discussions

The role of hospitalists in preventing clinical denials

I asked three experienced physician advisors – Dr. Locke, Dr. Shearer, and Deepak Pahuja, MD, chief medical officer at Aerolib Healthcare Solutions – what hospitalists can do to prevent clinical denials. The experts had the following five recommendations:

1. “THINK IN INK.”

The best tool in combating denials is well-documented clinical judgment that outlines:

• WHY the patient requires hospitalization, based on severity of presenting signs and symptoms, comorbidities, and risk of complications.
• WHAT the plan of care is, including diagnostic tests and/or interventions.
• HOW LONG you anticipate the patient will be in the hospital, including potential implications of social determinants (for example homelessness, active drug use) on discharge planning.

2. MASTER THE TWO-MIDNIGHT RULE.

If you expect that a Medicare Part A patient will require two or more midnights in the hospital, document it in the history and physical along with supporting clinical reasoning and sign an inpatient order. If the patient is discharged prior to the second midnight, document the reason in the progress notes and the discharge summary (for example, death, transfer to another hospital, departure against medical advice, faster than expected clinical improvement, or election of hospice in lieu of continued treatment in the hospital). Remember that Medicare Advantage plans may not follow the Two-Midnight rule and instead may use MCG guidelines, InterQual®, or internal criteria.

3. KNOW “SLAM DUNK” MCG CRITERIA FOR TOP DIAGNOSES.

Most large private payers utilize MCG guidelines to determine medical necessity for hospital admissions. Those guidelines are complex and change every year, and it is not required for hospitalists to know them all. However, it might help to remember a few key inpatient admission criteria for the top 5 to 10 diagnoses, such as:

• First episode of heart failure without prior history.
• Upper gastrointestinal bleeding with liver cirrhosis, syncope, or orthostatic hypotension.
• Pneumonia with documented hypoxia, outpatient treatment failure, pneumonia severity index (PSI) class 4 or 5, or CURB-65 score of 3 or greater.
• Cellulitis with outpatient treatment failure or high-risk comorbid conditions (cirrhosis, symptomatic heart failure, immunosuppression, or HbA1c greater than 10%).

4. EACH DAY, DEFEND WHY THE PATIENT NEEDS TO BE IN THE HOSPITAL.

Don’t let your progress notes be swallowed by a “copy-forward” monster and instead provide daily updates, such as:

• Up-to-date clinical status and response to interventions (for example, oxygenation or pain level).
• Updated plan of care: current interventions, additional diagnostic workup, or changes to the intensity of care (for example, increased intravenous pain medication dose or frequency).
• Why the patient cannot be safely discharged to a lower level of care (for example, a skilled nursing facility or home).

5. WORK WITH YOUR UTILIZATION REVIEW NURSES AND PHYSICIAN ADVISORS.

In the end, the two most powerful tools in combating clinical denials for hospital services are good medicine and clear documentation. Armed with an understanding of health care reimbursement and denial prevention, hospitalists can help their hospitals prevent unnecessary clinical denials and receive the reimbursements they deserve.”
 

Dr. Farah is a hospitalist, physician advisor, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. LaPointe J. $262B of Total Hospital Charges in 2016 Initially Claim Denials. RevCycle Intelligence. 2017 June 26.

2. The Advisory Board. An ounce of prevention pays off: 90% of denials are preventable. 2014 Dec 11. [www.advisory.com/research/revenue-cycle-advancement-center/at-the-margins/2014/12/denials-management]

3. Centers for Medicare & Medicaid Services, Office of the Actuary, National Health Statistics Group. The Nation’s Health Dollar: Where It Came From, Where It Went. [www.cms.gov/files/document/nations-health-dollar-where-it-came-where-it-went.pdf]

4. National Association of Insurance Commissioners. 2018 Market Share Reports. [www.naic.org/prod_serv/MSR-HB-19.pdf]

5. Centers for Medicare & Medicaid Services. Transforming the Healthcare System through Competition and Innovation. 2019 Nov. [www.cms.gov/files/document/cms-financial-report-fiscal-year-2019.pdf]

6. Centers for Medicare & Medicaid Services. MS-DRG Classifications and Software. 2020 Oct. [www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/AcuteInpatientPPS/MS-DRG-Classifications-and-Software]

7. Centers for Medicare & Medicaid Services. HCPCS Coding Questions. 2020 Feb. [www.cms.gov/Medicare/Coding/MedHCPCSGenInfo/HCPCS_Coding_Questions]

8. Healthinsurance.org. Health insurance and Obamacare terms. [www.healthinsurance.org/glossary/denial-of-claim/]

9. The Advisory Board. Latest Trends in Hospital Revenue Cycle Performance. 2017. [mahamweb.org/images/meeting/112817/maham_2017__latest_trends_in_hospital_rev_cycle_performance_abc.pdf]

10. Centers for Medicare & Medicaid Services. Medicare Program Integrity Manual. Chapter 6: Medicare Contractor Medical Review Guidelines for Specific Services. 2020 July. [www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/pim83c06.pdf]

11. MCG Health. Industry-Leading Evidence-Based Care Guidelines. [www.mcg.com/care-guidelines/care-guidelines/]

12. Change Healthcare. What Is InterQual? [www.changehealthcare.com/solutions/clinical-decision-support/interqual]

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Cancer patients who receive an immune checkpoint inhibitor have more than a doubled rate of venous thromboembolism during the subsequent 2 years, compared with their rate during the 2 years before treatment, according to a retrospective analysis of more than 2,800 patients treated at a single U.S. center.

The study focused on cancer patients treated with an immune checkpoint inhibitor (ICI) at Massachusetts General Hospital in Boston. It showed that during the 2 years prior to treatment with any type of ICI, the incidence of venous thromboembolic events (VTE) was 4.85/100 patient-years that then jumped to 11.75/100 patient-years during the 2 years following treatment. This translated into an incidence rate ratio of 2.43 during posttreatment follow-up, compared with pretreatment, Jingyi Gong, MD, said at the virtual American Heart Association scientific sessions.

The increased VTE rate resulted from rises in both the rate of deep vein thrombosis, which had an IRR of 3.23 during the posttreatment period, and for pulmonary embolism, which showed an IRR of 2.24, said Dr. Gong, a physician at Brigham and Women’s Hospital in Boston. She hypothesized that this effect may result from a procoagulant effect of the immune activation and inflammation triggered by ICIs.


Hypothesis-generating results

Cardiologists cautioned that these findings should only be considered hypothesis generating, but raise an important alert for clinicians to have heightened awareness of the potential for VTE following ICI treatment.

“A clear message is to be aware that there is this signal, and be vigilant for patients who might present with VTE following ICI treatment,” commented Richard J. Kovacs, MD, a cardiologist and professor at Indiana University, Indianapolis. The data that Dr. Gong reported are “moderately convincing,” he added in an interview.

“Awareness that patients who receive ICI may be at increased VTE risk is very important,” agreed Umberto Campia, MD, a cardiologist, vascular specialist, and member of the cardio-oncology group at Brigham and Women’s Hospital, who was not involved in the new study.

The potential impact of ICI treatment on VTE risk is slowly emerging, added Dr. Campia. Until recently, the literature primarily was case reports, but recently another retrospective, single-center study came out that reported a 13% incidence of VTE in cancer patients following ICI treatment. On the other hand, a recently published meta-analysis of more than 20,000 patients from 68 ICI studies failed to find a suggestion of increased VTE incidence following ICI interventions.

Attempting to assess the impact of treatment on VTE risk in cancer patients is challenging because cancer itself boosts the risk. Recommendations on the use of VTE prophylaxis in cancer patients most recently came out in 2014 from the American Society of Clinical Oncology, which said that VTE prophylaxis for ambulatory cancer patients “may be considered for highly select high-risk patients.” The impact of cancer therapy on VTE risk and the need for prophylaxis is usually assessed by applying the Khorana score, Dr. Campia said in an interview.
 

VTE spikes acutely after ICI treatment

Dr. Gong analyzed VTE incidence rates by time during the total 4-year period studied, and found that the rate gradually and steadily rose with time throughout the 2 years preceding treatment, spiked immediately following ICI treatment, and then gradually and steadily fell back to roughly the rate seen just before treatment, reaching that level about a year after treatment. She ran a sensitivity analysis that excluded patients who died during the first year following their ICI treatment, and in this calculation an acute spike in VTE following ICI treatment still occurred but with reduced magnitude.

She also reported the results of several subgroup analyses. The IRRs remained consistent among women and men, among patients who were aged over or under 65 years, and regardless of cancer type or treatment with corticosteroids. But the subgroup analyses identified two parameters that seemed to clearly split VTE rates.

Among patients on treatment with an anticoagulant agent at the time of their ICI treatment, roughly 10% of the patients, the IRR was 0.56, compared with a ratio of 3.86 among the other patients, suggesting possible protection. A second factor that seemed linked with VTE incidence was the number of ICI treatment cycles a patient received. Those who received more than five cycles had a risk ratio of 3.95, while those who received five or fewer cycles had a RR of 1.66.

Her analysis included 2,842 cancer patients who received treatment with an ICI at Massachusetts General Hospital. Patients averaged 64 years of age, slightly more than half were men, and 13% had a prior history of VTE. Patients received an average of 5 ICI treatment cycles, but a quarter of the patients received more than 10 cycles.

