An 11-year-old boy sought care at a small village’s health center in Panama for scalp itching and subtle hair loss. He was seen by a family physician (RU) and a team of medical students who were there as part of a humanitarian trip. The patient denied any hair pulling. He had a history of treatment for head lice.

Our physical examination revealed mild alopecia and scaling on the scalp (FIGURE 1), but what we saw through the dermatoscope (FIGURE 2) made the diagnosis clear.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Tinea capitis

On dermatoscopic examination (10× magnification), there were numerous “black dots” or broken hair shafts within patches of hair loss (FIGURE 3), which is indicative of tinea capitis.^1,2 This condition causes hair shafts to break, creating “comma hairs” and black dots. The hairs are uniform in thickness and color and bend distally, like a comma.³

Tinea capitis (commonly called ringworm of the scalp) is a fungal infection caused by Trichophyton and Microsporum dermatophytes. It is the most common pediatric dermatophyte infection in the world; the usual age of onset is 5 to 10 years.² The incidence of tinea capitis in the United States is not known because cases are no longer registered by public health agencies. That said, a Northern California study that tracked occurrences in children younger than 15 years from 1998 to 2007 found that the incidence was on the decline and lower in girls compared to boys (111.9 vs 146.4, respectively, in 1998; 27.9 vs 39.9, respectively, in 2007).⁴ Incidence rates were calculated per 10,000 eligible children.⁴

Tinea capitis can spread by contact with infected individuals and contaminated objects, including combs, towels, toys, and bedding.¹ Fungal spores can remain viable on these surfaces for months.

In a study of 69 patients with tinea capitis (23 females, 46 males; mean age, 12 years), the risk factors for spreading infection included participation in sports, contact with an animal, a recent haircut, and use of a swimming pool.⁵

4 conditions you’ll want to rule out

The following conditions should be considered as part of the differential when a patient presents with an itchy scalp and/or hair loss.

Continue to: Psoriasis of the scalp...

Psoriasis of the scalp is characterized by scaling of the scalp along with crusted plaques. It is often accompanied by similar psoriatic plaques on the elbows, knees, and other areas of the body. Examination of our patient showed no psoriatic plaques.

Seborrhea of the scalp (also known as dandruff) is a very common diagnosis. However, it is unlikely to cause hair loss. It has widespread involvement of the scalp compared to tinea capitis, which is local and patchy. Our patient’s patches of hair loss indicated that seborrhea was unlikely.

Alopecia areata. Individuals develop this condition due to an autoimmune process affecting hair follicles. However, the resulting hair loss does not cause significant scaling, inflammation, scarring, or pain in the affected area. Further, this condition can cause the loss of the entire hair shaft.

Trichotillomania is an impulse control disorder that causes patients to pull out their own hair. There is no scaling of the scalp in this condition.

A dermatoscope can beuseful in making the Dx

Although clinical appearance and patient presentation are adequate to establish the diagnosis of tinea capitis, this case demonstrates the utility of a dermatoscope in making the diagnosis of tinea capitis. Previous studies have shown that dermoscopy allows for rapid identification of the broken hair shafts, which are a key distinction from alopecia areata.^3,6

Microscopic inspection. Samples from the scaling of the scalp can be examined with potassium hydroxide (KOH) on a microscope slide. Hyphae, spores, and endo/ectothrix invasion can be seen through the microsope.  

Continue to: Laboratory testing is helpful, but not needed.

Newer antifungalsprovide a Tx advantage

Oral antifungal medications are the treatment of choice for tinea capitis. Newer antifungals, such as terbinafine and fluconazole, require a 3- to 6-week course compared to the standard 6- to 8-week course of griseofulvin.¹ Also, antifungal shampoos—such as those that contain selenium sulfide—may be used for topical treatment but only as adjuvant therapy.^1,2

For our patient, we dispensed a 3-week course of oral fluconazole, 3 to 6 mg/kg, to be given daily by his parents. We also recommended the use of an antidandruff shampoo, if possible. The treatment outcome was not known because our team’s humanitarian global health trip had ended.

An 11-year-old boy sought care at a small village’s health center in Panama for scalp itching and subtle hair loss. He was seen by a family physician (RU) and a team of medical students who were there as part of a humanitarian trip. The patient denied any hair pulling. He had a history of treatment for head lice.

Our physical examination revealed mild alopecia and scaling on the scalp (FIGURE 1), but what we saw through the dermatoscope (FIGURE 2) made the diagnosis clear.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Tinea capitis

On dermatoscopic examination (10× magnification), there were numerous “black dots” or broken hair shafts within patches of hair loss (FIGURE 3), which is indicative of tinea capitis.^1,2 This condition causes hair shafts to break, creating “comma hairs” and black dots. The hairs are uniform in thickness and color and bend distally, like a comma.³

Tinea capitis (commonly called ringworm of the scalp) is a fungal infection caused by Trichophyton and Microsporum dermatophytes. It is the most common pediatric dermatophyte infection in the world; the usual age of onset is 5 to 10 years.² The incidence of tinea capitis in the United States is not known because cases are no longer registered by public health agencies. That said, a Northern California study that tracked occurrences in children younger than 15 years from 1998 to 2007 found that the incidence was on the decline and lower in girls compared to boys (111.9 vs 146.4, respectively, in 1998; 27.9 vs 39.9, respectively, in 2007).⁴ Incidence rates were calculated per 10,000 eligible children.⁴

Tinea capitis can spread by contact with infected individuals and contaminated objects, including combs, towels, toys, and bedding.¹ Fungal spores can remain viable on these surfaces for months.

In a study of 69 patients with tinea capitis (23 females, 46 males; mean age, 12 years), the risk factors for spreading infection included participation in sports, contact with an animal, a recent haircut, and use of a swimming pool.⁵

4 conditions you’ll want to rule out

The following conditions should be considered as part of the differential when a patient presents with an itchy scalp and/or hair loss.

Continue to: Psoriasis of the scalp...

Psoriasis of the scalp is characterized by scaling of the scalp along with crusted plaques. It is often accompanied by similar psoriatic plaques on the elbows, knees, and other areas of the body. Examination of our patient showed no psoriatic plaques.

Seborrhea of the scalp (also known as dandruff) is a very common diagnosis. However, it is unlikely to cause hair loss. It has widespread involvement of the scalp compared to tinea capitis, which is local and patchy. Our patient’s patches of hair loss indicated that seborrhea was unlikely.

Alopecia areata. Individuals develop this condition due to an autoimmune process affecting hair follicles. However, the resulting hair loss does not cause significant scaling, inflammation, scarring, or pain in the affected area. Further, this condition can cause the loss of the entire hair shaft.

Trichotillomania is an impulse control disorder that causes patients to pull out their own hair. There is no scaling of the scalp in this condition.

A dermatoscope can beuseful in making the Dx

Although clinical appearance and patient presentation are adequate to establish the diagnosis of tinea capitis, this case demonstrates the utility of a dermatoscope in making the diagnosis of tinea capitis. Previous studies have shown that dermoscopy allows for rapid identification of the broken hair shafts, which are a key distinction from alopecia areata.^3,6

Microscopic inspection. Samples from the scaling of the scalp can be examined with potassium hydroxide (KOH) on a microscope slide. Hyphae, spores, and endo/ectothrix invasion can be seen through the microsope.  

Continue to: Laboratory testing is helpful, but not needed.

Newer antifungalsprovide a Tx advantage

Oral antifungal medications are the treatment of choice for tinea capitis. Newer antifungals, such as terbinafine and fluconazole, require a 3- to 6-week course compared to the standard 6- to 8-week course of griseofulvin.¹ Also, antifungal shampoos—such as those that contain selenium sulfide—may be used for topical treatment but only as adjuvant therapy.^1,2

For our patient, we dispensed a 3-week course of oral fluconazole, 3 to 6 mg/kg, to be given daily by his parents. We also recommended the use of an antidandruff shampoo, if possible. The treatment outcome was not known because our team’s humanitarian global health trip had ended.

An 11-year-old boy sought care at a small village’s health center in Panama for scalp itching and subtle hair loss. He was seen by a family physician (RU) and a team of medical students who were there as part of a humanitarian trip. The patient denied any hair pulling. He had a history of treatment for head lice.

Our physical examination revealed mild alopecia and scaling on the scalp (FIGURE 1), but what we saw through the dermatoscope (FIGURE 2) made the diagnosis clear.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Tinea capitis

On dermatoscopic examination (10× magnification), there were numerous “black dots” or broken hair shafts within patches of hair loss (FIGURE 3), which is indicative of tinea capitis.^1,2 This condition causes hair shafts to break, creating “comma hairs” and black dots. The hairs are uniform in thickness and color and bend distally, like a comma.³

Tinea capitis (commonly called ringworm of the scalp) is a fungal infection caused by Trichophyton and Microsporum dermatophytes. It is the most common pediatric dermatophyte infection in the world; the usual age of onset is 5 to 10 years.² The incidence of tinea capitis in the United States is not known because cases are no longer registered by public health agencies. That said, a Northern California study that tracked occurrences in children younger than 15 years from 1998 to 2007 found that the incidence was on the decline and lower in girls compared to boys (111.9 vs 146.4, respectively, in 1998; 27.9 vs 39.9, respectively, in 2007).⁴ Incidence rates were calculated per 10,000 eligible children.⁴

Tinea capitis can spread by contact with infected individuals and contaminated objects, including combs, towels, toys, and bedding.¹ Fungal spores can remain viable on these surfaces for months.

In a study of 69 patients with tinea capitis (23 females, 46 males; mean age, 12 years), the risk factors for spreading infection included participation in sports, contact with an animal, a recent haircut, and use of a swimming pool.⁵

4 conditions you’ll want to rule out

The following conditions should be considered as part of the differential when a patient presents with an itchy scalp and/or hair loss.

Continue to: Psoriasis of the scalp...

Psoriasis of the scalp is characterized by scaling of the scalp along with crusted plaques. It is often accompanied by similar psoriatic plaques on the elbows, knees, and other areas of the body. Examination of our patient showed no psoriatic plaques.

Seborrhea of the scalp (also known as dandruff) is a very common diagnosis. However, it is unlikely to cause hair loss. It has widespread involvement of the scalp compared to tinea capitis, which is local and patchy. Our patient’s patches of hair loss indicated that seborrhea was unlikely.

Alopecia areata. Individuals develop this condition due to an autoimmune process affecting hair follicles. However, the resulting hair loss does not cause significant scaling, inflammation, scarring, or pain in the affected area. Further, this condition can cause the loss of the entire hair shaft.

Trichotillomania is an impulse control disorder that causes patients to pull out their own hair. There is no scaling of the scalp in this condition.

A dermatoscope can beuseful in making the Dx

Although clinical appearance and patient presentation are adequate to establish the diagnosis of tinea capitis, this case demonstrates the utility of a dermatoscope in making the diagnosis of tinea capitis. Previous studies have shown that dermoscopy allows for rapid identification of the broken hair shafts, which are a key distinction from alopecia areata.^3,6

Microscopic inspection. Samples from the scaling of the scalp can be examined with potassium hydroxide (KOH) on a microscope slide. Hyphae, spores, and endo/ectothrix invasion can be seen through the microsope.  

Continue to: Laboratory testing is helpful, but not needed.

Newer antifungalsprovide a Tx advantage

Oral antifungal medications are the treatment of choice for tinea capitis. Newer antifungals, such as terbinafine and fluconazole, require a 3- to 6-week course compared to the standard 6- to 8-week course of griseofulvin.¹ Also, antifungal shampoos—such as those that contain selenium sulfide—may be used for topical treatment but only as adjuvant therapy.^1,2

For our patient, we dispensed a 3-week course of oral fluconazole, 3 to 6 mg/kg, to be given daily by his parents. We also recommended the use of an antidandruff shampoo, if possible. The treatment outcome was not known because our team’s humanitarian global health trip had ended.

Here is our problem: Family medicine has allowed itself, and its patients, to be picked apart by the forces of reductionism and a system that profits from the sick and suffering. We have lost sight of our purpose and our vision to care for the whole person. We have lost our way as healers.

The result is not only a decline in the specialty of family medicine as a leader in primary care but declining value and worsening outcomes in health care overall. We need to get our mojo back. We can do this by focusing less on trying to be all things to all people at all times, and more on creating better models for preventing, managing, and reversing chronic disease. This means providing health care that is person centered, relationship based, recovery focused, and paid for comprehensively.

I call this model Advanced Primary Care, or APC ­(FIGURE). In this article, I describe exemplars of APC from across the United States. I also provide tools to help you recover its central feature, holism—care of the whole person in mind, body, community, and spirit—in your practice, thus returning us to the core purpose of family medicine.

Holism is central to family medicine

More than 40 years ago, psychiatrist George Engel, MD, published a seminal article in Science that inspired a radical vision of how health care should be practiced.¹ Called the biopsychosocial model, it stated what, in some ways, is obvious: Human beings are complex organisms embedded in complex environments made up of distinct, yet interacting, dimensions. These dimensions included physical, psychological, and social components. Engel’s radical proposition was that these dimensions are definable and measurable and that good medicine cannot afford to ignore any of them.

Engel’s assertion that good medicine requires holism was a clarion call during a time of rapidly expanding knowledge and subspecialization. That call was the inspiration for a new medical specialty called family medicine, which dared to proclaim that the best way to heal was to care for the whole person within the context of that person’s emotional and social environment. Family medicine reinvigorated primary care and grew rapidly, becoming a preeminent primary care specialty in the United States.

Continue to : Reductionism is relentless

Reductionism is relentless

But the forces of medicine were—and still are—driving relentlessly the other way. The science of the small and particular (reductionism), with dazzling technology and exploding subspecialty knowledge, and backed by powerful economic drivers, rewards health care for pulling the patient and the medical profession apart. We pay more to those who treat small parts of a person over a short period than to those who attend to the whole person over the lifetime.

Today, family medicine—for all of its common sense, scientific soundness, connectedness to patients, and demonstrated value—struggles to survive.^2-6 The holistic vision of Engel is declining. The struggle in primary care is that its holistic vision gets co-opted by specialized medical science—and then it desperately attempts to apply those small and specialized tools to the care of patients in their wholeness. Holism is largely dead in health care, and everyone pays the consequences.⁷

Health care is losing its value

The damage from this decline in holism is not just to primary care but to the value of health care in general. Most medical care being delivered today—comprising diagnosis, treatment, and payment (the innermost circle of the FIGURE)—is not producing good health.⁸ Only 15% to 20% of the healing of an individual or a population comes from health care.⁹ The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life, including those related to food, movement, sleep, stress, and substance use.¹⁰ Increasingly, it is the economic and social determinants of health that influence this behavior and have a greater impact on health and lifespan than physiology or genes.¹¹ The same social determinants of health also influence patients’ ability to obtain medical care and pursue a meaningful life.¹²

The result of this decline in holism and in the value of health care in general has been a relentless rise in the cost of medical care^13-15 and the need for social services; declining life expectancy^16,17 and quality of life¹⁸; growing patient dissatisfaction; and burnout in providers.^19,20 Health care has become, as investor and business leader Warren Buffet remarked, the “tapeworm” of the economy and a major contributor to growing disparities in health and well-being between the haves and have-nots.²¹ Engel’s prediction that good medicine cannot afford to ignore holism has come to pass.