During the 2-year follow-up, 244 patients (9%) developed VTE. The patients who developed VTE were significantly younger than those who did not, with an average age of 63 years, compared with 65. And the patients who eventually developed VTE had a significantly higher prevalence of prior VTE at 18%, compared with 12% among the patients who stayed VTE free.

The cancer types patients had were non–small cell lung, 29%; melanoma, 28%; head and neck, 12%; renal genitourinary, 6%; and other, 25%. ICIs have been available for routine U.S. practice since 2011. The class includes agents such as pembrolizumab (Keytruda) and durvalumab (Imfinzi).

Researchers would need to perform a prospective, randomized study to determine whether anticoagulant prophylaxis is clearly beneficial for patients receiving ICI treatment, Dr. Gong said. But both Dr. Kovacs and Dr. Campia said that more data on this topic are first needed.

“We need to confirm that treatment with ICI is associated with VTEs. Retrospective data are not definitive,” said Dr. Campia. “We would need to prospectively assess the impact of ICI,” which will not be easy, as it’s quickly become a cornerstone for treating many cancers. “We need to become more familiar with the adverse effects of these drugs. We are still learning about their toxicities.”

The study had no commercial funding. Dr. Gong, Dr. Kovacs, and Dr. Campia had no disclosures.

mzoler@mdedge.com

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Care of the patient with a fibrosing interstitial lung disease (ILD) presents constant challenges not just in the diagnosis of ILD but in the choice of treatment. Since the FDA approval of both nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2014, interest has grown for their employ in treating other non-IPF ILDs. This is especially true in cases with the pattern of radiographic or histopathological disease is similar to IPF – a usual interstitial pneumonia (UIP) pattern – despite not meeting criteria for an IPF diagnosis due to the identification of a predisposing etiology. As research evolves, clinicians may have more options to fight the vast variety of fibrosing ILDs encountered in practice.

In 2014, the publication of separate clinical trials of nintedanib and pirfenidone in patients with IPF marked a new beginning in the treatment of this disease. Nintedanib, a tyrosine kinase inhibitor with multiple targets, was shown to decrease progression of disease as measured by the annual rate of decline in forced vital capacity (FVC) (Richeldi L, et al. N Engl J Med. 2014 May;370[22]:2071-82). Pirfenidone, whose antifibrotic mechanisms are not completely understood, similarly slowed disease progression via a decrease in the percent change of predicted FVC (Lederer DJ, et al. N Engl J Med. 2014 May;370[19]:2083-92). Clinicians were now armed with two therapeutic options following the subsequent FDA approval of both drugs for the treatment of IPF. This represented a giant leap forward in the management of the disease, as prior to 2014 the only available options were supportive care and lung transplant for appropriate candidates.

As IPF represents but 20% of ILDs in the United States, a significant proportion of diseases were left without an antifibrotic option after the arrival of nintedanib and pirfenidone. (Lederer DJ. N Engl J Med. 2018 May;378:1811-23). For the others, such as chronic hypersensitivity pneumonitis and the many connective tissue disease-associated ILDs, treatment revolved around a variety of anti-inflammatory pharmaceuticals. Common treatment choices include corticosteroids, mycophenolate, and azathioprine. The data in support of these treatments for non-IPF ILD is comparatively lean in contrast to the more robust pirfenidone and nintedanib IPF trials.

One notable exception includes the Scleroderma Lung Studies. In Scleroderma Lung Study II (SLS II), 142 patients with scleroderma-related interstitial lung disease were randomized to oral mycophenolate for 24 months vs oral cyclophosphamide for 12 months plus placebo for 12 months (Tashkin DP, et al. Lancet Respir Med. 2016 Sep;4(9):708-19). The 2006 Scleroderma Lung Study established oral cyclophosphamide in scleroderma lung disease as a reasonable standard of care after demonstrating a slowing of disease progression after 12 months of therapy (Tashkin DP, et al. N Engl J Med. 2006 Jun;354[25]:2655-66). In SLS II, both cyclophosphamide and mycophenolate improved lung function at 24 months, but mycophenolate was better tolerated with less toxicity.

Other supportive data for immunosuppressive treatments for non-IPF ILD rely heavily on smaller studies, case reports, and retrospective reviews. Choices of who and when to treat are often unclear and typically come from physician preferences and patient values discussions. In the cases of connective tissue disease-associated ILD, patients may already require treatment for the underlying condition. And, while some therapies could be beneficial in a concurrent manner for a patient’s lung disease, many others are not (TNF-alpha antibody therapy, for example).

A major step forward for patients with scleroderma lung disease came with the publication of the SENSCIS trial (Oliver D, et al. N Engl J Med. 2019 Jun;380:2518-28). A total of 576 patients with scleroderma of recent onset (< 7 years) and at least 10% fibrosis on chest CT were randomized to receive either nintedanib or placebo. Patients were allowed to be supported by other therapies at stable doses prior to enrollment, and as such almost half of the patients were receiving mycophenolate. A significant improvement in annual FVC decline was reported in the treatment group, although the effect was tempered in the subgroup analysis when considering patients already on mycophenolate. Thus, the role of nintedanib in patients taking mycophenolate is less clear.

An ongoing study may clarify the role of mycophenolate and antifibrotic therapy in these patients. The phase 2 Scleroderma Lung Study III has a planned enrollment of 150 patients who are either treatment-naïve or only recently started on therapy (www.clinicaltrials.gov; NCT03221257). Patients are randomized to mycophenolate plus pirfenidone vs mycophenolate plus placebo, and the treatment phase will last 18 months. The primary outcome is change in baseline FVC. This trial design will hopefully answer whether the combination of an antifibrotic with an anti-inflammatory medication is superior to the anti-inflammatory therapy alone, in patients with at least some evidence of inflammation (ground-glass opacifications) on high-resolution CT scan (HRCT).

In ILD other than that associated with scleroderma, nintedanib was again explored in a large randomized controlled clinical trial. In INBUILD, 663 patients with progressive ILD not caused by IPF or scleroderma were randomized to nintedanib vs placebo for one year (Flaherty KR. N Engl J Med. 2019 Sep;381:1718-27). A majority of the patients (62%) had a UIP pattern on CT scan. There was overall improvement in the annual rate of decline in FVC in the treatment group, especially in the pr-determined subgroup of patients with a UIP pattern. The most common ILDs in the study were chronic hypersensitivity pneumonitis and that associated with connective tissue disease.

Pirfenidone is also being studied in multiple trials for various types of non-IPF ILD. Studies are either completed and nearing publication, or are ongoing. Some examples include the TRAIL1 study examining pirfenidone vs placebo in patients with rheumatoid arthritis (www.clinicaltrials.gov; NCT02808871), and the phase 2 RELIEF study that explores pirfenidone vs placebo in patients with progressive ILD from a variety of etiologies.

As more clinical trials are published, clinicians are now facing a different dilemma. Whereas the options for treatment were limited to only various anti-inflammatory medications in past years for patients with non-IPF ILDs, the growing body of literature supporting antifibrotics present a new therapeutic avenue to explore. Which patients should be started on anti-inflammatory medications, and which should start antifibrotics? Those questions may never be answered satisfactorily in clinical trials. Mycophenolate has become so entrenched in many treatment plans, enrollment into such a study comparing the two therapeutic classes head-to-head would be challenging.

However, a consideration of the specific phenotype of the patient’s ILD is a suggested approach that comes from clinical experience. Patients with more inflammatory changes on CT scan, such as more ground glass opacifications or a non-UIP pattern, might benefit from initiation of anti-inflammatory therapies such as a combination of corticosteroids and mycophenolate. Conversely, initiating antifibrotic therapy upfront, with or without concomitant mycophenolate, is a consideration if the pattern of disease is consistent with UIP on CT scan.

Ultimately, referral to a dedicated interstitial lung disease center for expert evaluation and multidisciplinary discussion may be warranted to sift through these difficult situations, especially as the field of research grows more robust. In any event, the future for patients with these diseases, though still challenged, is brighter than before.
 

Dr. Kershaw is Associate Professor of Medicine, Division of Pulmonary & Critical Care Medicine, University of Texas Southwestern Medical Center. He is the current section editor for Pulmonary
Perpsectives®and Vice Chair of the Interstitial and Diffuse Lung Disease NetWork at CHEST.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Traditional delivery of palliative care to outpatients with cancer is associated with many challenges.

Telehealth can eliminate some of these challenges but comes with issues of its own, according to results of the REACH PC trial.

Jennifer S. Temel, MD, of Massachusetts General Hospital in Boston, discussed the use of telemedicine in palliative care, including results from REACH PC, during an educational session at the ASCO Virtual Quality Care Symposium 2020.

Dr. Temel noted that, for cancer patients, an in-person visit with a palliative care specialist can cost time, induce fatigue, and increase financial burden from transportation and parking expenses.

For caregivers and family, an in-person visit may necessitate absence from family and/or work, require complex scheduling to coordinate with other office visits, and result in additional transportation and/or parking expenses.

For health care systems, to have a dedicated palliative care clinic requires precious space and financial expenditures for office personnel and other resources.

These issues make it attractive to consider whether telehealth could be used for palliative care services.
 

Scarcity of palliative care specialists

In the United States, there is roughly 1 palliative care physician for every 20,000 older adults with a life-limiting illness, according to research published in Annual Review of Public Health in 2014.