Family medicine has allowed itself, and patients, to be picked apart by forces of reductionism and a system that profits from the sick and suffering.

3-step solution:Return to whole-person care

Family medicine needs to return to whole-person care, but it can do so only if it attends to, and effectively delivers on, the prevention, treatment, and reversal of chronic disease and the enhancement of health and well-­being. This can happen only if family medicine stops trying to be all things to all people at all times and, instead, focuses on what matters to the patient as a person.

Continue to: This means that the core...

This means that the core interaction in family medicine must be to assess the whole person—mind, body, social, spirit—and help that person make changes that improve his/her/their health and well-being based on his/her/their individualized needs and social context. In other words, family medicine needs to deliver a holistic model of APC that is person centered, relationship based, recovery focused, and paid for comprehensively.

How does one get from “standard” primary care of today (the innermost circle of the FIGURE) to a framework that truly delivers on the promise of healing? I propose 3 steps to return holism to family medicine.

STEP 1: Start with comprehensive, coordinated primary care. We know that this works. Starfield and others demonstrated this 2 decades ago, defining and devising what we know as quality primary care—characterized by first-contact care, comprehensive primary care (CPC), continuous care, and coordinated care.²² This type of primary care improves outcomes, lowers costs, and is satisfying to patients and providers.²³ The physician cares for the patient throughout that person’s entire life cycle and provides all evidence-based services needed to prevent and treat common conditions. Comprehensive primary care is positioned in the first circle outward from the innermost circle of the FIGURE.

As medicine has become increasingly complex and subspecialized, however, the ability to coordinate care is often frayed, adding cost and reducing quality.^24-26 Today, comprehensive primary care needs enhanced coordination. At a minimum, this means coordinating services for:

• chronic disease management (outpatient and inpatient transitions and emergency department use)
• referral (specialists and tests)
• pharmacy services (including delivery and patient education support).

An example of a primary care system that meets these requirements is the Catalyst Health Network in central Texas, which supplies coordination services to more than 1000 comprehensive primary care practices and 1.5 million patients.²⁷ The Catalyst Network makes money for those practices, saves money in the system, enhances patient and provider satisfaction, and improves population health in the community.²⁷ I call this enhanced primary care (EPC), shown in the second circle out from the innermost circle of the FIGURE.

STEP 2: Add integrative medicine and mental health. EPC improves fragmented care but does not necessarily address a patient’s underlying determinants of healing. We know that health behaviors such as smoking cessation, avoidance of alcohol and drug abuse, improved diet, physical activity, sleep, and stress management contribute 40% to 60% of a person’s and a population’s health.¹⁰ In addition, evidence shows that behavioral health services, along with lifestyle change support, can even reverse many chronic diseases seen in primary care, such as obesity, diabetes, hypertension, cardiovascular disease, depression, and substance abuse.^28,29

Continue to: Therefore, we need to add...

Therefore, we need to add routine mental health services and nonpharmacotherapeutic approaches (eg, complementary and alternative medicine) to primary care.³⁰ Doing so requires that behavioral change and self-care become a central feature of the ­doctor–patient dialogue and team skills³¹ and be added to primary care.^30,31 I call this integrative primary care (IPC), shown on the left side in the third circle out from the innermost circle of the FIGURE.
 

Only 15% to 20% of individual and population healing comes from health care; the rest, from behavioral and lifestyle choices rarely addressed in primary care.

An example of IPC is Whole Health, an initiative of the US Veteran’s Health Administration. Whole Health empowers and informs a person-centered approach and integrates it into the delivery of routine care.³² Evaluation of Whole Health implementation, which involved more than 130,000 veterans followed for 2 years, found a net overall reduction in the total cost of care of 20%—saving nearly $650 million or, on average, more than $4500 per veteran.³³

STEP 3: Address social determinants of health. Primary care will not fully be part of the solution for producing health and well-being unless it becomes instrumental in addressing the social determinants of health (SDH), defined as “… conditions in the environments in which people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks.”³⁴ These determinants include not only basic needs, such as housing, food, safety, and transportation (ie, social needs), but also what are known as structural determinants, such as income, education, language, and racial and ethnic bias. Health care cannot solve all of these social ills,but it is increasingly being called on to be the nexus of coordination for services that address these needs when they affect health outcomes.^35,36

Examples of health systems that provide for social needs include the free “food prescription” program of Pennsylvania’s Geisinger Health System, for patients with diabetes who do not have the resources to pay for food.³⁷ This approach improves blood glucose control by patients and saves money on medications and other interventions. Similarly, Kaiser Permanente has experimented with housing vouchers for homeless patients,and most Federally Qualified Health Centers provide bus or other transportation tickets to patients for their appointments and free or discounted tests and specialty care.³⁸

Implementing whole-person care for all

I propose that we make APC the central focus of family medicine. This model would comprise CPC, plus EPC, IPC, and community coordination to address SDH. This is expressed as:

CPC + EPC + IPC + SDH = APC

Continue to: APC would mean...

APC would mean health for the whole person and for all people. Again, the FIGURE shows how this model, encompassing the entire third circle out from the center circle, could be created from current models of care.

How do we pay for this? We already do—and way too much. The problem is not lack of money in the health care system but how it is organized and distributed. The Centers for Medicare and Medicaid Services and other payers are developing value-based payment models to help cover this type of care,³⁹ but payers cannot pay for something if it is unavailable.

Can family physicians deliver APC? I believe they can, and have given a few examples here to show how this is already happening. To help primary care providers start to deliver APC in their system, my team and I have built the HOPE (Healing Oriented Practices & Environments) Note Toolkit to use in daily practice.⁴⁰ These and other tools are being used by a number of large hospital systems and health care networks around the country. (You can download the HOPE Note Toolkit, at no cost, at https://drwaynejonas.com/­resources/hope-note/.)

At a minimum, comprehensive primary care needs to coordinate services for chronic disease management, referral (to specialists and testing), and pharmacy services.

Whatever we call this new type of primary care, it needs to care for the whole person and to be available to all. It finds expression in these assertions:

• We cannot ignore an essential part of what a human being is and expect them to heal or become whole.
• We cannot ignore essential people in our communities and expect our costs to go down or our compassion to go up.
• We need to stop allowing family medicine to be co-opted by reductionism and its profits.

In sum, we need a new vision of primary care—like Engel’s holistic vision in the 1970s—to motivate us, and we need to return to fundamental concepts of how healing works in medicine.⁴¹

CORRESPONDENCE

Wayne B. Jonas, MD, Samueli Integrative Health Programs, 1800 Diagonal Road, Suite 617, Alexandria, VA 22314; wayne@drwaynejonas.com.

Here is our problem: Family medicine has allowed itself, and its patients, to be picked apart by the forces of reductionism and a system that profits from the sick and suffering. We have lost sight of our purpose and our vision to care for the whole person. We have lost our way as healers.

The result is not only a decline in the specialty of family medicine as a leader in primary care but declining value and worsening outcomes in health care overall. We need to get our mojo back. We can do this by focusing less on trying to be all things to all people at all times, and more on creating better models for preventing, managing, and reversing chronic disease. This means providing health care that is person centered, relationship based, recovery focused, and paid for comprehensively.

I call this model Advanced Primary Care, or APC ­(FIGURE). In this article, I describe exemplars of APC from across the United States. I also provide tools to help you recover its central feature, holism—care of the whole person in mind, body, community, and spirit—in your practice, thus returning us to the core purpose of family medicine.

Holism is central to family medicine

More than 40 years ago, psychiatrist George Engel, MD, published a seminal article in Science that inspired a radical vision of how health care should be practiced.¹ Called the biopsychosocial model, it stated what, in some ways, is obvious: Human beings are complex organisms embedded in complex environments made up of distinct, yet interacting, dimensions. These dimensions included physical, psychological, and social components. Engel’s radical proposition was that these dimensions are definable and measurable and that good medicine cannot afford to ignore any of them.

Engel’s assertion that good medicine requires holism was a clarion call during a time of rapidly expanding knowledge and subspecialization. That call was the inspiration for a new medical specialty called family medicine, which dared to proclaim that the best way to heal was to care for the whole person within the context of that person’s emotional and social environment. Family medicine reinvigorated primary care and grew rapidly, becoming a preeminent primary care specialty in the United States.

Continue to : Reductionism is relentless

Reductionism is relentless

But the forces of medicine were—and still are—driving relentlessly the other way. The science of the small and particular (reductionism), with dazzling technology and exploding subspecialty knowledge, and backed by powerful economic drivers, rewards health care for pulling the patient and the medical profession apart. We pay more to those who treat small parts of a person over a short period than to those who attend to the whole person over the lifetime.

Today, family medicine—for all of its common sense, scientific soundness, connectedness to patients, and demonstrated value—struggles to survive.^2-6 The holistic vision of Engel is declining. The struggle in primary care is that its holistic vision gets co-opted by specialized medical science—and then it desperately attempts to apply those small and specialized tools to the care of patients in their wholeness. Holism is largely dead in health care, and everyone pays the consequences.⁷

Health care is losing its value

The damage from this decline in holism is not just to primary care but to the value of health care in general. Most medical care being delivered today—comprising diagnosis, treatment, and payment (the innermost circle of the FIGURE)—is not producing good health.⁸ Only 15% to 20% of the healing of an individual or a population comes from health care.⁹ The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life, including those related to food, movement, sleep, stress, and substance use.¹⁰ Increasingly, it is the economic and social determinants of health that influence this behavior and have a greater impact on health and lifespan than physiology or genes.¹¹ The same social determinants of health also influence patients’ ability to obtain medical care and pursue a meaningful life.¹²

The result of this decline in holism and in the value of health care in general has been a relentless rise in the cost of medical care^13-15 and the need for social services; declining life expectancy^16,17 and quality of life¹⁸; growing patient dissatisfaction; and burnout in providers.^19,20 Health care has become, as investor and business leader Warren Buffet remarked, the “tapeworm” of the economy and a major contributor to growing disparities in health and well-being between the haves and have-nots.²¹ Engel’s prediction that good medicine cannot afford to ignore holism has come to pass.

Family medicine has allowed itself, and patients, to be picked apart by forces of reductionism and a system that profits from the sick and suffering.

3-step solution:Return to whole-person care

Family medicine needs to return to whole-person care, but it can do so only if it attends to, and effectively delivers on, the prevention, treatment, and reversal of chronic disease and the enhancement of health and well-­being. This can happen only if family medicine stops trying to be all things to all people at all times and, instead, focuses on what matters to the patient as a person.

Continue to: This means that the core...

This means that the core interaction in family medicine must be to assess the whole person—mind, body, social, spirit—and help that person make changes that improve his/her/their health and well-being based on his/her/their individualized needs and social context. In other words, family medicine needs to deliver a holistic model of APC that is person centered, relationship based, recovery focused, and paid for comprehensively.

How does one get from “standard” primary care of today (the innermost circle of the FIGURE) to a framework that truly delivers on the promise of healing? I propose 3 steps to return holism to family medicine.

STEP 1: Start with comprehensive, coordinated primary care. We know that this works. Starfield and others demonstrated this 2 decades ago, defining and devising what we know as quality primary care—characterized by first-contact care, comprehensive primary care (CPC), continuous care, and coordinated care.²² This type of primary care improves outcomes, lowers costs, and is satisfying to patients and providers.²³ The physician cares for the patient throughout that person’s entire life cycle and provides all evidence-based services needed to prevent and treat common conditions. Comprehensive primary care is positioned in the first circle outward from the innermost circle of the FIGURE.

As medicine has become increasingly complex and subspecialized, however, the ability to coordinate care is often frayed, adding cost and reducing quality.^24-26 Today, comprehensive primary care needs enhanced coordination. At a minimum, this means coordinating services for:

• chronic disease management (outpatient and inpatient transitions and emergency department use)
• referral (specialists and tests)
• pharmacy services (including delivery and patient education support).

An example of a primary care system that meets these requirements is the Catalyst Health Network in central Texas, which supplies coordination services to more than 1000 comprehensive primary care practices and 1.5 million patients.²⁷ The Catalyst Network makes money for those practices, saves money in the system, enhances patient and provider satisfaction, and improves population health in the community.²⁷ I call this enhanced primary care (EPC), shown in the second circle out from the innermost circle of the FIGURE.

STEP 2: Add integrative medicine and mental health. EPC improves fragmented care but does not necessarily address a patient’s underlying determinants of healing. We know that health behaviors such as smoking cessation, avoidance of alcohol and drug abuse, improved diet, physical activity, sleep, and stress management contribute 40% to 60% of a person’s and a population’s health.¹⁰ In addition, evidence shows that behavioral health services, along with lifestyle change support, can even reverse many chronic diseases seen in primary care, such as obesity, diabetes, hypertension, cardiovascular disease, depression, and substance abuse.^28,29

Continue to: Therefore, we need to add...

Therefore, we need to add routine mental health services and nonpharmacotherapeutic approaches (eg, complementary and alternative medicine) to primary care.³⁰ Doing so requires that behavioral change and self-care become a central feature of the ­doctor–patient dialogue and team skills³¹ and be added to primary care.^30,31 I call this integrative primary care (IPC), shown on the left side in the third circle out from the innermost circle of the FIGURE.
 

Only 15% to 20% of individual and population healing comes from health care; the rest, from behavioral and lifestyle choices rarely addressed in primary care.

An example of IPC is Whole Health, an initiative of the US Veteran’s Health Administration. Whole Health empowers and informs a person-centered approach and integrates it into the delivery of routine care.³² Evaluation of Whole Health implementation, which involved more than 130,000 veterans followed for 2 years, found a net overall reduction in the total cost of care of 20%—saving nearly $650 million or, on average, more than $4500 per veteran.³³

STEP 3: Address social determinants of health. Primary care will not fully be part of the solution for producing health and well-being unless it becomes instrumental in addressing the social determinants of health (SDH), defined as “… conditions in the environments in which people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks.”³⁴ These determinants include not only basic needs, such as housing, food, safety, and transportation (ie, social needs), but also what are known as structural determinants, such as income, education, language, and racial and ethnic bias. Health care cannot solve all of these social ills,but it is increasingly being called on to be the nexus of coordination for services that address these needs when they affect health outcomes.^35,36

Examples of health systems that provide for social needs include the free “food prescription” program of Pennsylvania’s Geisinger Health System, for patients with diabetes who do not have the resources to pay for food.³⁷ This approach improves blood glucose control by patients and saves money on medications and other interventions. Similarly, Kaiser Permanente has experimented with housing vouchers for homeless patients,and most Federally Qualified Health Centers provide bus or other transportation tickets to patients for their appointments and free or discounted tests and specialty care.³⁸

Implementing whole-person care for all

I propose that we make APC the central focus of family medicine. This model would comprise CPC, plus EPC, IPC, and community coordination to address SDH. This is expressed as:

CPC + EPC + IPC + SDH = APC

Continue to: APC would mean...