In its 2019 state-by-state report card, the Center to Advance Palliative Care noted that only 72% of U.S. hospitals with 50 or more beds have a palliative care team.

For patients with serious illnesses and those who are socioeconomically or geographically disadvantaged, palliative care is often inaccessible.

Inefficiencies in the current system are an additional impediment. Palliative care specialists frequently see patients during a portion of the patient’s routine visit to subspecialty or primary care clinics. This limits the palliative care specialist’s ability to perform comprehensive assessments and provide patient-centered care efficiently.
 

Special considerations regarding telehealth for palliative care

As a specialty, palliative care involves interactions that could make the use of telehealth problematic. For example, conveyance of interest, warmth, and touch are challenging or impossible in a video format.

Palliative care specialists engage with patients regarding relatively serious topics such as prognosis and end-of-life preferences. There is uncertainty about how those discussions would be received by patients and their caregivers via video.

Furthermore, there are logistical impediments such as prescribing opioids with video or across state lines.

Despite these concerns, the ENABLE study showed that supplementing usual oncology care with weekly (transitioning to monthly) telephone-based educational palliative care produced higher quality of life and mood than did usual oncology care alone. These results were published in JAMA in 2009.
 

REACH PC study demonstrates feasibility of telehealth model

Dr. Temel described the ongoing REACH PC trial in which palliative care is delivered via video visits and compared with in-person palliative care for patients with advanced non–small cell lung cancer.

The primary aim of REACH PC is to determine whether telehealth palliative care is equivalent to traditional palliative care in improving quality of life as a supplement to routine oncology care.

Currently, REACH PC has enrolled 581 patients at its 20 sites, spanning a geographically diverse area. Just over half of patients approached about REACH PC agreed to enroll in it. Ultimately, 1,250 enrollees are sought.

Among patients who declined to participate, 7.6% indicated “discomfort with technology” as the reason. Most refusals were due to lack of interest in research (35.1%) and/or palliative care (22.9%).

Older adults were prominent among enrollees. More than 60% were older than 60 years of age, and more than one-third were older than 70 years.

Among patients who began the trial, there were slightly more withdrawals in the telehealth participants, in comparison with in-person participants (13.6% versus 9.1%).

When palliative care clinicians were queried about video visits, 64.3% said there were no challenges. This is comparable to the 65.5% of clinicians who had no challenges with in-person visits.

When problems occurred with video visits, they were most frequently technical (19.1%). Only 1.4% of clinicians reported difficulty addressing topics that felt uncomfortable over video, and 1.5% reported difficulty establishing rapport.

The success rates of video and in-person visits were similar. About 80% of visits accomplished planned goals.
 

‘Webside’ manner

Strategies such as reflective listening and summarizing what patients say (to verify an accurate understanding of the patient’s perspective) are key to successful palliative care visits, regardless of the setting.

For telehealth visits, Dr. Temel described techniques she defined as “webside manner,” to compensate for the inability of the clinician to touch a patient. These techniques include leaning in toward the camera, nodding, and pausing to be certain the patient has finished speaking before the clinician speaks again.
 

Is telehealth the future of palliative care?

I include myself among those oncologists who have voiced concern about moving from face-to-face to remote visits for complicated consultations such as those required for palliative care. Nonetheless, from the preliminary results of the REACH PC trial, it appears that telehealth could be a valuable tool.

To minimize differences between in-person and remote delivery of palliative care, practical strategies for ensuring rapport and facilitating a trusting relationship should be defined further and disseminated.

In addition, we need to be vigilant for widening inequities of care from rapid movement to the use of technology (i.e., an equity gap). In their telehealth experience during the COVID-19 pandemic, investigators at Houston Methodist Cancer Center found that patients declining virtual visits tended to be older, lower-income, and less likely to have commercial insurance. These results were recently published in JCO Oncology Practice.

For the foregoing reasons, hybrid systems for palliative care services will probably always be needed.

Going forward, we should heed the advice of Alvin Toffler in his book Future Shock. Mr. Toffler said, “The illiterate of the 21st century will not be those who cannot read and write, but those who cannot learn, unlearn, and relearn.”

The traditional model for delivering palliative care will almost certainly need to be reimagined and relearned.

Dr. Temel disclosed institutional research funding from Pfizer.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, reflects on the most important and clinically relevant studies on ulcerative colitis presented at the American College of Gastroenterology 2020 virtual annual scientific meeting. He starts with four studies from the OCTAVE clinical trials program. These studies examined the efficacy and safety of tofacitinib after treatment interruption and in pregnant women, presenting almost 7 years of follow-up. Long-term follow-up remains the theme as he turns to the VISIBLE open-label extension of treatment with vedolizumab SC, where the long-term safety of the drug was confirmed and clinical remission rates were maintained out to 2 years. He reports that a post-hoc analysis of the VARSITY trial appeared to show that vedolizumab achieves greater early control vs adalimumab. Dr Regueiro next discusses the late-breaking, phase 3 True North study of ozanimod for moderate to severe ulcerative colitis before finishing up with an analysis of the long-term trends for colectomy since the turn of the century.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, reflects on the most important and clinically relevant studies on ulcerative colitis presented at the American College of Gastroenterology 2020 virtual annual scientific meeting. He starts with four studies from the OCTAVE clinical trials program. These studies examined the efficacy and safety of tofacitinib after treatment interruption and in pregnant women, presenting almost 7 years of follow-up. Long-term follow-up remains the theme as he turns to the VISIBLE open-label extension of treatment with vedolizumab SC, where the long-term safety of the drug was confirmed and clinical remission rates were maintained out to 2 years. He reports that a post-hoc analysis of the VARSITY trial appeared to show that vedolizumab achieves greater early control vs adalimumab. Dr Regueiro next discusses the late-breaking, phase 3 True North study of ozanimod for moderate to severe ulcerative colitis before finishing up with an analysis of the long-term trends for colectomy since the turn of the century.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, reflects on the most important and clinically relevant studies on ulcerative colitis presented at the American College of Gastroenterology 2020 virtual annual scientific meeting. He starts with four studies from the OCTAVE clinical trials program. These studies examined the efficacy and safety of tofacitinib after treatment interruption and in pregnant women, presenting almost 7 years of follow-up. Long-term follow-up remains the theme as he turns to the VISIBLE open-label extension of treatment with vedolizumab SC, where the long-term safety of the drug was confirmed and clinical remission rates were maintained out to 2 years. He reports that a post-hoc analysis of the VARSITY trial appeared to show that vedolizumab achieves greater early control vs adalimumab. Dr Regueiro next discusses the late-breaking, phase 3 True North study of ozanimod for moderate to severe ulcerative colitis before finishing up with an analysis of the long-term trends for colectomy since the turn of the century.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

The siblings of patients with bipolar disorder not only face a significantly increased lifetime risk of that affective disorder, but a whole panoply of other psychiatric disorders, according to a new Danish longitudinal national registry study.

“Our data show the healthy siblings of patients with bipolar disorder are themselves at increased risk of developing any kind of psychiatric disorder. Mainly bipolar disorder, but all other kinds as well,” Lars Vedel Kessing, MD, DMSc, said in presenting the results of the soon-to-be-published Danish study at the virtual congress of the European College of Neuropsychopharmacology.

Moreover, the long-term Danish study also demonstrated that several major psychiatric disorders follow a previously unappreciated bimodal distribution of age of onset in the siblings of patients with bipolar disorder. For example, the incidence of new-onset bipolar disorder and unipolar depression in the siblings was markedly increased during youth and early adulthood, compared with controls drawn from the general Danish population. Then, incidence rates dropped off and plateaued at a lower level in midlife before surging after age 60 years. The same was true for somatoform disorders as well as alcohol and substance use disorders.

“Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifelong, likely with differentiated age-specific approaches. And this is not now the case.

“Generally, most researchers and clinicians are focusing more on the early part of life and not the later part of life from age 60 and up, even though this is indeed also a risk period for any kind of psychiatric illness as well as bipolar disorder,” according to Dr. Kessing, professor of psychiatry at the University of Copenhagen.

Dr. Kessing, a past recipient of the Brain and Behavior Research Foundation’s Outstanding Achievement in Mood Disorders Research Award, also described his research group’s successful innovative efforts to prevent first recurrences after a single manic episode or bipolar disorder.
 

Danish national sibling study

The longitudinal registry study included all 19,995 Danish patients with a primary diagnosis of bipolar disorder during 1995-2017, along with 13,923 of their siblings and 278,460 age- and gender-matched controls drawn from the general population.

The cumulative incidence of any psychiatric disorder was 66% greater in siblings than controls. Leading the way was a 374% increased risk of bipolar disorder.
 

Strategies to prevent a first relapse of bipolar disorder

Dr. Kessing and coinvestigators demonstrated in a meta-analysis that, with current standard therapies, the risk of recurrence among patients after a single manic or mixed episode is high in both adult and pediatric patients. In three studies of adults, the risk of recurrence was 35% during the first year after recovery from the index episode and 59% at 2 years. In three studies of children and adolescents, the risk of recurrence within 1 year after recovery was 40% in children and 52% in adolescents. This makes a compelling case for starting maintenance therapy following onset of a single manic or mixed episode, according to the investigators.