APC would mean health for the whole person and for all people. Again, the FIGURE shows how this model, encompassing the entire third circle out from the center circle, could be created from current models of care.

How do we pay for this? We already do—and way too much. The problem is not lack of money in the health care system but how it is organized and distributed. The Centers for Medicare and Medicaid Services and other payers are developing value-based payment models to help cover this type of care,³⁹ but payers cannot pay for something if it is unavailable.

Can family physicians deliver APC? I believe they can, and have given a few examples here to show how this is already happening. To help primary care providers start to deliver APC in their system, my team and I have built the HOPE (Healing Oriented Practices & Environments) Note Toolkit to use in daily practice.⁴⁰ These and other tools are being used by a number of large hospital systems and health care networks around the country. (You can download the HOPE Note Toolkit, at no cost, at https://drwaynejonas.com/­resources/hope-note/.)

At a minimum, comprehensive primary care needs to coordinate services for chronic disease management, referral (to specialists and testing), and pharmacy services.

Whatever we call this new type of primary care, it needs to care for the whole person and to be available to all. It finds expression in these assertions:

• We cannot ignore an essential part of what a human being is and expect them to heal or become whole.
• We cannot ignore essential people in our communities and expect our costs to go down or our compassion to go up.
• We need to stop allowing family medicine to be co-opted by reductionism and its profits.

In sum, we need a new vision of primary care—like Engel’s holistic vision in the 1970s—to motivate us, and we need to return to fundamental concepts of how healing works in medicine.⁴¹

CORRESPONDENCE

Wayne B. Jonas, MD, Samueli Integrative Health Programs, 1800 Diagonal Road, Suite 617, Alexandria, VA 22314; wayne@drwaynejonas.com.

Here is our problem: Family medicine has allowed itself, and its patients, to be picked apart by the forces of reductionism and a system that profits from the sick and suffering. We have lost sight of our purpose and our vision to care for the whole person. We have lost our way as healers.

The result is not only a decline in the specialty of family medicine as a leader in primary care but declining value and worsening outcomes in health care overall. We need to get our mojo back. We can do this by focusing less on trying to be all things to all people at all times, and more on creating better models for preventing, managing, and reversing chronic disease. This means providing health care that is person centered, relationship based, recovery focused, and paid for comprehensively.

I call this model Advanced Primary Care, or APC ­(FIGURE). In this article, I describe exemplars of APC from across the United States. I also provide tools to help you recover its central feature, holism—care of the whole person in mind, body, community, and spirit—in your practice, thus returning us to the core purpose of family medicine.

Holism is central to family medicine

More than 40 years ago, psychiatrist George Engel, MD, published a seminal article in Science that inspired a radical vision of how health care should be practiced.¹ Called the biopsychosocial model, it stated what, in some ways, is obvious: Human beings are complex organisms embedded in complex environments made up of distinct, yet interacting, dimensions. These dimensions included physical, psychological, and social components. Engel’s radical proposition was that these dimensions are definable and measurable and that good medicine cannot afford to ignore any of them.

Engel’s assertion that good medicine requires holism was a clarion call during a time of rapidly expanding knowledge and subspecialization. That call was the inspiration for a new medical specialty called family medicine, which dared to proclaim that the best way to heal was to care for the whole person within the context of that person’s emotional and social environment. Family medicine reinvigorated primary care and grew rapidly, becoming a preeminent primary care specialty in the United States.

Continue to : Reductionism is relentless

Reductionism is relentless

But the forces of medicine were—and still are—driving relentlessly the other way. The science of the small and particular (reductionism), with dazzling technology and exploding subspecialty knowledge, and backed by powerful economic drivers, rewards health care for pulling the patient and the medical profession apart. We pay more to those who treat small parts of a person over a short period than to those who attend to the whole person over the lifetime.

Today, family medicine—for all of its common sense, scientific soundness, connectedness to patients, and demonstrated value—struggles to survive.^2-6 The holistic vision of Engel is declining. The struggle in primary care is that its holistic vision gets co-opted by specialized medical science—and then it desperately attempts to apply those small and specialized tools to the care of patients in their wholeness. Holism is largely dead in health care, and everyone pays the consequences.⁷

Health care is losing its value

The damage from this decline in holism is not just to primary care but to the value of health care in general. Most medical care being delivered today—comprising diagnosis, treatment, and payment (the innermost circle of the FIGURE)—is not producing good health.⁸ Only 15% to 20% of the healing of an individual or a population comes from health care.⁹ The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life, including those related to food, movement, sleep, stress, and substance use.¹⁰ Increasingly, it is the economic and social determinants of health that influence this behavior and have a greater impact on health and lifespan than physiology or genes.¹¹ The same social determinants of health also influence patients’ ability to obtain medical care and pursue a meaningful life.¹²

The result of this decline in holism and in the value of health care in general has been a relentless rise in the cost of medical care^13-15 and the need for social services; declining life expectancy^16,17 and quality of life¹⁸; growing patient dissatisfaction; and burnout in providers.^19,20 Health care has become, as investor and business leader Warren Buffet remarked, the “tapeworm” of the economy and a major contributor to growing disparities in health and well-being between the haves and have-nots.²¹ Engel’s prediction that good medicine cannot afford to ignore holism has come to pass.

Family medicine has allowed itself, and patients, to be picked apart by forces of reductionism and a system that profits from the sick and suffering.

3-step solution:Return to whole-person care

Family medicine needs to return to whole-person care, but it can do so only if it attends to, and effectively delivers on, the prevention, treatment, and reversal of chronic disease and the enhancement of health and well-­being. This can happen only if family medicine stops trying to be all things to all people at all times and, instead, focuses on what matters to the patient as a person.

Continue to: This means that the core...

This means that the core interaction in family medicine must be to assess the whole person—mind, body, social, spirit—and help that person make changes that improve his/her/their health and well-being based on his/her/their individualized needs and social context. In other words, family medicine needs to deliver a holistic model of APC that is person centered, relationship based, recovery focused, and paid for comprehensively.

How does one get from “standard” primary care of today (the innermost circle of the FIGURE) to a framework that truly delivers on the promise of healing? I propose 3 steps to return holism to family medicine.

STEP 1: Start with comprehensive, coordinated primary care. We know that this works. Starfield and others demonstrated this 2 decades ago, defining and devising what we know as quality primary care—characterized by first-contact care, comprehensive primary care (CPC), continuous care, and coordinated care.²² This type of primary care improves outcomes, lowers costs, and is satisfying to patients and providers.²³ The physician cares for the patient throughout that person’s entire life cycle and provides all evidence-based services needed to prevent and treat common conditions. Comprehensive primary care is positioned in the first circle outward from the innermost circle of the FIGURE.

As medicine has become increasingly complex and subspecialized, however, the ability to coordinate care is often frayed, adding cost and reducing quality.^24-26 Today, comprehensive primary care needs enhanced coordination. At a minimum, this means coordinating services for:

• chronic disease management (outpatient and inpatient transitions and emergency department use)
• referral (specialists and tests)
• pharmacy services (including delivery and patient education support).

An example of a primary care system that meets these requirements is the Catalyst Health Network in central Texas, which supplies coordination services to more than 1000 comprehensive primary care practices and 1.5 million patients.²⁷ The Catalyst Network makes money for those practices, saves money in the system, enhances patient and provider satisfaction, and improves population health in the community.²⁷ I call this enhanced primary care (EPC), shown in the second circle out from the innermost circle of the FIGURE.

STEP 2: Add integrative medicine and mental health. EPC improves fragmented care but does not necessarily address a patient’s underlying determinants of healing. We know that health behaviors such as smoking cessation, avoidance of alcohol and drug abuse, improved diet, physical activity, sleep, and stress management contribute 40% to 60% of a person’s and a population’s health.¹⁰ In addition, evidence shows that behavioral health services, along with lifestyle change support, can even reverse many chronic diseases seen in primary care, such as obesity, diabetes, hypertension, cardiovascular disease, depression, and substance abuse.^28,29

Continue to: Therefore, we need to add...

Therefore, we need to add routine mental health services and nonpharmacotherapeutic approaches (eg, complementary and alternative medicine) to primary care.³⁰ Doing so requires that behavioral change and self-care become a central feature of the ­doctor–patient dialogue and team skills³¹ and be added to primary care.^30,31 I call this integrative primary care (IPC), shown on the left side in the third circle out from the innermost circle of the FIGURE.
 

Only 15% to 20% of individual and population healing comes from health care; the rest, from behavioral and lifestyle choices rarely addressed in primary care.

An example of IPC is Whole Health, an initiative of the US Veteran’s Health Administration. Whole Health empowers and informs a person-centered approach and integrates it into the delivery of routine care.³² Evaluation of Whole Health implementation, which involved more than 130,000 veterans followed for 2 years, found a net overall reduction in the total cost of care of 20%—saving nearly $650 million or, on average, more than $4500 per veteran.³³

STEP 3: Address social determinants of health. Primary care will not fully be part of the solution for producing health and well-being unless it becomes instrumental in addressing the social determinants of health (SDH), defined as “… conditions in the environments in which people are born, live, learn, work, play, worship, and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks.”³⁴ These determinants include not only basic needs, such as housing, food, safety, and transportation (ie, social needs), but also what are known as structural determinants, such as income, education, language, and racial and ethnic bias. Health care cannot solve all of these social ills,but it is increasingly being called on to be the nexus of coordination for services that address these needs when they affect health outcomes.^35,36

Examples of health systems that provide for social needs include the free “food prescription” program of Pennsylvania’s Geisinger Health System, for patients with diabetes who do not have the resources to pay for food.³⁷ This approach improves blood glucose control by patients and saves money on medications and other interventions. Similarly, Kaiser Permanente has experimented with housing vouchers for homeless patients,and most Federally Qualified Health Centers provide bus or other transportation tickets to patients for their appointments and free or discounted tests and specialty care.³⁸

Implementing whole-person care for all

I propose that we make APC the central focus of family medicine. This model would comprise CPC, plus EPC, IPC, and community coordination to address SDH. This is expressed as:

CPC + EPC + IPC + SDH = APC

Continue to: APC would mean...

APC would mean health for the whole person and for all people. Again, the FIGURE shows how this model, encompassing the entire third circle out from the center circle, could be created from current models of care.

How do we pay for this? We already do—and way too much. The problem is not lack of money in the health care system but how it is organized and distributed. The Centers for Medicare and Medicaid Services and other payers are developing value-based payment models to help cover this type of care,³⁹ but payers cannot pay for something if it is unavailable.

Can family physicians deliver APC? I believe they can, and have given a few examples here to show how this is already happening. To help primary care providers start to deliver APC in their system, my team and I have built the HOPE (Healing Oriented Practices & Environments) Note Toolkit to use in daily practice.⁴⁰ These and other tools are being used by a number of large hospital systems and health care networks around the country. (You can download the HOPE Note Toolkit, at no cost, at https://drwaynejonas.com/­resources/hope-note/.)

At a minimum, comprehensive primary care needs to coordinate services for chronic disease management, referral (to specialists and testing), and pharmacy services.

Whatever we call this new type of primary care, it needs to care for the whole person and to be available to all. It finds expression in these assertions:

• We cannot ignore an essential part of what a human being is and expect them to heal or become whole.
• We cannot ignore essential people in our communities and expect our costs to go down or our compassion to go up.
• We need to stop allowing family medicine to be co-opted by reductionism and its profits.

In sum, we need a new vision of primary care—like Engel’s holistic vision in the 1970s—to motivate us, and we need to return to fundamental concepts of how healing works in medicine.⁴¹

CORRESPONDENCE

Wayne B. Jonas, MD, Samueli Integrative Health Programs, 1800 Diagonal Road, Suite 617, Alexandria, VA 22314; wayne@drwaynejonas.com.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.

Insect, arachnid, and other arthropod bites and stings are common patient complaints in a primary care office. A thorough history and physical exam can often isolate the specific offender and guide management. In this article, we outline how to identify, diagnose, and treat common bites and stings from bees and wasps; centipedes and spiders; fleas; flies and biting midges; mosquitoes; and ticks, and discuss how high-risk patients should be triaged and referred for additional testing and treatment, such as venom immunotherapy (VIT).

Insects and arachnids:Background and epidemiology

Insects are arthropods with 3-part exoskeletons: head, thorax, and abdomen. They have 6 jointed legs, compound eyes, and antennae. There are approximately 91,000 insect species in the United States, the most abundant orders being Coleoptera (beetles), Diptera (flies), and Hymenoptera (includes ants, bees, wasps, and sawflies).¹

The reported incidence of insect bites and stings varies widely because most people experience mild symptoms and therefore do not seek medical care. Best statistics are for Hymenoptera stings, which are more likely to cause a severe reaction. In Europe, 56% to 94% of the general population has reported being bitten or stung by one of the Hymenoptera species.² In many areas of Australia, the incidence of jack jumper ant stings is only 2% to 3%³; in the United States, 55% of people report being stung by nonnative fire ants within 3 weeks of moving into an endemic area.⁴

Arachnids are some of the earliest terrestrial organisms, of the class Arachnida, which includes scorpions, ticks, spiders, mites, and daddy longlegs (harvestmen).⁵ Arachnids are wingless and characterized by segmented bodies, jointed appendages, and exoskeletons.^6,7 In most, the body is separated into 2 segments (the cephalothorax and abdomen), except for mites, ticks, and daddy longlegs, in which the entire body comprises a single segment.⁵

Arthropod bites are common in the United States; almost one-half are caused by spiders.⁷ Brown recluse (Loxosceles spp) and black widow (Latrodectus spp) spider bites are the most concerning: Although usually mild, these bites can be life-threatening but are rarely fatal. In 2013, almost 3500 bites by black widow and brown recluse spiders were reported.⁸

Among beekeepers, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.

Risk factors

Risk factors for insect, arachnid, and other arthropod bites and stings are primarily environmental. People who live or work in proximity of biting or stinging insects (eg, gardeners and beekeepers) are more likely to be affected; so are those who work with animals or live next to standing water or grassy or wooded locales.

Continue to: There are also risk factors...

There are also risk factors for a systemic sting reaction:

• A sting reaction < 2 months earlier increases the risk of a subsequent systemic sting reaction by ≥ 50%.⁹
• Among beekeepers, paradoxically, the risk of a systemic reaction is higher in those stung < 15 times a year than in those stung > 200 times.¹⁰
• Patients with an elevated baseline serum level of tryptase (reference range, < 11.4 ng/mL), which is part of the allergenic response, or with biopsy-proven systemic mastocytosis are at increased risk of a systemic sting reaction.¹¹

Presentation: Signs and symptomsvary with severity

Insect bites and stings usually cause transient local inflammation and, occasionally, a toxic reaction. Allergic hypersensitivity can result in a large local reaction or a generalized systemic reaction¹²:

• A small local reaction is transient and mild, develops directly at the site of the sting, and can last several days.¹³
• A large (or significant) local reaction, defined as swelling > 10 cm in diameter (FIGURE 1) and lasting > 24 hours, occurs in 2% to 26% of people who have been bitten or stung.¹⁴ This is an immunoglobulin (Ig) E–mediated late-phase reaction that can be accompanied by fatigue and nausea.^12,13,15 For a patient with a large local reaction, the risk of a concomitant systemic reaction is 4% to 10%, typically beginning within 30 minutes after envenomation or, possibly, delayed for several hours or marked by a biphasic interval.¹⁶
• Characteristics of a systemic reaction are urticaria, angioedema, bronchospasm, large-airway edema, hypotension, and other clinical manifestations of anaphylaxis.¹⁷ In the United States, a systemic sting reaction is reported to occur in approximately 3% of bite and sting victims. Mortality among the general population from a systemic bite or sting reaction is 0.16 for every 100,000 people,² and at least 40 to 100 die every year in the United States from anaphylaxis resulting from an insect bite or sting.¹⁸
• The most severe anaphylactic reactions involve the cardiovascular and respiratory systems, commonly including hypotension and symptoms of upper- or lower-airway obstruction. Laryngeal edema and circulatory failure are the most common mechanisms of anaphylactic death.¹⁹

Bees and wasps

Hymenoptera stinging insects include the family Apidae (honey bee, bumblebee, and sweat bee) and Vespidae (yellow jacket, yellow- and white-faced hornets, and paper wasp). A worker honey bee can sting only once, leaving its barbed stinger in the skin; a wasp, hornet, and yellow jacket can sting multiple times (FIGURE 2).²

Continue to: Bee and wasp sting...

Bee and wasp sting allergies are the most common insect venom allergic reactions. A bee sting is more likely to lead to a severe allergic reaction than a wasp sting. Allergic reactions to hornet and bumblebee stings are less common but can occur in patients already sensitized to wasp and honey bee stings.^20,21

Management. Remove honey bee stingers by scraping the skin with a fingernail or credit card. Ideally, the stinger should be removed in the first 30 seconds, before the venom sac empties. Otherwise, intense local inflammation, with possible lymphangitic streaking, can result.²²

For guidance on localized symptomatic care of bee and wasp stings and bites and stings from other sources discussed in this article, see “Providing relief and advanced care” on page E6.

Centipedes and spiders

Centipedes are arthropods of the class Chilopoda, subphylum Myriapoda, that are characterized by repeating linear (metameric) segments, each containing 1 pair of legs.²³ Centipedes have a pair of poison claws behind the head that are used to paralyze prey—usually, small insects.^23,24 The bite of a larger centipede can cause a painful reaction that generally subsides after a few hours but can last several days. Centipede bites are usually nonfatal to humans.²³

Spiders belong to the class Arachnida, order Araneae. They have 8 legs with chelicerae (mouthpiece, or “jaws”) that inject venom into prey.²⁵ Most spiders found in the United States cannot bite through human skin.^26,27 Common exceptions are black widow and brown recluse spiders, which each produce a distinct toxic venom that can cause significant morbidity in humans through a bite, although bites are rarely fatal.^26,27

The brown recluse spider is described as having a violin-shaped marking on the abdomen; the body is yellowish, tan, or dark brown. A bite can produce tiny fang marks and cause dull pain at the site of the bite that spreads quickly; myalgia; and pain in the stomach, back, chest, and legs.^28,29 The bite takes approximately 7 days to resolve. In a minority of cases, a tender erythematous halo develops, followed by a severe necrotic ulcer, or loxoscelism (FIGURE 3; 40% of cases) or scarring (13%), or both.^29,30

Continue to: In contrast...

A bee sting is more likely to lead to a severe allergic reaction than a wasp sting.

Management. Again, see “Providing relief and advanced care” on page E6. Consider providing antivenin treatment for moderate or severe bites of brown recluse and black widow spiders.

Fleas

Fleas are members of the order Siphonaptera. They are small (1.5-3.2 mm long), reddish brown, wingless, blood-sucking insects with long legs that allow them to jump far (12 or 13 inches) and high (6 or 7 inches).³³ Domesticated cats and dogs are the source of most flea infestations, resulting in an increased risk of exposure for humans.^34,35 Flea bites, which generally occur on lower extremities, develop into a small, erythematous papule with a halo (FIGURE 4) and associated mild edema, and cause intense pruritus 30 minutes after the bite.^35-37

Fleas are a vector for severe microbial infections, including bartonellosis, bubonic plague, cat-flea typhus, murine typhus, cat-scratch disease, rickettsial disease, and tularemia. Tungiasis is an inflammatory burrowing flea infestation—not a secondary infection for which the flea is a vector.^34,35

Preventive management. Repellents, including products that contain DEET (N,N-diethyl-meta-toluamide), picaridin (2-[2-hydroxyethyl]-1-piperidinecarboxylic acid 1-methylpropyl ester), and PMD (p-menthane-3,8-diol, a chemical constituent of Eucalyptus citriodora oil) can be used to prevent flea bites in humans.^33,38 Studies show that the scent of other botanic oils, including lavender, cedarwood, and peppermint, can also help prevent infestation by fleas; however, these compounds are not as effective as traditional insect repellents.^33,38

Flea control is difficult, requiring a multimodal approach to treating the infested animal and its environment.³⁹ Treatment of the infested domestic animal is the primary method of preventing human bites. Nonpesticidal control involves frequent cleaning of carpeting, furniture, animal bedding, and kennels. Insecticides can be applied throughout the house to combat severe infestation.^33,38

Continue to: The Centers for Disease Control and Prevention...

Flies and biting midges

Flies are 2-winged insects belonging to the order Diptera. Several fly species can bite, causing a local inflammatory reaction; these include black flies, deer flies, horse flies, and sand flies. Signs and symptoms of a fly bite include pain, pruritus, erythema, and mild swelling (FIGURE 5).^41,42 Flies can transmit several infections, including bartonellosis, enteric bacterial disease (eg, caused by Campylobacter spp), leishmaniasis, loiasis, onchocerciasis, and trypanosomiasis.⁴³

Biting midges, also called “no-see-ums,” biting gnats, moose flies, and “punkies,”⁴⁴ are tiny (1-3 mm long) blood-sucking flies.⁴⁵ Bitten patients often report not having seen the midge because it is so small. The bite typically starts as a small, erythematous papule that develops into a dome-shaped blister and can be extraordinarily pruritic and painful.⁴⁴ The majority of people who have been bitten develop a hypersensitivity reaction, which usually resolves in a few weeks.

Management. Suppressing adult biting midges with an environmental insecticide is typically insufficient because the insecticide must be sprayed daily to eradicate active midges and generally does not affect larval habitat. Insect repellents and biopesticides, such as oil of lemon eucalyptus, can be effective in reducing the risk of bites.^44,45

Mosquitoes

Mosquitoes are flying, blood-sucking insects of the order Diptera and family Culicidae. Anopheles, Culex, and Aedes genera are responsible for most bites of humans.

Most spiders found in the United States can’t bite through human skin. Common exceptions are black widow and brown recluse spiders.

The bite of a mosquito produces an indurated, limited local reaction characterized by a pruritic wheal (3-29 mm in diameter) with surrounding erythema (FIGURE 6) that peaks in approximately 30 minutes, although patients might have a delayed reaction hours later.⁴⁶ Immunocompromised patients might experience a more significant local inflammatory reaction that is accompanied by low-grade fever, hives, or swollen lymph nodes.^46,47

Mosquitoes are a vector for serious infections, including dengue, Japanese encephalitis, malaria, and yellow fever, and disease caused by Chikungunya, West Nile, and Zika viruses.

Continue to: Management

Ticks

Ticks belong to the order Parasitiformes and families Ixodidae and Argasidae. Hard ticks are found in brushy fields and tall grasses and can bite and feed on humans for days. Soft ticks are generally found around animal nests.²⁹ Tick bites can cause a local reaction that includes painful, erythematous, inflammatory papular lesions (FIGURE 7).⁴⁹

Ticks can transmit several infectious diseases. Depending on the microbial pathogen and the genus and species of tick, it takes 2 to 96 hours for the tick to attach to skin and transmit the pathogen to the human host. The TABLE^29,49,50 provides an overview of tick species in the United States, diseases that they can transmit, and the geographic distribution of those diseases.

Management. Ticks should be removed with fine-tipped tweezers. Grasp the body of the tick close to the skin and pull upward while applying steady, even pressure. After removing the tick, clean the bite and the surrounding area with alcohol or with soap and water. Dispose of a live tick by flushing it down the toilet; or, kill it in alcohol and either seal it in a bag with tape or place it in a container.⁵⁰

Diagnosis and the utilityof special testing

The diagnosis of insect, arachnid, and other arthropod bites and stings depends on the history, including obtaining a record of possible exposure and a travel history; the timing of the bite or sting; and associated signs and symptoms.^18,51

Venom skin testing. For Hymenoptera stings, intradermal tests using a venom concentration of 0.001 to 1 μg/mL are positive in 65% to 80% of patients with a history of a systemic insect-sting allergic reaction. A negative venom skin test can occur during the 3-to-6-week refractory period after a sting reaction or many years later, which represents a loss of sensitivity. Positive venom skin tests are used to confirm allergy and identify specific insects to which the patient is allergic.^11,12

Continue to: Allergen-specific IgE antibody testing.

Providing reliefand advanced care

Symptomatic treatment of mild bites and stings includes washing the affected area with soap and water and applying a cold compress to reduce swelling.⁵⁴ For painful lesions, an oral analgesic can be prescribed.

For mild or moderate pruritus, a low- to midpotency topical corticosteroid (eg, hydrocortisone valerate cream 0.2% bid), topical calamine, or pramoxine can be applied,or a nonsedating oral antihistamine, such as loratadine (10 mg/d) or cetirizine (10 mg/d), can be used.^14,55 For severe itching, a sedating antihistamine, such as hydroxyzine (10-25 mg every 4 to 6 hours prn), might help relieve symptoms; H₁- and H₂-receptor antagonists can be used concomitantly.^54,55

Significant local symptoms. Large local reactions are treated with a midpotency topical corticosteroid (eg, triamcinolone acetonide cream 0.1% bid) plus an oral antihistamine to relieve pruritus and reduce allergic inflammation. For a more severe reaction, an oral corticosteroid (prednisone 1 mg/kg; maximum dosage, 50 mg/d) can be given for 5 to 7 days.^54-56

Management of a necrotic ulcer secondary to a brown recluse spider bite is symptomatic and supportive. The size of these wounds can increase for as long as 10 days after the bite; resolution can require months of wound care, possibly with debridement. Rarely, skin grafting is required.^27,28,31

VIT. Some studies show that VIT can improve quality of life in patients with prolonged, frequent, and worsening reactions to insect bites or stings and repeated, unavoidable exposures.^55,56 VIT is recommended for patients with systemic hypersensitivity and a positive venom skin test result. It is approximately 95% effective in preventing or reducing severe systemic reactions and reduces the risk of anaphylaxis (see next section) and death.⁵⁷ The maintenance dosage of VIT is usually 100 μg every 4 to 6 weeks; optimal duration of treatment is 3 to 5 years.⁵⁸

Continue to: After VIT is complete...

• a history of severe, life-threatening allergic reactions to bites and stings
• honey bee sting allergy
• mast-cell disease
• a history of anaphylaxis while receiving VIT.

Absolute contraindications to VIT include a history of serious immune disease, chronic infection, or cancer.^58,59

Managing anaphylaxis

This severe allergic reaction can lead to death if untreated. First-line therapy is intramuscular epinephrine, 0.01 mg/kg (maximum single dose, 0.5 mg) given every 5 to 15 minutes.^14,60 Epinephrine auto-injectors deliver a fixed dose and are labeled according to weight. Administration of O₂ and intravenous fluids is recommended for hemodynamically unstable patients.^60,61 Antihistamines and corticosteroids can be used as secondary treatment but should not replace epinephrine.⁵⁶

After preliminary improvement, patients might decompensate when the epinephrine dose wears off. Furthermore, a biphasic reaction, variously reported in < 5% to as many as 20% of patients,^61,62 occurs hours after the initial anaphylactic reaction. Patients should be monitored, therefore, for at least 6 to 8 hours after an anaphylactic reaction, preferably in a facility equipped to treat anaphylaxis.^17,56
 

The scent of botanic oils, including lavender and peppermint, can help prevent infestation by fleas.

Before discharge, patients who have had an anaphylactic reaction should be given a prescription for epinephrine and training in the use of an epinephrine auto-injector. Allergen avoidance, along with an emergency plan in the event of a bite or sting, is recommended. Follow-up evaluation with an allergist or immunologist is essential for proper diagnosis and to determine whether the patient is a candidate for VIT.^14,17

CORRESPONDENCE
Ecler Ercole Jaqua, MD, DipABLM, FAAFP, 1200 California Street, Suite 240, Redlands, CA 92374; ejaqua@llu.edu.

CASE 

Mr. A is a 30-year-old man with neurofibromatosis and myelopathy with associated quadriplegia, complicated by dysphasia and chronic hypercapnic respiratory failure requiring a tracheostomy. He is cared for at home by his very competent mother but requires regular visits with his medical providers for assistance with his complex care needs. Due to logistical challenges, he had been receiving regular home visits even before the ­COVID-19 pandemic.

After estimating the risk of exposure to the patient, Mr. A’s family and his physician’s office staff scheduled a home visit. Before the appointment, the doctor conducted a virtual visit with the patient and family members to screen for COVID-19 infection, which proved negative. The doctor arranged a visit to coincide with Mr. A’s regular appointment with the home health nurse. He invited the patient’s social worker to attend, as well.

The providers donned masks, face shields, and gloves before entering the home. Mr. A’s temperature was checked and was normal. The team completed a physical exam, assessed the patient’s current needs, and refilled prescriptions. The doctor, nurse, and social worker met afterward in the family’s driveway to coordinate plans for the patient’s future care.

This encounter allowed a vulnerable patient with special needs to have access to care while reducing his risk of undesirable exposure. Also, his health care team’s provision of care in the home setting reduced Mr. A’s anxiety and that of his family members.