More than half a decade ago, Dr. Kessing and colleagues demonstrated in a study of 4,714 Danish patients with bipolar disorder who were prescribed lithium while in a psychiatric hospital that those who started the drug for prophylaxis early – that is, following their first psychiatric contact – had a significantly higher response to lithium monotherapy than those who started it only after repeated contacts. Indeed, their risk of nonresponse to lithium prophylaxis as evidenced by repeat hospital admission after a 6-month lithium stabilization period was 13% lower than in those starting the drug later.

Early intervention aiming to stop clinical progression of bipolar disorder intuitively seems appealing, so Dr. Kessing and colleagues created a specialized outpatient mood disorders clinic combining optimized pharmacotherapy and evidence-based group psychoeducation. They then put it to the test in a clinical trial in which 158 patients discharged from an initial psychiatric hospital admission for bipolar disorder were randomized to the specialized outpatient mood disorders clinic or standard care.

The rate of psychiatric hospital readmission within the next 6 years was 40% lower in the group assigned to the specialized early intervention clinic. Their rate of adherence to medication – mostly lithium and antipsychotics – was significantly higher. So were their treatment satisfaction scores. And the clincher: The total net direct cost of treatment in the specialized mood disorders clinic averaged 3,194 euro less per patient, an 11% reduction relative to the cost of standard care, a striking economic benefit achieved mainly through avoided hospitalizations.

In a subsequent subgroup analysis of the randomized trial data, Dr. Kessing and coinvestigators demonstrated that young adults with bipolar disorder not only benefited from participation in the specialized outpatient clinic, but they appeared to have derived greater benefit than the older patients. The rehospitalization rate was 67% lower in 18- to 25-year-old patients randomized to the specialized outpatient mood disorder clinic than in standard-care controls, compared with a 32% relative risk reduction in outpatient clinic patients aged 26 years or older).

“There are now several centers around the world which also use this model involving early intervention,” Dr. Kessing said. “It is so important that, when the diagnosis is made for the first time, the patient gets sufficient evidence-based treatment comprised of mood maintenance medication as well as group-based psychoeducation, which is the psychotherapeutic intervention for which there is the strongest evidence of an effect.”

The sibling study was funded free of commercial support. Dr. Kessing reported serving as a consultant to Lundbeck.

bjancin@mdedge.com

SOURCE: Kessing LV. ECNP 2020, Session S.25.

The siblings of patients with bipolar disorder not only face a significantly increased lifetime risk of that affective disorder, but a whole panoply of other psychiatric disorders, according to a new Danish longitudinal national registry study.

“Our data show the healthy siblings of patients with bipolar disorder are themselves at increased risk of developing any kind of psychiatric disorder. Mainly bipolar disorder, but all other kinds as well,” Lars Vedel Kessing, MD, DMSc, said in presenting the results of the soon-to-be-published Danish study at the virtual congress of the European College of Neuropsychopharmacology.

Moreover, the long-term Danish study also demonstrated that several major psychiatric disorders follow a previously unappreciated bimodal distribution of age of onset in the siblings of patients with bipolar disorder. For example, the incidence of new-onset bipolar disorder and unipolar depression in the siblings was markedly increased during youth and early adulthood, compared with controls drawn from the general Danish population. Then, incidence rates dropped off and plateaued at a lower level in midlife before surging after age 60 years. The same was true for somatoform disorders as well as alcohol and substance use disorders.

“Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifelong, likely with differentiated age-specific approaches. And this is not now the case.

“Generally, most researchers and clinicians are focusing more on the early part of life and not the later part of life from age 60 and up, even though this is indeed also a risk period for any kind of psychiatric illness as well as bipolar disorder,” according to Dr. Kessing, professor of psychiatry at the University of Copenhagen.

Dr. Kessing, a past recipient of the Brain and Behavior Research Foundation’s Outstanding Achievement in Mood Disorders Research Award, also described his research group’s successful innovative efforts to prevent first recurrences after a single manic episode or bipolar disorder.
 

Danish national sibling study

The longitudinal registry study included all 19,995 Danish patients with a primary diagnosis of bipolar disorder during 1995-2017, along with 13,923 of their siblings and 278,460 age- and gender-matched controls drawn from the general population.

The cumulative incidence of any psychiatric disorder was 66% greater in siblings than controls. Leading the way was a 374% increased risk of bipolar disorder.
 

Strategies to prevent a first relapse of bipolar disorder

Dr. Kessing and coinvestigators demonstrated in a meta-analysis that, with current standard therapies, the risk of recurrence among patients after a single manic or mixed episode is high in both adult and pediatric patients. In three studies of adults, the risk of recurrence was 35% during the first year after recovery from the index episode and 59% at 2 years. In three studies of children and adolescents, the risk of recurrence within 1 year after recovery was 40% in children and 52% in adolescents. This makes a compelling case for starting maintenance therapy following onset of a single manic or mixed episode, according to the investigators.

More than half a decade ago, Dr. Kessing and colleagues demonstrated in a study of 4,714 Danish patients with bipolar disorder who were prescribed lithium while in a psychiatric hospital that those who started the drug for prophylaxis early – that is, following their first psychiatric contact – had a significantly higher response to lithium monotherapy than those who started it only after repeated contacts. Indeed, their risk of nonresponse to lithium prophylaxis as evidenced by repeat hospital admission after a 6-month lithium stabilization period was 13% lower than in those starting the drug later.

Early intervention aiming to stop clinical progression of bipolar disorder intuitively seems appealing, so Dr. Kessing and colleagues created a specialized outpatient mood disorders clinic combining optimized pharmacotherapy and evidence-based group psychoeducation. They then put it to the test in a clinical trial in which 158 patients discharged from an initial psychiatric hospital admission for bipolar disorder were randomized to the specialized outpatient mood disorders clinic or standard care.

The rate of psychiatric hospital readmission within the next 6 years was 40% lower in the group assigned to the specialized early intervention clinic. Their rate of adherence to medication – mostly lithium and antipsychotics – was significantly higher. So were their treatment satisfaction scores. And the clincher: The total net direct cost of treatment in the specialized mood disorders clinic averaged 3,194 euro less per patient, an 11% reduction relative to the cost of standard care, a striking economic benefit achieved mainly through avoided hospitalizations.

In a subsequent subgroup analysis of the randomized trial data, Dr. Kessing and coinvestigators demonstrated that young adults with bipolar disorder not only benefited from participation in the specialized outpatient clinic, but they appeared to have derived greater benefit than the older patients. The rehospitalization rate was 67% lower in 18- to 25-year-old patients randomized to the specialized outpatient mood disorder clinic than in standard-care controls, compared with a 32% relative risk reduction in outpatient clinic patients aged 26 years or older).

“There are now several centers around the world which also use this model involving early intervention,” Dr. Kessing said. “It is so important that, when the diagnosis is made for the first time, the patient gets sufficient evidence-based treatment comprised of mood maintenance medication as well as group-based psychoeducation, which is the psychotherapeutic intervention for which there is the strongest evidence of an effect.”

The sibling study was funded free of commercial support. Dr. Kessing reported serving as a consultant to Lundbeck.

bjancin@mdedge.com

SOURCE: Kessing LV. ECNP 2020, Session S.25.

The siblings of patients with bipolar disorder not only face a significantly increased lifetime risk of that affective disorder, but a whole panoply of other psychiatric disorders, according to a new Danish longitudinal national registry study.

“Our data show the healthy siblings of patients with bipolar disorder are themselves at increased risk of developing any kind of psychiatric disorder. Mainly bipolar disorder, but all other kinds as well,” Lars Vedel Kessing, MD, DMSc, said in presenting the results of the soon-to-be-published Danish study at the virtual congress of the European College of Neuropsychopharmacology.

Moreover, the long-term Danish study also demonstrated that several major psychiatric disorders follow a previously unappreciated bimodal distribution of age of onset in the siblings of patients with bipolar disorder. For example, the incidence of new-onset bipolar disorder and unipolar depression in the siblings was markedly increased during youth and early adulthood, compared with controls drawn from the general Danish population. Then, incidence rates dropped off and plateaued at a lower level in midlife before surging after age 60 years. The same was true for somatoform disorders as well as alcohol and substance use disorders.

“Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifelong, likely with differentiated age-specific approaches. And this is not now the case.

“Generally, most researchers and clinicians are focusing more on the early part of life and not the later part of life from age 60 and up, even though this is indeed also a risk period for any kind of psychiatric illness as well as bipolar disorder,” according to Dr. Kessing, professor of psychiatry at the University of Copenhagen.

Dr. Kessing, a past recipient of the Brain and Behavior Research Foundation’s Outstanding Achievement in Mood Disorders Research Award, also described his research group’s successful innovative efforts to prevent first recurrences after a single manic episode or bipolar disorder.
 

Danish national sibling study

The longitudinal registry study included all 19,995 Danish patients with a primary diagnosis of bipolar disorder during 1995-2017, along with 13,923 of their siblings and 278,460 age- and gender-matched controls drawn from the general population.

The cumulative incidence of any psychiatric disorder was 66% greater in siblings than controls. Leading the way was a 374% increased risk of bipolar disorder.
 