Home visits have long been an integral part of what it means to be a family physician. In 1930, roughly 40% of all patient-physician encounters in the United States occurred in patients’ homes. By 1980, this number had dropped to < 1%.¹ Still, a 1994 survey of American doctors in 3 primary care specialties revealed that 63% of family physicians, more than the other 2 specialties, still made house calls.² A 2016 analysis of Medicare claims data showed that between 2006 and 2011, only 5% of American doctors overall made house calls on Medicare recipients, but interestingly, the total number of home visits was increasing.³

This resurgence of interest in home health care is due in part to the increasing number of homebound patients in America, which exceeds the number of those in nursing homes.⁴ Further, a growing body of evidence indicates that home visits improve patient outcomes. And finally, many family physicians whose work lives have been centered around a busy office or hospital practice have found satisfaction in once again seeing patients in their own homes.

The COVID-19 pandemic has of course presented unique challenges—and opportunities, too—for home visits, which we discuss at the end of the article.

In the elderly, home visits have reduced functional decline, nursing home admissions, and mortality by 25% to 33%.

Why aren’t more of us making home visits?

For most of us, the decision not to make home visits is simply a matter of time and money. Although Medicare reimbursement for a home visit is typically about 150% that of a comparable office visit,⁵ it’s difficult, if not impossible, to make 2 home visits in the time you could see 3 patients in the office. So, economically it’s a net loss. Furthermore, we tend to feel less comfortable in our patients’ homes than in our offices. We have less control outside our own environment, and what happens away from our office is often less predictable—sometimes to the point that we may be concerned for our safety.

Continue to: So why make home visits at all?

So why make home visits at all?

First and foremost, home visits improve patient outcomes. This is most evident in our more vulnerable patients: newborns and the elderly, those who have been recently hospitalized, and those at risk because of their particular home situation. Multiple studies have shown that, for elders, home visits reduce functional decline, nursing home admissions, and mortality by around 25% to 33%.^6-8 For those at risk of abuse, a recent systematic review showed that home visits reduce intimate partner violence and child abuse.⁹ Another systematic review demonstrated that patients with diabetes who received home visits vs usual care were more likely to show improvements in quality of life.¹⁰ These patients were also more likely to have lower HbA1c levels and lower systolic blood pressure readings.¹⁰ A few caveats apply to these studies:

• all of them targeted “vulnerable” patients
• most studies enlisted interdisciplinary teams and had regular team meetings
• most findings reached significance only after multiple home visits.

A further reason for choosing to become involved in home care is that it builds relationships, understanding, and empathy with our patients. “There is deep symbolism in the home visit.... It says, ‘I care enough about you to leave my power base … to come and see you on your own ground.’”¹¹ And this benefit is 2-way; we also grow to understand and appreciate our patients better, especially if they are different from us culturally or socioeconomically.

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention. For the patient, home visits foster a strong sense of trust with the individual doctor and our health delivery network, and they decrease the need to seek emergency services. Finally, it has been demonstrated that provider satisfaction improves when home visits are incorporated into the work week.¹²

What is the role of community health workers in home-based care?

Community health workers (CHWs), defined as “frontline public health workers who are trusted members of and/or have an unusually close understanding of the community they serve,”¹³ can be an integral part of the home-based care team. Although CHWs have variable amounts of formal training, they have a unique perspective on local health beliefs and practices, which can assist the home-care team in providing culturally competent health care services and reduce health care costs.

In a study of children with asthma in Seattle, Washington, patients were randomized to a group that had 4 home visits by CHWs and a group that received usual care. The group that received home visits demonstrated more asthma symptom–free days, improved quality-of-life scores, and fewer urgent care visits.¹⁴ Furthermore, the intervention was estimated to save approximately $1300 per patient, resulting in a return on investment of 190%. Similarly, in a study comparing inappropriate emergency department (ED) visits between children who received CHW visits and those who did not, patients in the intervention group were significantly less likely to visit the ED for ambulatory complaints (18.2% vs 35.1%; P = .004).¹⁵

Continue to: What is the role of social workersin home-based care?

What is the role of social workersin home-based care?

Social workers can help meet the complex medical and biopsychosocial needs of the homebound population.¹⁶ A study by Cohen et al based in Israel concluded that homebound participants had a significantly higher risk for mortality, higher rates of depression, and difficulty completing instrumental activities of daily living when compared with their non-homebound counterparts.¹⁷

The Mount Sinai (New York) Visiting Doctors Program (MSVD) is a home-based care team that uses social workers to meet the needs of their complex patients.¹⁸ The social workers in the MSVD program provide direct counseling, make referrals to government and community resources, and monitor caregiver burden. Using a combination of measurement tools to assess caregiver burden, Ornstein et al demonstrated that the MSVD program led to a decrease in unmet needs and in caregiver burden.^19,20 Caregiver burnout can be assessed using the Caregiver Burden Inventory, a validated 24-item questionnaire.²¹

What electronic tools are availableto monitor patients at home?

Although expensive in terms of both dollars and personnel time, telemonitoring allows home care providers to receive real-time, updated information regarding their patients.

Chronic obstructive pulmonary disease (COPD). One systematic review showed that although telemonitoring of patients with COPD improved quality of life and decreased COPD exacerbations, it did not reduce the risk of hospitalization and, therefore, did not reduce health care costs.²² Telemonitoring in COPD can include transmission of data about spirometry parameters, weight, temperature, blood pressure, sputum color, and 6-minute walk distance.^23,24

Congestive heart failure (CHF). A 2010 Cochrane review found that telemonitoring of patients with CHF reduced all-cause mortality (risk ratio [RR] = 0.66; P < .0001).²⁵ The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial,conducted from 2013 to 2017, compared usual care for CHF patients with care incorporating daily transmission of body weight, blood pressure, heart rate, electrocardiogram tracings, pulse oximetry, and self-rated health status.²⁶ This study showed that the average number of days lost per year due to hospital admission was less in the telemonitoring group than in the usual care group (17.8 days vs. 24.2 days; P = .046). All-cause mortality was also reduced in the telemonitoring group (hazard ratio = 0.70; P = .028).

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention.

Continue to: What role do “home hospitals” play?

What role do “home hospitals” play?

Home hospitals provide acute or subacute treatment in a patient’s home for a condition that would normally require hospitalization.²⁷ In a meta-analysis of 61 studies evaluating the effectiveness of home hospitals, this option was more likely to reduce mortality (odds ratio [OR] = 0.81; P = .008) and to reduce readmission rates (OR = 0.75; P = .02).²⁸ In a study of 455 older adults, Leff et al found that hospital-at-home was associated with a shorter length of stay (3.2 vs. 4.9 days; P = .004) and that the mean cost was lower for hospital-at-home vs traditional hospital care.²⁹

However, a 2016 Cochrane review of 16 randomized controlled trials comparing hospital-at-home with traditional hospital care showed that while care in a hospital-­at-home may decrease formal costs, if costs for caregivers are taken into account, any difference in cost may disappear.³⁰

Although the evidence for cost saving is variable, hospital-at-home admission has been shown to reduce the likelihood of living in a residential care facility at 6 months (RR = 0.35; P < .0001).³⁰ Further, the same Cochrane review showed that admission avoidance may increase patient satisfaction with the care provided.³⁰

Finally, a recent randomized trial in a Boston-area hospital system showed that patients cared for in hospital-at-home were significantly less likely to be readmitted within 30 days and that adjusted cost was about two-thirds the cost of traditional hospital care.³¹

What is the physician’s rolein home health care?

While home health care is a team effort, the physician has several crucial roles. First, he or she must make the determination that home care is appropriate and feasible for a particular patient. Appropriate, meaning there is evidence that this patient is likely to benefit from home care. Feasible, meaning there are resources available in the community and family to safely care for the patient at home. “Often a house call will serve as the first step in developing a home-based-management plan.”³²

Patients with diabetes receiving home care are more likely to have improved quality of life, lower HbA1c levels, and lower systolic BP readings.

Continue to: Second, the physician serves...

Second, the physician serves an important role in directing and coordinating the team of professionals involved. This primarily means helping the team to communicate with one another. Before home visits begin, the physician’s office should reach out not only to the patient and family, but also to any other health care personnel involved in the patient’s home care. Otherwise, many of the health care providers involved will never have face-to-face interaction with the physician. Creation of the coordinated health team minimizes duplication and miscommunication; it also builds a valuable bond.

How does one go about making a home visit?

Scheduling. What often works best in a busy practice is to schedule home visits for the end of the workday or to devote an entire afternoon to making home visits to several patients in one locale. Also important is scheduling times, if possible, when important family members or other caregivers are at home or when other members of the home care team can accompany you.

What to bring along. Carry a “home visit bag” that includes equipment you’re likely to need and that is not available away from your office. A minimally equipped visit bag would include different-sized blood pressure cuffs, a glucometer, a pulse oximeter, thermometers, and patient education materials. Other suggested contents are listed in TABLE 1. Due to the COVID-19 pandemic, providers should also carry adequate personal protective equipment (PPE), including an N-95 mask.

Dos and don’ts. Take a few minutes when you first arrive to simply visit with the patient. Sit down and introduce yourself and any members of the home care team that the patient has not met. Take an interim history. While you’re doing this, be observant: Is the home neat or cluttered? Is the indoor temperature comfortable? Are there fall hazards? Is there a smell of cigarette smoke? Are there any indoor combustion sources (eg, wood stove or kerosene heater)? Ask questions such as: Who lives here with you? Can you show me where you keep your medicines? (If the patient keeps insulin or any other medicines in the refrigerator, ask to see it. Note any apparent food scarcity.)

During your exam, pay particular attention to whether vital signs are appreciably different than those measured in the office or hospital. Pay special attention to the patient’s functional abilities. “A subtle, but critical distinction between medical management in the home and medical management in the hospital, clinic, or office is the emphasis on the patient’s functional abilities, family assistance, and environmental factors.”³³

Observe the patient’s use of any home technology, if possible; this can be as simple as home oxygenation or as complex as home hemodialysis. Assess for any apparent caregiver stress. Finally, don’t neglect to offer appropriate emotional and spiritual support to the patient and family and to schedule the next follow-up visit before you leave.

Continue to:  Documentation and reimbursement.

Not all assessments will be able to be done at each visit but seeing them listed in the template can be helpful. Billing follows the same principles as for office visits and has similar requirements for documentation. Codes for the most common types of home visits are listed in TABLE 3.

Where can I get help?

Graduates of family medicine residency programs are required to receive training in home visits by the Accreditation Council for Graduate Medical Education (ACGME). Current ACGME program requirements stipulate that “residents must demonstrate competence to independently diagnose, manage, and integrate the care of patients of all ages in various outpatient settings, including the FMP [family medicine practice] site and home environment,” and “residents must be primarily responsible for a panel of continuity patients, integrating each patient’s care across all settings, including the home ...” [emphasis added].³⁴

For those already in practice, one of the hardest parts of doing home visits is feeling alone, especially if few other providers in your community engage in home care. As you run into questions and challenges with incorporating home care of patients into your practice, one excellent resource is the American Academy of Home Care Medicine (www.aahcm.org/). Founded in 1988 and headquartered in Chicago, it not only provides numerous helpful resources, but serves as a networking tool for physicians involved in home care.

Using a home visit template can help with documentation and reimbursement.

This unprecedented pandemichas allowed home visits to shine

As depicted in our opening patient case, patients who have high-risk conditions and those who are older than 65 years of age may be cared for more appropriately in a home visit rather than having them come to the office. Home visits may also be a way for providers to “lay eyes” on patients who do not have technology available to participate in virtual visits.

Before performing a home visit, inquire as to whether the patient has symptoms of COVID-19. Adequate PPE should be donned at all times and social distancing should be practiced when appropriate. With adequate PPE, home visits may also allow providers to care for low-risk patients known to have ­COVID-19 and thereby minimize risks to staff and other patients in the office. JFP

CORRESPONDENCE
Curt Elliott, MD, Prisma Health USC Family Medicine Center, 3209 Colonial Drive, Columbia, SC 29203; curtis.elliott@uscmed.sc.edu.

CASE 

Mr. A is a 30-year-old man with neurofibromatosis and myelopathy with associated quadriplegia, complicated by dysphasia and chronic hypercapnic respiratory failure requiring a tracheostomy. He is cared for at home by his very competent mother but requires regular visits with his medical providers for assistance with his complex care needs. Due to logistical challenges, he had been receiving regular home visits even before the ­COVID-19 pandemic.

After estimating the risk of exposure to the patient, Mr. A’s family and his physician’s office staff scheduled a home visit. Before the appointment, the doctor conducted a virtual visit with the patient and family members to screen for COVID-19 infection, which proved negative. The doctor arranged a visit to coincide with Mr. A’s regular appointment with the home health nurse. He invited the patient’s social worker to attend, as well.

The providers donned masks, face shields, and gloves before entering the home. Mr. A’s temperature was checked and was normal. The team completed a physical exam, assessed the patient’s current needs, and refilled prescriptions. The doctor, nurse, and social worker met afterward in the family’s driveway to coordinate plans for the patient’s future care.

This encounter allowed a vulnerable patient with special needs to have access to care while reducing his risk of undesirable exposure. Also, his health care team’s provision of care in the home setting reduced Mr. A’s anxiety and that of his family members.

Home visits have long been an integral part of what it means to be a family physician. In 1930, roughly 40% of all patient-physician encounters in the United States occurred in patients’ homes. By 1980, this number had dropped to < 1%.¹ Still, a 1994 survey of American doctors in 3 primary care specialties revealed that 63% of family physicians, more than the other 2 specialties, still made house calls.² A 2016 analysis of Medicare claims data showed that between 2006 and 2011, only 5% of American doctors overall made house calls on Medicare recipients, but interestingly, the total number of home visits was increasing.³

This resurgence of interest in home health care is due in part to the increasing number of homebound patients in America, which exceeds the number of those in nursing homes.⁴ Further, a growing body of evidence indicates that home visits improve patient outcomes. And finally, many family physicians whose work lives have been centered around a busy office or hospital practice have found satisfaction in once again seeing patients in their own homes.

The COVID-19 pandemic has of course presented unique challenges—and opportunities, too—for home visits, which we discuss at the end of the article.

In the elderly, home visits have reduced functional decline, nursing home admissions, and mortality by 25% to 33%.

Why aren’t more of us making home visits?

For most of us, the decision not to make home visits is simply a matter of time and money. Although Medicare reimbursement for a home visit is typically about 150% that of a comparable office visit,⁵ it’s difficult, if not impossible, to make 2 home visits in the time you could see 3 patients in the office. So, economically it’s a net loss. Furthermore, we tend to feel less comfortable in our patients’ homes than in our offices. We have less control outside our own environment, and what happens away from our office is often less predictable—sometimes to the point that we may be concerned for our safety.

Continue to: So why make home visits at all?

So why make home visits at all?

First and foremost, home visits improve patient outcomes. This is most evident in our more vulnerable patients: newborns and the elderly, those who have been recently hospitalized, and those at risk because of their particular home situation. Multiple studies have shown that, for elders, home visits reduce functional decline, nursing home admissions, and mortality by around 25% to 33%.^6-8 For those at risk of abuse, a recent systematic review showed that home visits reduce intimate partner violence and child abuse.⁹ Another systematic review demonstrated that patients with diabetes who received home visits vs usual care were more likely to show improvements in quality of life.¹⁰ These patients were also more likely to have lower HbA1c levels and lower systolic blood pressure readings.¹⁰ A few caveats apply to these studies:

• all of them targeted “vulnerable” patients
• most studies enlisted interdisciplinary teams and had regular team meetings
• most findings reached significance only after multiple home visits.

A further reason for choosing to become involved in home care is that it builds relationships, understanding, and empathy with our patients. “There is deep symbolism in the home visit.... It says, ‘I care enough about you to leave my power base … to come and see you on your own ground.’”¹¹ And this benefit is 2-way; we also grow to understand and appreciate our patients better, especially if they are different from us culturally or socioeconomically.

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention. For the patient, home visits foster a strong sense of trust with the individual doctor and our health delivery network, and they decrease the need to seek emergency services. Finally, it has been demonstrated that provider satisfaction improves when home visits are incorporated into the work week.¹²

What is the role of community health workers in home-based care?

Community health workers (CHWs), defined as “frontline public health workers who are trusted members of and/or have an unusually close understanding of the community they serve,”¹³ can be an integral part of the home-based care team. Although CHWs have variable amounts of formal training, they have a unique perspective on local health beliefs and practices, which can assist the home-care team in providing culturally competent health care services and reduce health care costs.

In a study of children with asthma in Seattle, Washington, patients were randomized to a group that had 4 home visits by CHWs and a group that received usual care. The group that received home visits demonstrated more asthma symptom–free days, improved quality-of-life scores, and fewer urgent care visits.¹⁴ Furthermore, the intervention was estimated to save approximately $1300 per patient, resulting in a return on investment of 190%. Similarly, in a study comparing inappropriate emergency department (ED) visits between children who received CHW visits and those who did not, patients in the intervention group were significantly less likely to visit the ED for ambulatory complaints (18.2% vs 35.1%; P = .004).¹⁵

Continue to: What is the role of social workersin home-based care?

What is the role of social workersin home-based care?

Social workers can help meet the complex medical and biopsychosocial needs of the homebound population.¹⁶ A study by Cohen et al based in Israel concluded that homebound participants had a significantly higher risk for mortality, higher rates of depression, and difficulty completing instrumental activities of daily living when compared with their non-homebound counterparts.¹⁷

The Mount Sinai (New York) Visiting Doctors Program (MSVD) is a home-based care team that uses social workers to meet the needs of their complex patients.¹⁸ The social workers in the MSVD program provide direct counseling, make referrals to government and community resources, and monitor caregiver burden. Using a combination of measurement tools to assess caregiver burden, Ornstein et al demonstrated that the MSVD program led to a decrease in unmet needs and in caregiver burden.^19,20 Caregiver burnout can be assessed using the Caregiver Burden Inventory, a validated 24-item questionnaire.²¹

What electronic tools are availableto monitor patients at home?

Although expensive in terms of both dollars and personnel time, telemonitoring allows home care providers to receive real-time, updated information regarding their patients.

Chronic obstructive pulmonary disease (COPD). One systematic review showed that although telemonitoring of patients with COPD improved quality of life and decreased COPD exacerbations, it did not reduce the risk of hospitalization and, therefore, did not reduce health care costs.²² Telemonitoring in COPD can include transmission of data about spirometry parameters, weight, temperature, blood pressure, sputum color, and 6-minute walk distance.^23,24

Congestive heart failure (CHF). A 2010 Cochrane review found that telemonitoring of patients with CHF reduced all-cause mortality (risk ratio [RR] = 0.66; P < .0001).²⁵ The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial,conducted from 2013 to 2017, compared usual care for CHF patients with care incorporating daily transmission of body weight, blood pressure, heart rate, electrocardiogram tracings, pulse oximetry, and self-rated health status.²⁶ This study showed that the average number of days lost per year due to hospital admission was less in the telemonitoring group than in the usual care group (17.8 days vs. 24.2 days; P = .046). All-cause mortality was also reduced in the telemonitoring group (hazard ratio = 0.70; P = .028).

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention.

Continue to: What role do “home hospitals” play?

What role do “home hospitals” play?

Home hospitals provide acute or subacute treatment in a patient’s home for a condition that would normally require hospitalization.²⁷ In a meta-analysis of 61 studies evaluating the effectiveness of home hospitals, this option was more likely to reduce mortality (odds ratio [OR] = 0.81; P = .008) and to reduce readmission rates (OR = 0.75; P = .02).²⁸ In a study of 455 older adults, Leff et al found that hospital-at-home was associated with a shorter length of stay (3.2 vs. 4.9 days; P = .004) and that the mean cost was lower for hospital-at-home vs traditional hospital care.²⁹

However, a 2016 Cochrane review of 16 randomized controlled trials comparing hospital-at-home with traditional hospital care showed that while care in a hospital-­at-home may decrease formal costs, if costs for caregivers are taken into account, any difference in cost may disappear.³⁰

Although the evidence for cost saving is variable, hospital-at-home admission has been shown to reduce the likelihood of living in a residential care facility at 6 months (RR = 0.35; P < .0001).³⁰ Further, the same Cochrane review showed that admission avoidance may increase patient satisfaction with the care provided.³⁰

Finally, a recent randomized trial in a Boston-area hospital system showed that patients cared for in hospital-at-home were significantly less likely to be readmitted within 30 days and that adjusted cost was about two-thirds the cost of traditional hospital care.³¹

What is the physician’s rolein home health care?

While home health care is a team effort, the physician has several crucial roles. First, he or she must make the determination that home care is appropriate and feasible for a particular patient. Appropriate, meaning there is evidence that this patient is likely to benefit from home care. Feasible, meaning there are resources available in the community and family to safely care for the patient at home. “Often a house call will serve as the first step in developing a home-based-management plan.”³²

Patients with diabetes receiving home care are more likely to have improved quality of life, lower HbA1c levels, and lower systolic BP readings.

Continue to: Second, the physician serves...

Second, the physician serves an important role in directing and coordinating the team of professionals involved. This primarily means helping the team to communicate with one another. Before home visits begin, the physician’s office should reach out not only to the patient and family, but also to any other health care personnel involved in the patient’s home care. Otherwise, many of the health care providers involved will never have face-to-face interaction with the physician. Creation of the coordinated health team minimizes duplication and miscommunication; it also builds a valuable bond.

How does one go about making a home visit?

Scheduling. What often works best in a busy practice is to schedule home visits for the end of the workday or to devote an entire afternoon to making home visits to several patients in one locale. Also important is scheduling times, if possible, when important family members or other caregivers are at home or when other members of the home care team can accompany you.

What to bring along. Carry a “home visit bag” that includes equipment you’re likely to need and that is not available away from your office. A minimally equipped visit bag would include different-sized blood pressure cuffs, a glucometer, a pulse oximeter, thermometers, and patient education materials. Other suggested contents are listed in TABLE 1. Due to the COVID-19 pandemic, providers should also carry adequate personal protective equipment (PPE), including an N-95 mask.

Dos and don’ts. Take a few minutes when you first arrive to simply visit with the patient. Sit down and introduce yourself and any members of the home care team that the patient has not met. Take an interim history. While you’re doing this, be observant: Is the home neat or cluttered? Is the indoor temperature comfortable? Are there fall hazards? Is there a smell of cigarette smoke? Are there any indoor combustion sources (eg, wood stove or kerosene heater)? Ask questions such as: Who lives here with you? Can you show me where you keep your medicines? (If the patient keeps insulin or any other medicines in the refrigerator, ask to see it. Note any apparent food scarcity.)

During your exam, pay particular attention to whether vital signs are appreciably different than those measured in the office or hospital. Pay special attention to the patient’s functional abilities. “A subtle, but critical distinction between medical management in the home and medical management in the hospital, clinic, or office is the emphasis on the patient’s functional abilities, family assistance, and environmental factors.”³³

Observe the patient’s use of any home technology, if possible; this can be as simple as home oxygenation or as complex as home hemodialysis. Assess for any apparent caregiver stress. Finally, don’t neglect to offer appropriate emotional and spiritual support to the patient and family and to schedule the next follow-up visit before you leave.

Continue to:  Documentation and reimbursement.

Not all assessments will be able to be done at each visit but seeing them listed in the template can be helpful. Billing follows the same principles as for office visits and has similar requirements for documentation. Codes for the most common types of home visits are listed in TABLE 3.

Where can I get help?

Graduates of family medicine residency programs are required to receive training in home visits by the Accreditation Council for Graduate Medical Education (ACGME). Current ACGME program requirements stipulate that “residents must demonstrate competence to independently diagnose, manage, and integrate the care of patients of all ages in various outpatient settings, including the FMP [family medicine practice] site and home environment,” and “residents must be primarily responsible for a panel of continuity patients, integrating each patient’s care across all settings, including the home ...” [emphasis added].³⁴

For those already in practice, one of the hardest parts of doing home visits is feeling alone, especially if few other providers in your community engage in home care. As you run into questions and challenges with incorporating home care of patients into your practice, one excellent resource is the American Academy of Home Care Medicine (www.aahcm.org/). Founded in 1988 and headquartered in Chicago, it not only provides numerous helpful resources, but serves as a networking tool for physicians involved in home care.

Using a home visit template can help with documentation and reimbursement.

This unprecedented pandemichas allowed home visits to shine

As depicted in our opening patient case, patients who have high-risk conditions and those who are older than 65 years of age may be cared for more appropriately in a home visit rather than having them come to the office. Home visits may also be a way for providers to “lay eyes” on patients who do not have technology available to participate in virtual visits.

Before performing a home visit, inquire as to whether the patient has symptoms of COVID-19. Adequate PPE should be donned at all times and social distancing should be practiced when appropriate. With adequate PPE, home visits may also allow providers to care for low-risk patients known to have ­COVID-19 and thereby minimize risks to staff and other patients in the office. JFP

CORRESPONDENCE
Curt Elliott, MD, Prisma Health USC Family Medicine Center, 3209 Colonial Drive, Columbia, SC 29203; curtis.elliott@uscmed.sc.edu.

CASE 

Mr. A is a 30-year-old man with neurofibromatosis and myelopathy with associated quadriplegia, complicated by dysphasia and chronic hypercapnic respiratory failure requiring a tracheostomy. He is cared for at home by his very competent mother but requires regular visits with his medical providers for assistance with his complex care needs. Due to logistical challenges, he had been receiving regular home visits even before the ­COVID-19 pandemic.

After estimating the risk of exposure to the patient, Mr. A’s family and his physician’s office staff scheduled a home visit. Before the appointment, the doctor conducted a virtual visit with the patient and family members to screen for COVID-19 infection, which proved negative. The doctor arranged a visit to coincide with Mr. A’s regular appointment with the home health nurse. He invited the patient’s social worker to attend, as well.

The providers donned masks, face shields, and gloves before entering the home. Mr. A’s temperature was checked and was normal. The team completed a physical exam, assessed the patient’s current needs, and refilled prescriptions. The doctor, nurse, and social worker met afterward in the family’s driveway to coordinate plans for the patient’s future care.

This encounter allowed a vulnerable patient with special needs to have access to care while reducing his risk of undesirable exposure. Also, his health care team’s provision of care in the home setting reduced Mr. A’s anxiety and that of his family members.

Home visits have long been an integral part of what it means to be a family physician. In 1930, roughly 40% of all patient-physician encounters in the United States occurred in patients’ homes. By 1980, this number had dropped to < 1%.¹ Still, a 1994 survey of American doctors in 3 primary care specialties revealed that 63% of family physicians, more than the other 2 specialties, still made house calls.² A 2016 analysis of Medicare claims data showed that between 2006 and 2011, only 5% of American doctors overall made house calls on Medicare recipients, but interestingly, the total number of home visits was increasing.³

This resurgence of interest in home health care is due in part to the increasing number of homebound patients in America, which exceeds the number of those in nursing homes.⁴ Further, a growing body of evidence indicates that home visits improve patient outcomes. And finally, many family physicians whose work lives have been centered around a busy office or hospital practice have found satisfaction in once again seeing patients in their own homes.

The COVID-19 pandemic has of course presented unique challenges—and opportunities, too—for home visits, which we discuss at the end of the article.

In the elderly, home visits have reduced functional decline, nursing home admissions, and mortality by 25% to 33%.

Why aren’t more of us making home visits?

For most of us, the decision not to make home visits is simply a matter of time and money. Although Medicare reimbursement for a home visit is typically about 150% that of a comparable office visit,⁵ it’s difficult, if not impossible, to make 2 home visits in the time you could see 3 patients in the office. So, economically it’s a net loss. Furthermore, we tend to feel less comfortable in our patients’ homes than in our offices. We have less control outside our own environment, and what happens away from our office is often less predictable—sometimes to the point that we may be concerned for our safety.

Continue to: So why make home visits at all?

So why make home visits at all?

First and foremost, home visits improve patient outcomes. This is most evident in our more vulnerable patients: newborns and the elderly, those who have been recently hospitalized, and those at risk because of their particular home situation. Multiple studies have shown that, for elders, home visits reduce functional decline, nursing home admissions, and mortality by around 25% to 33%.^6-8 For those at risk of abuse, a recent systematic review showed that home visits reduce intimate partner violence and child abuse.⁹ Another systematic review demonstrated that patients with diabetes who received home visits vs usual care were more likely to show improvements in quality of life.¹⁰ These patients were also more likely to have lower HbA1c levels and lower systolic blood pressure readings.¹⁰ A few caveats apply to these studies:

• all of them targeted “vulnerable” patients
• most studies enlisted interdisciplinary teams and had regular team meetings
• most findings reached significance only after multiple home visits.

A further reason for choosing to become involved in home care is that it builds relationships, understanding, and empathy with our patients. “There is deep symbolism in the home visit.... It says, ‘I care enough about you to leave my power base … to come and see you on your own ground.’”¹¹ And this benefit is 2-way; we also grow to understand and appreciate our patients better, especially if they are different from us culturally or socioeconomically.

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention. For the patient, home visits foster a strong sense of trust with the individual doctor and our health delivery network, and they decrease the need to seek emergency services. Finally, it has been demonstrated that provider satisfaction improves when home visits are incorporated into the work week.¹²

What is the role of community health workers in home-based care?