Strategies to prevent a first relapse of bipolar disorder

Dr. Kessing and coinvestigators demonstrated in a meta-analysis that, with current standard therapies, the risk of recurrence among patients after a single manic or mixed episode is high in both adult and pediatric patients. In three studies of adults, the risk of recurrence was 35% during the first year after recovery from the index episode and 59% at 2 years. In three studies of children and adolescents, the risk of recurrence within 1 year after recovery was 40% in children and 52% in adolescents. This makes a compelling case for starting maintenance therapy following onset of a single manic or mixed episode, according to the investigators.

More than half a decade ago, Dr. Kessing and colleagues demonstrated in a study of 4,714 Danish patients with bipolar disorder who were prescribed lithium while in a psychiatric hospital that those who started the drug for prophylaxis early – that is, following their first psychiatric contact – had a significantly higher response to lithium monotherapy than those who started it only after repeated contacts. Indeed, their risk of nonresponse to lithium prophylaxis as evidenced by repeat hospital admission after a 6-month lithium stabilization period was 13% lower than in those starting the drug later.

Early intervention aiming to stop clinical progression of bipolar disorder intuitively seems appealing, so Dr. Kessing and colleagues created a specialized outpatient mood disorders clinic combining optimized pharmacotherapy and evidence-based group psychoeducation. They then put it to the test in a clinical trial in which 158 patients discharged from an initial psychiatric hospital admission for bipolar disorder were randomized to the specialized outpatient mood disorders clinic or standard care.

The rate of psychiatric hospital readmission within the next 6 years was 40% lower in the group assigned to the specialized early intervention clinic. Their rate of adherence to medication – mostly lithium and antipsychotics – was significantly higher. So were their treatment satisfaction scores. And the clincher: The total net direct cost of treatment in the specialized mood disorders clinic averaged 3,194 euro less per patient, an 11% reduction relative to the cost of standard care, a striking economic benefit achieved mainly through avoided hospitalizations.

In a subsequent subgroup analysis of the randomized trial data, Dr. Kessing and coinvestigators demonstrated that young adults with bipolar disorder not only benefited from participation in the specialized outpatient clinic, but they appeared to have derived greater benefit than the older patients. The rehospitalization rate was 67% lower in 18- to 25-year-old patients randomized to the specialized outpatient mood disorder clinic than in standard-care controls, compared with a 32% relative risk reduction in outpatient clinic patients aged 26 years or older).

“There are now several centers around the world which also use this model involving early intervention,” Dr. Kessing said. “It is so important that, when the diagnosis is made for the first time, the patient gets sufficient evidence-based treatment comprised of mood maintenance medication as well as group-based psychoeducation, which is the psychotherapeutic intervention for which there is the strongest evidence of an effect.”

The sibling study was funded free of commercial support. Dr. Kessing reported serving as a consultant to Lundbeck.

bjancin@mdedge.com

SOURCE: Kessing LV. ECNP 2020, Session S.25.

Bundled opt-out HIV/hepatitis C virus (HCV) testing increased the percentage of syringe service program (SSP) clients who received HIV and HCV rapid tests at enrollment into the program. Researchers conducted a retrospective comparative analysis of patient testing patterns before and after opt-out policy implementation in a single SSP program, according to a report published online in the International Journal of Drug Policy.

Because HCV is the most common infectious disease among people who inject drugs (PWID), engaging PWID in harm reduction services, such as SSPs, is critical to reduce HCV and HIV transmission, according to Tyler S. Bartholomew of the University of Miami, and colleagues. They added that testing for HIV and HCV among PWID is important for improvement of diagnosis and linkage to care.

Their study, conducted in the 37 months between December 2016 and January 2020 assessed 512 SSP participants 15 months prior to and 547 SSP participants 22 months after implementation of bundled HIV/HCV opt-out testing.

Opt-out optimal

There was a significant increase in uptake of HIV/HCV testing by 42.4% (95% confidence interval, 26.2%-58.5%; P < 0.001) immediately after the policy changed to opt-out testing, according to the researchers. In addition, they found that the significant predictors of accepting both HIV/HCV tests were cocaine injection (adjusted odds ratio, 2.36), self-reported HIV-positive status (aOR, 0.39), and self-reported HCV-positive status (aOR, 0.27).

The authors explained that participants who injected cocaine in the previous 30 days, compared with other drugs, might have had higher odds of accepting HIV/HCV testing because of their known added risk factors. Previous studies have shown that people who use stimulants describe higher rates of condomless sex, sex work, and sex in exchange for money or drugs, compared with people who use nonstimulant drugs.

“Our paper is the first of which we are aware to suggest that implementation of routine opt-out HIV/HCV testing among PWID at SSPs could enhance HIV/HCV testing among this high incidence population,” the researchers concluded.

The authors reported funding from the National Cancer Institute and the Frontlines of Communities in the United States, a program of Gilead Sciences. They provided no other disclosures.

mlesney@mdedge.com

SOURCE: Bartholomew TS et al. Int J Drug Policy. 2020; doi: 10.1016/j.drugpo.2020.102875.

Bundled opt-out HIV/hepatitis C virus (HCV) testing increased the percentage of syringe service program (SSP) clients who received HIV and HCV rapid tests at enrollment into the program. Researchers conducted a retrospective comparative analysis of patient testing patterns before and after opt-out policy implementation in a single SSP program, according to a report published online in the International Journal of Drug Policy.

Because HCV is the most common infectious disease among people who inject drugs (PWID), engaging PWID in harm reduction services, such as SSPs, is critical to reduce HCV and HIV transmission, according to Tyler S. Bartholomew of the University of Miami, and colleagues. They added that testing for HIV and HCV among PWID is important for improvement of diagnosis and linkage to care.

Their study, conducted in the 37 months between December 2016 and January 2020 assessed 512 SSP participants 15 months prior to and 547 SSP participants 22 months after implementation of bundled HIV/HCV opt-out testing.

Opt-out optimal

There was a significant increase in uptake of HIV/HCV testing by 42.4% (95% confidence interval, 26.2%-58.5%; P < 0.001) immediately after the policy changed to opt-out testing, according to the researchers. In addition, they found that the significant predictors of accepting both HIV/HCV tests were cocaine injection (adjusted odds ratio, 2.36), self-reported HIV-positive status (aOR, 0.39), and self-reported HCV-positive status (aOR, 0.27).

The authors explained that participants who injected cocaine in the previous 30 days, compared with other drugs, might have had higher odds of accepting HIV/HCV testing because of their known added risk factors. Previous studies have shown that people who use stimulants describe higher rates of condomless sex, sex work, and sex in exchange for money or drugs, compared with people who use nonstimulant drugs.

“Our paper is the first of which we are aware to suggest that implementation of routine opt-out HIV/HCV testing among PWID at SSPs could enhance HIV/HCV testing among this high incidence population,” the researchers concluded.

The authors reported funding from the National Cancer Institute and the Frontlines of Communities in the United States, a program of Gilead Sciences. They provided no other disclosures.

mlesney@mdedge.com

SOURCE: Bartholomew TS et al. Int J Drug Policy. 2020; doi: 10.1016/j.drugpo.2020.102875.

Bundled opt-out HIV/hepatitis C virus (HCV) testing increased the percentage of syringe service program (SSP) clients who received HIV and HCV rapid tests at enrollment into the program. Researchers conducted a retrospective comparative analysis of patient testing patterns before and after opt-out policy implementation in a single SSP program, according to a report published online in the International Journal of Drug Policy.

Because HCV is the most common infectious disease among people who inject drugs (PWID), engaging PWID in harm reduction services, such as SSPs, is critical to reduce HCV and HIV transmission, according to Tyler S. Bartholomew of the University of Miami, and colleagues. They added that testing for HIV and HCV among PWID is important for improvement of diagnosis and linkage to care.

Their study, conducted in the 37 months between December 2016 and January 2020 assessed 512 SSP participants 15 months prior to and 547 SSP participants 22 months after implementation of bundled HIV/HCV opt-out testing.

Opt-out optimal

There was a significant increase in uptake of HIV/HCV testing by 42.4% (95% confidence interval, 26.2%-58.5%; P < 0.001) immediately after the policy changed to opt-out testing, according to the researchers. In addition, they found that the significant predictors of accepting both HIV/HCV tests were cocaine injection (adjusted odds ratio, 2.36), self-reported HIV-positive status (aOR, 0.39), and self-reported HCV-positive status (aOR, 0.27).

The authors explained that participants who injected cocaine in the previous 30 days, compared with other drugs, might have had higher odds of accepting HIV/HCV testing because of their known added risk factors. Previous studies have shown that people who use stimulants describe higher rates of condomless sex, sex work, and sex in exchange for money or drugs, compared with people who use nonstimulant drugs.

“Our paper is the first of which we are aware to suggest that implementation of routine opt-out HIV/HCV testing among PWID at SSPs could enhance HIV/HCV testing among this high incidence population,” the researchers concluded.

The authors reported funding from the National Cancer Institute and the Frontlines of Communities in the United States, a program of Gilead Sciences. They provided no other disclosures.

mlesney@mdedge.com

SOURCE: Bartholomew TS et al. Int J Drug Policy. 2020; doi: 10.1016/j.drugpo.2020.102875.

Over 818,000 plans were selected for the 2021 coverage year during the first week, Nov.1-7, of this year’s open enrollment on the federal health insurance exchange, according to the Centers for Medicare & Medicaid Services.

The bulk of those plans, nearly 79%, were renewals by consumers who had coverage through the federal exchange this year. The balance covers new plans selected by individuals who were not covered through HealthCare.gov this year, the CMS noted in a written statement.