Community health workers (CHWs), defined as “frontline public health workers who are trusted members of and/or have an unusually close understanding of the community they serve,”¹³ can be an integral part of the home-based care team. Although CHWs have variable amounts of formal training, they have a unique perspective on local health beliefs and practices, which can assist the home-care team in providing culturally competent health care services and reduce health care costs.

In a study of children with asthma in Seattle, Washington, patients were randomized to a group that had 4 home visits by CHWs and a group that received usual care. The group that received home visits demonstrated more asthma symptom–free days, improved quality-of-life scores, and fewer urgent care visits.¹⁴ Furthermore, the intervention was estimated to save approximately $1300 per patient, resulting in a return on investment of 190%. Similarly, in a study comparing inappropriate emergency department (ED) visits between children who received CHW visits and those who did not, patients in the intervention group were significantly less likely to visit the ED for ambulatory complaints (18.2% vs 35.1%; P = .004).¹⁵

Continue to: What is the role of social workersin home-based care?

What is the role of social workersin home-based care?

Social workers can help meet the complex medical and biopsychosocial needs of the homebound population.¹⁶ A study by Cohen et al based in Israel concluded that homebound participants had a significantly higher risk for mortality, higher rates of depression, and difficulty completing instrumental activities of daily living when compared with their non-homebound counterparts.¹⁷

The Mount Sinai (New York) Visiting Doctors Program (MSVD) is a home-based care team that uses social workers to meet the needs of their complex patients.¹⁸ The social workers in the MSVD program provide direct counseling, make referrals to government and community resources, and monitor caregiver burden. Using a combination of measurement tools to assess caregiver burden, Ornstein et al demonstrated that the MSVD program led to a decrease in unmet needs and in caregiver burden.^19,20 Caregiver burnout can be assessed using the Caregiver Burden Inventory, a validated 24-item questionnaire.²¹

What electronic tools are availableto monitor patients at home?

Although expensive in terms of both dollars and personnel time, telemonitoring allows home care providers to receive real-time, updated information regarding their patients.

Chronic obstructive pulmonary disease (COPD). One systematic review showed that although telemonitoring of patients with COPD improved quality of life and decreased COPD exacerbations, it did not reduce the risk of hospitalization and, therefore, did not reduce health care costs.²² Telemonitoring in COPD can include transmission of data about spirometry parameters, weight, temperature, blood pressure, sputum color, and 6-minute walk distance.^23,24

Congestive heart failure (CHF). A 2010 Cochrane review found that telemonitoring of patients with CHF reduced all-cause mortality (risk ratio [RR] = 0.66; P < .0001).²⁵ The Telemedical Interventional Management in Heart Failure II (TIM-HF2) trial,conducted from 2013 to 2017, compared usual care for CHF patients with care incorporating daily transmission of body weight, blood pressure, heart rate, electrocardiogram tracings, pulse oximetry, and self-rated health status.²⁶ This study showed that the average number of days lost per year due to hospital admission was less in the telemonitoring group than in the usual care group (17.8 days vs. 24.2 days; P = .046). All-cause mortality was also reduced in the telemonitoring group (hazard ratio = 0.70; P = .028).

Home visits allow the medical team to see challenges the patient has grown accustomed to, and perhaps ones that the patient has deemed too insignificant to mention.

Continue to: What role do “home hospitals” play?

What role do “home hospitals” play?

Home hospitals provide acute or subacute treatment in a patient’s home for a condition that would normally require hospitalization.²⁷ In a meta-analysis of 61 studies evaluating the effectiveness of home hospitals, this option was more likely to reduce mortality (odds ratio [OR] = 0.81; P = .008) and to reduce readmission rates (OR = 0.75; P = .02).²⁸ In a study of 455 older adults, Leff et al found that hospital-at-home was associated with a shorter length of stay (3.2 vs. 4.9 days; P = .004) and that the mean cost was lower for hospital-at-home vs traditional hospital care.²⁹

However, a 2016 Cochrane review of 16 randomized controlled trials comparing hospital-at-home with traditional hospital care showed that while care in a hospital-­at-home may decrease formal costs, if costs for caregivers are taken into account, any difference in cost may disappear.³⁰

Although the evidence for cost saving is variable, hospital-at-home admission has been shown to reduce the likelihood of living in a residential care facility at 6 months (RR = 0.35; P < .0001).³⁰ Further, the same Cochrane review showed that admission avoidance may increase patient satisfaction with the care provided.³⁰

Finally, a recent randomized trial in a Boston-area hospital system showed that patients cared for in hospital-at-home were significantly less likely to be readmitted within 30 days and that adjusted cost was about two-thirds the cost of traditional hospital care.³¹

What is the physician’s rolein home health care?

While home health care is a team effort, the physician has several crucial roles. First, he or she must make the determination that home care is appropriate and feasible for a particular patient. Appropriate, meaning there is evidence that this patient is likely to benefit from home care. Feasible, meaning there are resources available in the community and family to safely care for the patient at home. “Often a house call will serve as the first step in developing a home-based-management plan.”³²

Patients with diabetes receiving home care are more likely to have improved quality of life, lower HbA1c levels, and lower systolic BP readings.

Continue to: Second, the physician serves...

Second, the physician serves an important role in directing and coordinating the team of professionals involved. This primarily means helping the team to communicate with one another. Before home visits begin, the physician’s office should reach out not only to the patient and family, but also to any other health care personnel involved in the patient’s home care. Otherwise, many of the health care providers involved will never have face-to-face interaction with the physician. Creation of the coordinated health team minimizes duplication and miscommunication; it also builds a valuable bond.

How does one go about making a home visit?

Scheduling. What often works best in a busy practice is to schedule home visits for the end of the workday or to devote an entire afternoon to making home visits to several patients in one locale. Also important is scheduling times, if possible, when important family members or other caregivers are at home or when other members of the home care team can accompany you.

What to bring along. Carry a “home visit bag” that includes equipment you’re likely to need and that is not available away from your office. A minimally equipped visit bag would include different-sized blood pressure cuffs, a glucometer, a pulse oximeter, thermometers, and patient education materials. Other suggested contents are listed in TABLE 1. Due to the COVID-19 pandemic, providers should also carry adequate personal protective equipment (PPE), including an N-95 mask.

Dos and don’ts. Take a few minutes when you first arrive to simply visit with the patient. Sit down and introduce yourself and any members of the home care team that the patient has not met. Take an interim history. While you’re doing this, be observant: Is the home neat or cluttered? Is the indoor temperature comfortable? Are there fall hazards? Is there a smell of cigarette smoke? Are there any indoor combustion sources (eg, wood stove or kerosene heater)? Ask questions such as: Who lives here with you? Can you show me where you keep your medicines? (If the patient keeps insulin or any other medicines in the refrigerator, ask to see it. Note any apparent food scarcity.)

During your exam, pay particular attention to whether vital signs are appreciably different than those measured in the office or hospital. Pay special attention to the patient’s functional abilities. “A subtle, but critical distinction between medical management in the home and medical management in the hospital, clinic, or office is the emphasis on the patient’s functional abilities, family assistance, and environmental factors.”³³

Observe the patient’s use of any home technology, if possible; this can be as simple as home oxygenation or as complex as home hemodialysis. Assess for any apparent caregiver stress. Finally, don’t neglect to offer appropriate emotional and spiritual support to the patient and family and to schedule the next follow-up visit before you leave.

Continue to:  Documentation and reimbursement.

Not all assessments will be able to be done at each visit but seeing them listed in the template can be helpful. Billing follows the same principles as for office visits and has similar requirements for documentation. Codes for the most common types of home visits are listed in TABLE 3.

Where can I get help?

Graduates of family medicine residency programs are required to receive training in home visits by the Accreditation Council for Graduate Medical Education (ACGME). Current ACGME program requirements stipulate that “residents must demonstrate competence to independently diagnose, manage, and integrate the care of patients of all ages in various outpatient settings, including the FMP [family medicine practice] site and home environment,” and “residents must be primarily responsible for a panel of continuity patients, integrating each patient’s care across all settings, including the home ...” [emphasis added].³⁴

For those already in practice, one of the hardest parts of doing home visits is feeling alone, especially if few other providers in your community engage in home care. As you run into questions and challenges with incorporating home care of patients into your practice, one excellent resource is the American Academy of Home Care Medicine (www.aahcm.org/). Founded in 1988 and headquartered in Chicago, it not only provides numerous helpful resources, but serves as a networking tool for physicians involved in home care.

Using a home visit template can help with documentation and reimbursement.

This unprecedented pandemichas allowed home visits to shine

As depicted in our opening patient case, patients who have high-risk conditions and those who are older than 65 years of age may be cared for more appropriately in a home visit rather than having them come to the office. Home visits may also be a way for providers to “lay eyes” on patients who do not have technology available to participate in virtual visits.

Before performing a home visit, inquire as to whether the patient has symptoms of COVID-19. Adequate PPE should be donned at all times and social distancing should be practiced when appropriate. With adequate PPE, home visits may also allow providers to care for low-risk patients known to have ­COVID-19 and thereby minimize risks to staff and other patients in the office. JFP

CORRESPONDENCE
Curt Elliott, MD, Prisma Health USC Family Medicine Center, 3209 Colonial Drive, Columbia, SC 29203; curtis.elliott@uscmed.sc.edu.

In this issue of The Journal of Family Practice, Dr. Wayne Jonas explains his model for Advanced Primary Care (see page 493). The figure he uses to illustrate Advanced Primary Care is compelling, and the effectiveness of this model of health care is supported by a great deal of research and evaluation over the past 20 years. Let me provide some historical context.

The idea that healing requires more than curative, biology-based medical care dates back to Greek mythology. Asclepius, the god of medicine, had 5 daughters, Hygeia (the goddess of good health and hygiene), Iaso (cures and remedies), Aceso (healing wounds), Aegle (radiant good health), and Panacea (cures).¹ Clearly, the Greeks believed that integrative care is essential for maintaining good health!

Modern, scientific medicine is a relatively recent development in human history. Other traditions of healing such as acupuncture and herbal medicines are actually much older than mainstream Western medicine. But they come together in family medicine—a specialty founded on the principles of whole person, whole family, and whole community care.

We can no longer go “halfway” into whole-person care.

The first modern model of comprehensive care, the patient-centered medical home (PCMH), was introduced by the American Academy of Pediatrics in 1967. This idea caught on widely and was institutionalized by the National Committee for Quality Assurance in 2008 with PCMH certification.

Advanced Primary Care is the latest and best rendition of comprehensive primary health care. Funding this model through our current payment mechanisms, however, has been difficult because of the need to support social and behavioral interventions in addition to medical care—areas of care not traditionally paid for by medical premiums. In 2011, CMS collaborated with private insurers in a national demonstration project to test the financial feasibility of implementing Advanced Primary Care. Some organizations have been highly successful; others not as much.

We can no longer go “halfway” into whole-person care. The COVID-19 pandemic has put a spotlight on our need to transform payment models away from fee-for-service to reimbursement for whole person primary care. Our nation’s health and the viability of our health care system depend on it. 

PS: I recommend reading Dr. Jonas’ book, How Healing Works, which provides a scientific rationale for the application of whole-person care to healing.
 

In this issue of The Journal of Family Practice, Dr. Wayne Jonas explains his model for Advanced Primary Care (see page 493). The figure he uses to illustrate Advanced Primary Care is compelling, and the effectiveness of this model of health care is supported by a great deal of research and evaluation over the past 20 years. Let me provide some historical context.

The idea that healing requires more than curative, biology-based medical care dates back to Greek mythology. Asclepius, the god of medicine, had 5 daughters, Hygeia (the goddess of good health and hygiene), Iaso (cures and remedies), Aceso (healing wounds), Aegle (radiant good health), and Panacea (cures).¹ Clearly, the Greeks believed that integrative care is essential for maintaining good health!

Modern, scientific medicine is a relatively recent development in human history. Other traditions of healing such as acupuncture and herbal medicines are actually much older than mainstream Western medicine. But they come together in family medicine—a specialty founded on the principles of whole person, whole family, and whole community care.

We can no longer go “halfway” into whole-person care.

The first modern model of comprehensive care, the patient-centered medical home (PCMH), was introduced by the American Academy of Pediatrics in 1967. This idea caught on widely and was institutionalized by the National Committee for Quality Assurance in 2008 with PCMH certification.

Advanced Primary Care is the latest and best rendition of comprehensive primary health care. Funding this model through our current payment mechanisms, however, has been difficult because of the need to support social and behavioral interventions in addition to medical care—areas of care not traditionally paid for by medical premiums. In 2011, CMS collaborated with private insurers in a national demonstration project to test the financial feasibility of implementing Advanced Primary Care. Some organizations have been highly successful; others not as much.

We can no longer go “halfway” into whole-person care. The COVID-19 pandemic has put a spotlight on our need to transform payment models away from fee-for-service to reimbursement for whole person primary care. Our nation’s health and the viability of our health care system depend on it. 

PS: I recommend reading Dr. Jonas’ book, How Healing Works, which provides a scientific rationale for the application of whole-person care to healing.
 

In this issue of The Journal of Family Practice, Dr. Wayne Jonas explains his model for Advanced Primary Care (see page 493). The figure he uses to illustrate Advanced Primary Care is compelling, and the effectiveness of this model of health care is supported by a great deal of research and evaluation over the past 20 years. Let me provide some historical context.

The idea that healing requires more than curative, biology-based medical care dates back to Greek mythology. Asclepius, the god of medicine, had 5 daughters, Hygeia (the goddess of good health and hygiene), Iaso (cures and remedies), Aceso (healing wounds), Aegle (radiant good health), and Panacea (cures).¹ Clearly, the Greeks believed that integrative care is essential for maintaining good health!

Modern, scientific medicine is a relatively recent development in human history. Other traditions of healing such as acupuncture and herbal medicines are actually much older than mainstream Western medicine. But they come together in family medicine—a specialty founded on the principles of whole person, whole family, and whole community care.

We can no longer go “halfway” into whole-person care.

The first modern model of comprehensive care, the patient-centered medical home (PCMH), was introduced by the American Academy of Pediatrics in 1967. This idea caught on widely and was institutionalized by the National Committee for Quality Assurance in 2008 with PCMH certification.

Advanced Primary Care is the latest and best rendition of comprehensive primary health care. Funding this model through our current payment mechanisms, however, has been difficult because of the need to support social and behavioral interventions in addition to medical care—areas of care not traditionally paid for by medical premiums. In 2011, CMS collaborated with private insurers in a national demonstration project to test the financial feasibility of implementing Advanced Primary Care. Some organizations have been highly successful; others not as much.

We can no longer go “halfway” into whole-person care. The COVID-19 pandemic has put a spotlight on our need to transform payment models away from fee-for-service to reimbursement for whole person primary care. Our nation’s health and the viability of our health care system depend on it. 