The total enrollment for week 1 marks a considerable increase over last year’s first week of open enrollment, which saw approximately 177,000 plans selected, but Nov. 1 fell on a Friday in 2019, so that total represents only 2 days since weeks are tracked as running from Sunday to Saturday, the CMS explained.

For the 2021 benefit year, the HealthCare.gov platform covers 36 states, down from 38 for the 2020 benefit year, because New Jersey and Pennsylvania have “transitioned to their own state-based exchange platforms,” the CMS noted, adding that the two accounted for 7% of all plans selected last year.

“The final number of plan selections associated with enrollment activity during a reporting period may change due to plan modifications or cancellations,” CMS said, and its weekly snapshot “does not report the number of consumers who have paid premiums to effectuate their enrollment.”

This year’s open-enrollment period on HealthCare.gov is scheduled to conclude Dec. 15.

rfranki@mdedge.com

Over 818,000 plans were selected for the 2021 coverage year during the first week, Nov.1-7, of this year’s open enrollment on the federal health insurance exchange, according to the Centers for Medicare & Medicaid Services.

The bulk of those plans, nearly 79%, were renewals by consumers who had coverage through the federal exchange this year. The balance covers new plans selected by individuals who were not covered through HealthCare.gov this year, the CMS noted in a written statement.

The total enrollment for week 1 marks a considerable increase over last year’s first week of open enrollment, which saw approximately 177,000 plans selected, but Nov. 1 fell on a Friday in 2019, so that total represents only 2 days since weeks are tracked as running from Sunday to Saturday, the CMS explained.

For the 2021 benefit year, the HealthCare.gov platform covers 36 states, down from 38 for the 2020 benefit year, because New Jersey and Pennsylvania have “transitioned to their own state-based exchange platforms,” the CMS noted, adding that the two accounted for 7% of all plans selected last year.

“The final number of plan selections associated with enrollment activity during a reporting period may change due to plan modifications or cancellations,” CMS said, and its weekly snapshot “does not report the number of consumers who have paid premiums to effectuate their enrollment.”

This year’s open-enrollment period on HealthCare.gov is scheduled to conclude Dec. 15.

rfranki@mdedge.com

Over 818,000 plans were selected for the 2021 coverage year during the first week, Nov.1-7, of this year’s open enrollment on the federal health insurance exchange, according to the Centers for Medicare & Medicaid Services.

The bulk of those plans, nearly 79%, were renewals by consumers who had coverage through the federal exchange this year. The balance covers new plans selected by individuals who were not covered through HealthCare.gov this year, the CMS noted in a written statement.

The total enrollment for week 1 marks a considerable increase over last year’s first week of open enrollment, which saw approximately 177,000 plans selected, but Nov. 1 fell on a Friday in 2019, so that total represents only 2 days since weeks are tracked as running from Sunday to Saturday, the CMS explained.

For the 2021 benefit year, the HealthCare.gov platform covers 36 states, down from 38 for the 2020 benefit year, because New Jersey and Pennsylvania have “transitioned to their own state-based exchange platforms,” the CMS noted, adding that the two accounted for 7% of all plans selected last year.

“The final number of plan selections associated with enrollment activity during a reporting period may change due to plan modifications or cancellations,” CMS said, and its weekly snapshot “does not report the number of consumers who have paid premiums to effectuate their enrollment.”

This year’s open-enrollment period on HealthCare.gov is scheduled to conclude Dec. 15.

rfranki@mdedge.com

Nail unit squamous cell carcinoma (NSCC) is a malignant neoplasm that can arise from any part of the nail unit. Diagnosis often is delayed due to its clinical presentation mimicking benign conditions such as onychomycosis, warts, and paronychia. Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion. It is imperative for dermatologists who are early in their training to recognize this entity and refer for treatment. Many approaches have been used to treat NSCC, including wide local excision, digital amputation, cryotherapy, topical modalities, and recently Mohs micrographic surgery (MMS). This article provides an overview of the clinical presentation and diagnosis of NSCC, the role of human papillomavirus (HPV) in NSCC pathogenesis, and the evidence supporting surgical management.

NSCC Clinical Presentation and Diagnosis

Nail unit squamous cell carcinoma is a malignant neoplasm that can arise from any part of the nail unit including the nail bed, matrix, groove, and nail fold.¹ Although NSCC is the most common malignant nail neoplasm, its diagnosis often is delayed partly due to the clinical presentation of NSCC mimicking benign conditions such as onychomycosis, warts, and paronychia.^2,3 Nail unit SCC most commonly is mistaken for verruca vulgaris, and thus it is important to exclude malignancy in nonresolving verrucae of the fingernails or toenails. Another reason for a delay in the diagnosis is the painless and often asymptomatic presentation of this tumor, which keeps patients from seeking care.⁴ While evaluating a subungual lesion, dermatologists should keep in mind red flags that would prompt a biopsy to rule out NSCC (Table 1), including chronic nonhealing lesions, nail plate nodularity, known history of infection with HPV types 16 and 18, history of radiation or arsenic exposure, and immunosuppression. Table 2 lists the differential diagnosis of a persisting or nonhealing subungual tumor.

Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion.⁵ Based on several reports, NSCC more commonly is found in middle-aged and older individuals, has a male predilection, and more often is seen on fingernails than toenails.^1,2,6 Figure A shows an example of the clinical presentation of NSCC affecting the right thumb.

Histologic Features

A biopsy from an NSCC tumor shows features similar to cutaneous SCC in the affected areas (ie, nail bed, nail matrix, nail groove, nail fold). Characteristic histologic findings include tongues or whorls of atypical squamous epithelium that invade deeply into the dermis.¹¹ The cells appear as atypical keratinocytes, exhibit distinct intracellular bridges, and possess hyperchromatic and pleomorphic nuclei with dyskeratosis and keratin pearls within the dermis.¹² Immunoperoxidase staining for cytokeratin AE1/AE3 can be helpful to confirm the diagnosis and assess whether the depth of invasion involves the bone.¹³ Figures B and C demonstrate the histopathology of NSCC biopsied from the tumor shown in Figure A.

Role of HPV in NSCC Pathogenesis

There is no clear pathogenic etiology for NSCC; however, there have been some reports of HPV as a risk factor. Shimizu et al¹⁴ reviewed 136 cases of HPV-associated NSCC and found that half of the cases were associated with high-risk HPV. They also found that 24% of the patients with NSCC had a history of other HPV-associated diseases. As such, the authors hypothesized that there is a possibility for genitodigital HPV transmission and that NSCC could be a reservoir for sexually transmitted high-risk HPV.¹⁴ Other risk factors are radiation exposure, chemical insult, and chronic trauma.¹⁵ The higher propensity for fingernails likely is reflective of the role of UV light exposure and infection with HPV in the development of these tumors.^14,15

Treatment Options for NSCC

Several nonsurgical approaches have been suggested to treat NSCC, including topical agents, cryotherapy, CO₂ laser, and photodynamic therapy.^3,16 Unfortunately, there are no large case series to demonstrate the cure rate or effectiveness of these methods.¹⁷ In one study, the authors did not recommend use of photodynamic therapy or topical modalities such as imiquimod cream 5% or fluorouracil cream 5% as first-line treatments of NSCC due to the difficulty in ensuring complete treatment of the sulci of the lateral and proximal nail folds.¹⁸

More evidence in the literature supports surgical approaches, including wide local excision, MMS, and digital amputation. Clinicians should consider relapse rates and the impact on digital functioning when choosing a surgical approach.

For wide local excisions, the most common approach is en bloc excision of the nail unit including the lateral nail folds, the proximal nail fold, and the distal nail fold. The excision starts with a transverse incision on the base of the distal phalanx, which is then prolonged laterally and distally to the distal nail fold down to the bone. After the incision is made to the depth of the bone, the matrical horns are destroyed by electrocoagulation, and the defect is closed either by a full-thickness skin graft or secondary intent.¹⁹

Topin-Ruiz et al¹⁹ followed patients with biopsy-proven NSCC without bone invasion who underwent en bloc excision followed by full-thickness skin graft. In their consecutive series of 55 patients with 5 years of follow-up, the rate of recurrence was only 4%. There was a low rate of complications including graft infection, delayed wound healing, and severe pain in a small percentage of patients. They also reported a high patient satisfaction rate.¹⁹ Due to the low recurrence rate, this study suggested that total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment of NSCC without bone involvement. Similarly, in another case series, wide local excision of the entire nail apparatus had a relapse rate of only 5%, in contrast to partial excision of the nail unit with a relapse of 56%.²⁰ These studies suggest that wide nail unit excision is an acceptable and effective approach; however, in cases in which invasion cannot be ruled out, histologic clearance would be a reasonable approach.²¹ As such, several case series demonstrated the merits of MMS for NSCC. de Berker et al²² reported 8 patients with NSCC treated using slow MMS and showed tumor clearance after a mean of 3 stages over a mean period of 6.9 days. In all cases, the wounds were allowed to heal by secondary intention, and the distal phalanx was preserved. During a mean follow-up period of 3.1 years, no recurrence was seen, and involved digits remained functional.²²

Other studies tested the efficacy of MMS for NSCC. Young et al²³ reported the outcomes of 14 NSCC cases treated with MMS. In their case series, they found that the mean number of MMS surgical stages required to achieve histologic clearance was 2, while the mean number of tissue sections was 4.²³ All cases were allowed to heal by secondary intent with excellent outcomes, except for 1 patient who received primary closure of a small defect. They reported a 78% cure rate with an average time to recurrence of 47 months.²³ In a series of 42 cases of NSCC treated with MMS, Gou et al¹⁷ noted a cure rate close to 93%. In their study, recurrences were observed in only 3 patients (7.1%). These recurrent cases were then successfully treated with another round of MMS.¹⁷ This study’s cure rate was comparable to the cure rate of MMS for SCC in other cutaneous areas. Goldminz and Bennett²⁴ demonstrated a cure rate of 92% in their case series of 25 patients. Two patients developed recurrent disease and were treated again with MMS resulting in no subsequent recurrence. In this study, the authors allowed all defects to heal by secondary intention and found that there were excellent cosmetic and functional outcomes.²⁴ Dika et al²⁵ evaluated the long-term effectiveness of MMS in the treatment of NSCC, in particular its ability to reduce the number of digital amputations. Fifteen patients diagnosed with NSCC were treated with MMS as the first-line surgical approach and were followed for 2 to 5 years. They found that in utilizing MMS, they were able to avoid amputations in 13 of 15 cases with no recurrence in any of these tumors. Two cases, however, still required amputation of the distal phalanx.²⁵

Although these studies suggest that MMS achieves a high cure rate ranging from 78% to 93%, it is not yet clear in the literature whether MMS is superior to wide local excision. More studies and clinical trials comparing these 2 surgical approaches should be performed to identify which surgical approach would be the gold standard for NSCC and which select cases would benefit from MMS as first-line treatment.

Final Thoughts

Nail unit SCC is one of the most common nail unit malignancies and can mimic several benign entities. Dermatologists who are early in their training should consider biopsy of subungual lesions with certain red flags (Table 1). It is important to diagnose NSCC for early intervention. Referral for wide local excision or MMS would be ideal. There are data in the literature supporting both surgical approaches as being effective; however, there are no trials comparing both approaches. Distal amputation should be considered as a last resort when wide local excision is not reasonable or when MMS fails to achieve clear margins, thereby reducing unnecessary amputations and patient morbidity.¹⁷

Nail unit squamous cell carcinoma (NSCC) is a malignant neoplasm that can arise from any part of the nail unit. Diagnosis often is delayed due to its clinical presentation mimicking benign conditions such as onychomycosis, warts, and paronychia. Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion. It is imperative for dermatologists who are early in their training to recognize this entity and refer for treatment. Many approaches have been used to treat NSCC, including wide local excision, digital amputation, cryotherapy, topical modalities, and recently Mohs micrographic surgery (MMS). This article provides an overview of the clinical presentation and diagnosis of NSCC, the role of human papillomavirus (HPV) in NSCC pathogenesis, and the evidence supporting surgical management.

NSCC Clinical Presentation and Diagnosis

Nail unit squamous cell carcinoma is a malignant neoplasm that can arise from any part of the nail unit including the nail bed, matrix, groove, and nail fold.¹ Although NSCC is the most common malignant nail neoplasm, its diagnosis often is delayed partly due to the clinical presentation of NSCC mimicking benign conditions such as onychomycosis, warts, and paronychia.^2,3 Nail unit SCC most commonly is mistaken for verruca vulgaris, and thus it is important to exclude malignancy in nonresolving verrucae of the fingernails or toenails. Another reason for a delay in the diagnosis is the painless and often asymptomatic presentation of this tumor, which keeps patients from seeking care.⁴ While evaluating a subungual lesion, dermatologists should keep in mind red flags that would prompt a biopsy to rule out NSCC (Table 1), including chronic nonhealing lesions, nail plate nodularity, known history of infection with HPV types 16 and 18, history of radiation or arsenic exposure, and immunosuppression. Table 2 lists the differential diagnosis of a persisting or nonhealing subungual tumor.

Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion.⁵ Based on several reports, NSCC more commonly is found in middle-aged and older individuals, has a male predilection, and more often is seen on fingernails than toenails.^1,2,6 Figure A shows an example of the clinical presentation of NSCC affecting the right thumb.

Histologic Features

A biopsy from an NSCC tumor shows features similar to cutaneous SCC in the affected areas (ie, nail bed, nail matrix, nail groove, nail fold). Characteristic histologic findings include tongues or whorls of atypical squamous epithelium that invade deeply into the dermis.¹¹ The cells appear as atypical keratinocytes, exhibit distinct intracellular bridges, and possess hyperchromatic and pleomorphic nuclei with dyskeratosis and keratin pearls within the dermis.¹² Immunoperoxidase staining for cytokeratin AE1/AE3 can be helpful to confirm the diagnosis and assess whether the depth of invasion involves the bone.¹³ Figures B and C demonstrate the histopathology of NSCC biopsied from the tumor shown in Figure A.

Role of HPV in NSCC Pathogenesis

There is no clear pathogenic etiology for NSCC; however, there have been some reports of HPV as a risk factor. Shimizu et al¹⁴ reviewed 136 cases of HPV-associated NSCC and found that half of the cases were associated with high-risk HPV. They also found that 24% of the patients with NSCC had a history of other HPV-associated diseases. As such, the authors hypothesized that there is a possibility for genitodigital HPV transmission and that NSCC could be a reservoir for sexually transmitted high-risk HPV.¹⁴ Other risk factors are radiation exposure, chemical insult, and chronic trauma.¹⁵ The higher propensity for fingernails likely is reflective of the role of UV light exposure and infection with HPV in the development of these tumors.^14,15

Treatment Options for NSCC

Several nonsurgical approaches have been suggested to treat NSCC, including topical agents, cryotherapy, CO₂ laser, and photodynamic therapy.^3,16 Unfortunately, there are no large case series to demonstrate the cure rate or effectiveness of these methods.¹⁷ In one study, the authors did not recommend use of photodynamic therapy or topical modalities such as imiquimod cream 5% or fluorouracil cream 5% as first-line treatments of NSCC due to the difficulty in ensuring complete treatment of the sulci of the lateral and proximal nail folds.¹⁸

More evidence in the literature supports surgical approaches, including wide local excision, MMS, and digital amputation. Clinicians should consider relapse rates and the impact on digital functioning when choosing a surgical approach.

For wide local excisions, the most common approach is en bloc excision of the nail unit including the lateral nail folds, the proximal nail fold, and the distal nail fold. The excision starts with a transverse incision on the base of the distal phalanx, which is then prolonged laterally and distally to the distal nail fold down to the bone. After the incision is made to the depth of the bone, the matrical horns are destroyed by electrocoagulation, and the defect is closed either by a full-thickness skin graft or secondary intent.¹⁹

Topin-Ruiz et al¹⁹ followed patients with biopsy-proven NSCC without bone invasion who underwent en bloc excision followed by full-thickness skin graft. In their consecutive series of 55 patients with 5 years of follow-up, the rate of recurrence was only 4%. There was a low rate of complications including graft infection, delayed wound healing, and severe pain in a small percentage of patients. They also reported a high patient satisfaction rate.¹⁹ Due to the low recurrence rate, this study suggested that total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment of NSCC without bone involvement. Similarly, in another case series, wide local excision of the entire nail apparatus had a relapse rate of only 5%, in contrast to partial excision of the nail unit with a relapse of 56%.²⁰ These studies suggest that wide nail unit excision is an acceptable and effective approach; however, in cases in which invasion cannot be ruled out, histologic clearance would be a reasonable approach.²¹ As such, several case series demonstrated the merits of MMS for NSCC. de Berker et al²² reported 8 patients with NSCC treated using slow MMS and showed tumor clearance after a mean of 3 stages over a mean period of 6.9 days. In all cases, the wounds were allowed to heal by secondary intention, and the distal phalanx was preserved. During a mean follow-up period of 3.1 years, no recurrence was seen, and involved digits remained functional.²²

Other studies tested the efficacy of MMS for NSCC. Young et al²³ reported the outcomes of 14 NSCC cases treated with MMS. In their case series, they found that the mean number of MMS surgical stages required to achieve histologic clearance was 2, while the mean number of tissue sections was 4.²³ All cases were allowed to heal by secondary intent with excellent outcomes, except for 1 patient who received primary closure of a small defect. They reported a 78% cure rate with an average time to recurrence of 47 months.²³ In a series of 42 cases of NSCC treated with MMS, Gou et al¹⁷ noted a cure rate close to 93%. In their study, recurrences were observed in only 3 patients (7.1%). These recurrent cases were then successfully treated with another round of MMS.¹⁷ This study’s cure rate was comparable to the cure rate of MMS for SCC in other cutaneous areas. Goldminz and Bennett²⁴ demonstrated a cure rate of 92% in their case series of 25 patients. Two patients developed recurrent disease and were treated again with MMS resulting in no subsequent recurrence. In this study, the authors allowed all defects to heal by secondary intention and found that there were excellent cosmetic and functional outcomes.²⁴ Dika et al²⁵ evaluated the long-term effectiveness of MMS in the treatment of NSCC, in particular its ability to reduce the number of digital amputations. Fifteen patients diagnosed with NSCC were treated with MMS as the first-line surgical approach and were followed for 2 to 5 years. They found that in utilizing MMS, they were able to avoid amputations in 13 of 15 cases with no recurrence in any of these tumors. Two cases, however, still required amputation of the distal phalanx.²⁵

Although these studies suggest that MMS achieves a high cure rate ranging from 78% to 93%, it is not yet clear in the literature whether MMS is superior to wide local excision. More studies and clinical trials comparing these 2 surgical approaches should be performed to identify which surgical approach would be the gold standard for NSCC and which select cases would benefit from MMS as first-line treatment.

Final Thoughts

Nail unit SCC is one of the most common nail unit malignancies and can mimic several benign entities. Dermatologists who are early in their training should consider biopsy of subungual lesions with certain red flags (Table 1). It is important to diagnose NSCC for early intervention. Referral for wide local excision or MMS would be ideal. There are data in the literature supporting both surgical approaches as being effective; however, there are no trials comparing both approaches. Distal amputation should be considered as a last resort when wide local excision is not reasonable or when MMS fails to achieve clear margins, thereby reducing unnecessary amputations and patient morbidity.¹⁷

Nail unit squamous cell carcinoma (NSCC) is a malignant neoplasm that can arise from any part of the nail unit. Diagnosis often is delayed due to its clinical presentation mimicking benign conditions such as onychomycosis, warts, and paronychia. Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion. It is imperative for dermatologists who are early in their training to recognize this entity and refer for treatment. Many approaches have been used to treat NSCC, including wide local excision, digital amputation, cryotherapy, topical modalities, and recently Mohs micrographic surgery (MMS). This article provides an overview of the clinical presentation and diagnosis of NSCC, the role of human papillomavirus (HPV) in NSCC pathogenesis, and the evidence supporting surgical management.

NSCC Clinical Presentation and Diagnosis

Nail unit squamous cell carcinoma is a malignant neoplasm that can arise from any part of the nail unit including the nail bed, matrix, groove, and nail fold.¹ Although NSCC is the most common malignant nail neoplasm, its diagnosis often is delayed partly due to the clinical presentation of NSCC mimicking benign conditions such as onychomycosis, warts, and paronychia.^2,3 Nail unit SCC most commonly is mistaken for verruca vulgaris, and thus it is important to exclude malignancy in nonresolving verrucae of the fingernails or toenails. Another reason for a delay in the diagnosis is the painless and often asymptomatic presentation of this tumor, which keeps patients from seeking care.⁴ While evaluating a subungual lesion, dermatologists should keep in mind red flags that would prompt a biopsy to rule out NSCC (Table 1), including chronic nonhealing lesions, nail plate nodularity, known history of infection with HPV types 16 and 18, history of radiation or arsenic exposure, and immunosuppression. Table 2 lists the differential diagnosis of a persisting or nonhealing subungual tumor.

Nail unit SCC has a low rate of metastasis; however, a delayed diagnosis often can result in local destruction and bone invasion.⁵ Based on several reports, NSCC more commonly is found in middle-aged and older individuals, has a male predilection, and more often is seen on fingernails than toenails.^1,2,6 Figure A shows an example of the clinical presentation of NSCC affecting the right thumb.

Histologic Features

A biopsy from an NSCC tumor shows features similar to cutaneous SCC in the affected areas (ie, nail bed, nail matrix, nail groove, nail fold). Characteristic histologic findings include tongues or whorls of atypical squamous epithelium that invade deeply into the dermis.¹¹ The cells appear as atypical keratinocytes, exhibit distinct intracellular bridges, and possess hyperchromatic and pleomorphic nuclei with dyskeratosis and keratin pearls within the dermis.¹² Immunoperoxidase staining for cytokeratin AE1/AE3 can be helpful to confirm the diagnosis and assess whether the depth of invasion involves the bone.¹³ Figures B and C demonstrate the histopathology of NSCC biopsied from the tumor shown in Figure A.

Role of HPV in NSCC Pathogenesis

There is no clear pathogenic etiology for NSCC; however, there have been some reports of HPV as a risk factor. Shimizu et al¹⁴ reviewed 136 cases of HPV-associated NSCC and found that half of the cases were associated with high-risk HPV. They also found that 24% of the patients with NSCC had a history of other HPV-associated diseases. As such, the authors hypothesized that there is a possibility for genitodigital HPV transmission and that NSCC could be a reservoir for sexually transmitted high-risk HPV.¹⁴ Other risk factors are radiation exposure, chemical insult, and chronic trauma.¹⁵ The higher propensity for fingernails likely is reflective of the role of UV light exposure and infection with HPV in the development of these tumors.^14,15

Treatment Options for NSCC

Several nonsurgical approaches have been suggested to treat NSCC, including topical agents, cryotherapy, CO₂ laser, and photodynamic therapy.^3,16 Unfortunately, there are no large case series to demonstrate the cure rate or effectiveness of these methods.¹⁷ In one study, the authors did not recommend use of photodynamic therapy or topical modalities such as imiquimod cream 5% or fluorouracil cream 5% as first-line treatments of NSCC due to the difficulty in ensuring complete treatment of the sulci of the lateral and proximal nail folds.¹⁸

More evidence in the literature supports surgical approaches, including wide local excision, MMS, and digital amputation. Clinicians should consider relapse rates and the impact on digital functioning when choosing a surgical approach.

For wide local excisions, the most common approach is en bloc excision of the nail unit including the lateral nail folds, the proximal nail fold, and the distal nail fold. The excision starts with a transverse incision on the base of the distal phalanx, which is then prolonged laterally and distally to the distal nail fold down to the bone. After the incision is made to the depth of the bone, the matrical horns are destroyed by electrocoagulation, and the defect is closed either by a full-thickness skin graft or secondary intent.¹⁹

Topin-Ruiz et al¹⁹ followed patients with biopsy-proven NSCC without bone invasion who underwent en bloc excision followed by full-thickness skin graft. In their consecutive series of 55 patients with 5 years of follow-up, the rate of recurrence was only 4%. There was a low rate of complications including graft infection, delayed wound healing, and severe pain in a small percentage of patients. They also reported a high patient satisfaction rate.¹⁹ Due to the low recurrence rate, this study suggested that total excision of the nail unit followed by a full-thickness skin graft is a safe and efficient treatment of NSCC without bone involvement. Similarly, in another case series, wide local excision of the entire nail apparatus had a relapse rate of only 5%, in contrast to partial excision of the nail unit with a relapse of 56%.²⁰ These studies suggest that wide nail unit excision is an acceptable and effective approach; however, in cases in which invasion cannot be ruled out, histologic clearance would be a reasonable approach.²¹ As such, several case series demonstrated the merits of MMS for NSCC. de Berker et al²² reported 8 patients with NSCC treated using slow MMS and showed tumor clearance after a mean of 3 stages over a mean period of 6.9 days. In all cases, the wounds were allowed to heal by secondary intention, and the distal phalanx was preserved. During a mean follow-up period of 3.1 years, no recurrence was seen, and involved digits remained functional.²²

Other studies tested the efficacy of MMS for NSCC. Young et al²³ reported the outcomes of 14 NSCC cases treated with MMS. In their case series, they found that the mean number of MMS surgical stages required to achieve histologic clearance was 2, while the mean number of tissue sections was 4.²³ All cases were allowed to heal by secondary intent with excellent outcomes, except for 1 patient who received primary closure of a small defect. They reported a 78% cure rate with an average time to recurrence of 47 months.²³ In a series of 42 cases of NSCC treated with MMS, Gou et al¹⁷ noted a cure rate close to 93%. In their study, recurrences were observed in only 3 patients (7.1%). These recurrent cases were then successfully treated with another round of MMS.¹⁷ This study’s cure rate was comparable to the cure rate of MMS for SCC in other cutaneous areas. Goldminz and Bennett²⁴ demonstrated a cure rate of 92% in their case series of 25 patients. Two patients developed recurrent disease and were treated again with MMS resulting in no subsequent recurrence. In this study, the authors allowed all defects to heal by secondary intention and found that there were excellent cosmetic and functional outcomes.²⁴ Dika et al²⁵ evaluated the long-term effectiveness of MMS in the treatment of NSCC, in particular its ability to reduce the number of digital amputations. Fifteen patients diagnosed with NSCC were treated with MMS as the first-line surgical approach and were followed for 2 to 5 years. They found that in utilizing MMS, they were able to avoid amputations in 13 of 15 cases with no recurrence in any of these tumors. Two cases, however, still required amputation of the distal phalanx.²⁵

Although these studies suggest that MMS achieves a high cure rate ranging from 78% to 93%, it is not yet clear in the literature whether MMS is superior to wide local excision. More studies and clinical trials comparing these 2 surgical approaches should be performed to identify which surgical approach would be the gold standard for NSCC and which select cases would benefit from MMS as first-line treatment.

Final Thoughts

Nail unit SCC is one of the most common nail unit malignancies and can mimic several benign entities. Dermatologists who are early in their training should consider biopsy of subungual lesions with certain red flags (Table 1). It is important to diagnose NSCC for early intervention. Referral for wide local excision or MMS would be ideal. There are data in the literature supporting both surgical approaches as being effective; however, there are no trials comparing both approaches. Distal amputation should be considered as a last resort when wide local excision is not reasonable or when MMS fails to achieve clear margins, thereby reducing unnecessary amputations and patient morbidity.¹⁷