PS: I recommend reading Dr. Jonas’ book, How Healing Works, which provides a scientific rationale for the application of whole-person care to healing.
 

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

THE CASE

A 17-year-old White girl with no known past medical history presented to the emergency department (ED) with complaints of abdominal pain and pruritus. The abdominal pain had started 9 days prior and lasted for 3 days. One day after resolution, she developed bilateral lower extremity itching, which was not relieved with loratadine.

Review of systems included dark urine and yellow eyes noted for several days. The patient denied nausea, vomiting, diarrhea, constipation, fevers, chills, arthralgias, recent illness, travel, or sick contacts. Immunizations were up to date. The patient had no history of surgery or liver disease and no pertinent family history. Her current medications included ethinyl estradiol/norethindrone acetate for birth control and minocycline for acne vulgaris. She had been taking the latter medication for 2 years. No additional medications were noted, including vitamins, over-the-counter medications, or supplements. She denied smoking and alcohol or recreational drug use.

In the ED, the patient had normal vital signs. Physical exam findings included bilateral scleral icterus and scattered skin excoriations on the hands, arms, back of the neck, and feet. At the time of hospital admission, the patient’s minocycline and birth control were held under the initial presumption that one or both might be contributing to her presentation.

Pertinent laboratory findings included aspartate transaminase (AST), 828 U/L (normal range, 2-40 U/L); alanine aminotransferase (ALT), 784 U/L (normal range, 3-30 U/L); lactic acid dehydrogenase, 520 U/L (normal range, 140-280 U/L); alkaline phosphatase, 119 U/L (normal range, 44-147 U/L); total bilirubin, 1.9 µmol/L (normal range, 2-18 µmol/L); and direct bilirubin, 1.3 µmol/L (normal range, 0-4 µmol/L). Baseline liver function test results (prior to admission) were unknown. Results of a coagulation panel, complete blood count, basic metabolic panel, amylase, lipase, urine toxicology, and urinalysis all were within normal limits.

Ultrasound of the abdomen revealed a normal abdomen, liver, pancreas, gallbladder, and common bile duct. This imaging study was negative for other obstructive pathologies.

THE DIAGNOSIS

During hospital admission, a noninvasive liver work-up was pursued by Gastroenterology. A hepatitis panel, Epstein-Barr virus testing, and levels of ceruloplasmin and acetaminophen were all found to be within normal limits, excluding additional causes of liver disease. Serum antinuclear antibody (ANA) testing was significantly positive, with a titer of 1:640 (range, < 1:20) and, as noted above, liver transaminases were severely elevated, leading to a presumptive diagnosis of drug-induced liver pathology.

Continue to: During outpatient follow-up...

During outpatient follow-up with Gastroenterology 2 days after discharge, the patient’s liver transaminases and bilirubin continued to trend upward (to a maximum ALT of 871 U/L; AST, 1097 U/L; alkaline phosphatase, 122 U/L; and bilirubin, 2.9 µmol/L). Immunoglobulin G was 1342 mg/mL (normal range, 694-1618 mg/mL).

An ultrasound-guided liver biopsy was performed; it demonstrated lobular, portal, and periportal hepatitis with focal bridging necrosis, consistent with a diagnosis of autoimmune hepatitis. Mild-to-moderate focal cholestasis was demonstrated, consistent with cholestatic hepatitis.

DISCUSSION

Autoimmune hepatitis is characterized by inflammation of the liver, secondary to the presence of circulating antibodies or hypergammaglobulinemia. The pathogenesis is thought to involve a T-cell–mediated immune attack on the liver. Based on case reports,the use of minocycline is associated with risk for liver injury, although the incidence is rare.^1-4 Use of this medication may be associated with autoimmune disease in patients who are predisposed to autoimmune tendencies or who have genetic predeterminants.

Diagnosis is typically made based on abnormalities in aminotransferases (AST, ALT), elevation in serum immunoglobulins, and positive auto-antibody titers including ANA, smooth muscle antibodies, and anti-liver kidney microsomal type 1 antibodies. Although clinical presentations tend to differ, the confirmatory diagnosis is typically made histologically, with the presence of lobular and perivenular necro-inflammatory changes and plasma cell infiltration.⁵

Other infectious and metabolic causes of hepatitis should be excluded. Many medications and herbal agents have been noted to cause autoimmune hepatitis or similar syndromes that mimic the condition.

Medication history. Review of the case patient’s medication list identified ethinyl estradiol/norethindrone acetate and minocycline as potential culprits. Ethinyl estradiol/norethindrone acetate is a low-dose combination oral contraceptive pill (OCP). Although earlier formulations of OCPs were associated with hepatobiliary complications, these adverse effects are noted to be rare in the absence of predisposing conditions.⁶ In some cases, OCPs have been linked to cholestasis, chronic hepatocellular carcinoma, or hepatic adenomas, but studies have shown that these medications do not affect the course of acute liver failure.⁷

Continue to: Minocycline...

Minocyclineassociated hepatotoxicity can be due to a systemic hypersensitivity reaction, occurring within a few weeks of therapy initiation, whereas autoimmune hepatitis manifests after a year or more of exposure to the medication.

In this case, given the patient’s 2-year history of minocycline use, it is possible that she developed an acute presentation of autoimmune hepatitis. With drug-induced autoimmune liver injury, complete resolution occurs after withdrawal of the offending medication, and a response to corticosteroid therapy supports the diagnosis. Recurrence of signs or symptoms following corticosteroid cessation may indicate idiopathic autoimmune hepatitis as opposed to a drug-induced form.²

Our patient was started on steroid and immunomodulator therapy, with prednisone 40 mg/d and mycophenolate 250 mg bid. At follow-up with Gastroenterology, the patient’s symptoms and liver function test results had improved significantly (AST, 27 U/L; ALT, 14 U/L; alkaline phosphatase, 51 U/L; and total bilirubin, 0.4 µmol/L). The patient was continued on a prednisone taper while simultaneously titrating mycophenolate. The ultimate plan of care included continuing mycophenolate for a total of 4 to 5 years.

THE TAKEAWAY

During evaluation of a patient with new-onset liver disease, it is important to inquire about prescription medications, drugs, vitamins, and herbal supplements as possible contributors to the disease process. This case highlights the importance of monitoring patients while on minocycline and of weighing the risks vs benefits of long-term therapy. It has been suggested that liver enzymes be tested before therapy initiation and about every 3 months during long-term antibiotic treatment.⁴ Careful consideration and caution should be taken prior to the initiation of medications that have been linked to rare, but important, adverse reactions.

ACKNOWLEDGEMENT

The authors would like to thank Frank Bauer, MD, and Eva Sotil, MD, for their contributions to this case presentation.

CORRESPONDENCE

Andrea Gillis, DO, Asylum Hill Family Medicine Center, 99 Woodland Street, Hartford, CT 06105; andrea.gillis@ trinityhealthofne.org

Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.

However, the data also showed that pregnancy does not increase the risk of cancer recurrence.

“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.

“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”

In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.

Study results

Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.

Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).

However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.

In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.

On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.

Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.

However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).

In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).

Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.

Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).

Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.

This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.

Close monitoring, early discussions are key

“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.

“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”

“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.

“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.

The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.

“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”

“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.

This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
 

SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.

Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.

However, the data also showed that pregnancy does not increase the risk of cancer recurrence.

“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.

“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”

In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.

Study results

Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.

Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).

However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.

In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.

On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.

Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.

However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).

In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).

Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.

Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).

Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.

This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.

Close monitoring, early discussions are key

“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.

“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”

“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.

“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.

The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.

“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”

“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.

This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
 

SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.

Breast cancer survivors are less likely to get pregnant and have higher risks of some delivery and fetal complications, according to a meta-analysis reported at the 2020 San Antonio Breast Cancer Symposium.

However, the data also showed that pregnancy does not increase the risk of cancer recurrence.

“With the availability of more effective anticancer treatments, survivorship and addressing the treatments’ potential long-term toxicities has gained substantial attention,” said study investigator Matteo Lambertini, MD, PhD, of University of Genova (Italy) – IRCCS Policlinico San Martino Hospital.

“Returning to a normal life after cancer diagnosis and treatment should be considered, in the 21st century, as a crucial ambition in cancer care,” Dr. Lambertini added. “In patients diagnosed during their reproductive years, this includes the possibility to complete their family planning. Due to the constant rise in age at first pregnancy over the past years, many women are diagnosed with breast cancer before completing their reproductive plans.”

In that context, certain cancer treatments have the potential to reduce fertility. In addition, many women need prolonged hormone therapy, and conception is contraindicated while they are receiving it.

Study results

Dr. Lambertini and colleagues performed a meta-analysis using data from 39 studies that included a total of 114,573 breast cancer patients and 8,093,401 women from the general population.

Results showed that breast cancer survivors were much less likely than women in the general population to become pregnant (relative risk, 0.40; P < .001).

However, “the majority of the studies included in our meta-analysis did not capture the information on how many women tried to get pregnant,” Dr. Lambertini cautioned.

In the few studies that did, more than half of women trying to conceive did become pregnant, and most of them were able to do so naturally, without need for assisted reproductive technologies.

On the flip side, analyses also showed that pregnancies occurred in some women who did not want to conceive, underscoring the importance of comprehensive oncofertility counseling that addresses not only fertility preservation, but also contraception, Dr. Lambertini said.

Among women who became pregnant, breast cancer survivors did not have higher odds of spontaneous abortion or complications such as preeclampsia, and their infants were not significantly more likely to have congenital abnormalities.

However, the breast cancer survivor group did have higher odds of cesarean birth (odds ratio, 1.14; P = .007), low birth weight (OR, 1.50; P < .001), preterm birth (OR, 1.45; P = .006), and infants small for gestational age (OR, 1.16; P = .039).

In stratified analysis, the higher risk of having an infant with low birth weight was significant only for women who had received chemotherapy, and the higher risk of having an infant small for gestational age was significant only for women who had received chemotherapy or who had a late pregnancy (more than 2 years to 5 years after cancer diagnosis).

Among breast cancer survivors, those who became pregnant actually had lower risks of disease-free survival events (hazard ratio, 0.73; P = .016) and death (HR, 0.56; P < .001). Findings were similar in the subset of studies that adjusted for the so-called healthy mother effect.

Pregnancy did not significantly affect disease-free survival among women with hormone receptor–positive disease and appeared protective among women with hormone receptor–negative disease (HR, 0.72).

Pregnancy also appeared safe in terms of overall survival, irrespective of survivors’ BRCA status, nodal status, receipt of chemotherapy, pregnancy outcome (completed vs. abortion), and pregnancy interval.

This study was limited by the lack of patient-level data and by the fact that most of the included studies had a retrospective design, Dr. Lambertini acknowledged.

Close monitoring, early discussions are key

“Results of this meta-analysis provide reassuring, updated evidence on the feasibility and safety of conceiving in young women with prior breast cancer diagnosis. They provide crucial information for improving the oncofertility counseling of young breast cancer patients, helping them and their treating physicians in making evidence-based decisions on future family planning,” Dr. Lambertini commented.

“The higher risk of delivery and fetal complications … calls for ensuring a closer monitoring of these pregnancies,” he added. “The lack of detrimental prognostic effect of pregnancy after breast cancer following appropriate treatment and follow-up strongly voices the need for a deeper consideration of patients’ pregnancy desire as a crucial component of their survivorship care plan and wish to return to a normal life.”

“The findings provide further support regarding the safety of pregnancy following a breast cancer diagnosis,” agreed Halle Moore, MD, of Cleveland Clinic Taussig Cancer Institute in Ohio, who was not involved in this study.

“I would add that we still have a lot to learn about optimal timing of pregnancy with respect to breast cancer treatment for women with hormone-sensitive breast cancer treated with endocrine therapy,” she said.

The study’s results serve as a reminder that providers should be routinely discussing future pregnancy wishes and fertility preservation options with breast cancer patients at the time of initial diagnosis, Dr. Moore said.

“The earlier we identify an interest in future fertility, the more we can do to improve the chances for a successful pregnancy outcome,” she elaborated. “It is important to assess interest in future pregnancy as soon as possible when a young woman is diagnosed with breast cancer, as fertility preservation options are most likely to be successful when applied prior to chemotherapy or hormonal treatment for breast cancer.”

“The findings also suggest that involvement of a high-risk obstetrics team should be considered for pregnant breast cancer survivors,” Dr. Moore noted.

This research was funded by the Italian Ministry of Health and the Italian Association for Cancer Research. Dr. Lambertini and Dr. Moore disclosed no conflicts of interest. Eva Blondeaux, MD, of University of Genova – IRCCS Policlinico San Martino Hospital, who presented this research at the meeting, disclosed no conflicts as well.
 

SOURCE: Blondeaux e et al. SABCS 2020, Abstract GS3-09.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Differences in gene expression between the skin and synovial tissues of individuals with psoriatic arthritis could explain why treatments targeting proinflammatory mechanisms don’t improve joint symptoms in some patients.

SilverV/Thinkstock

A paper published in Annals of the Rheumatic Diseases presents the results of an observational, open-label study involving 27 patients with active psoriatic arthritis, 18 of whom were treated with anti–tumor necrosis factor (anti-TNF) therapies and 9 with the monoclonal antibody ustekinumab (Stelara). This drug targets the axis of proinflammatory cytokine interleukin-23 and effector cytokine IL-12, which are believed to play an important role both in skin and nail psoriasis, and psoriatic arthritis.

However, while anti–IL-23 antibodies seem to work well to address skin manifestations of psoriasis, they tend to improve joint symptoms only in selected patients.

“The lack of a clear mechanism to explain such divergent responses prompted this study,” said Dr. Alessandra Nerviani, lead author of the study, from the Barts and The London School of Medicine & Dentistry.

Participants also had biopsies taken from the synovium – in particular, from joints that were clinically and ultrasonographically active – and from lesional and nonlesional skin for gene expression analysis.

In terms of treatment response, the ustekinumab-treated group showed significantly higher scores for erythrocyte sedimentation rate, joint pain, and disease activity, compared with the anti–TNF-treated group. Psoriasis Area and Severity Index scores were similar in both treatment arms, but significantly more patients in the anti-TNF group met the EULAR Disease Activity Score for response (70.6% vs. 22.2%).

The gene expression analysis, which assessed the activity of 80 genes related to inflammation in 14 patient samples from synovial tissue, lesional skin, and nonlesional skin, found that patterns of expression in the synovium clustered away from those from skin.

This was particularly the case when it came to genes related to drug targets. The targets for anti-TNF showed similar levels of expression in both skin and synovial tissue. However, the targets for ustekinumab – namely interleukin (IL)–23A, IL-23R and, IL-12B – showed higher levels of expression in lesional skin than in nonlesional skin and synovial tissue.

“Interestingly, we observed that, while some patients did express IL-23 cytokines/receptor in both skin and joint, others had discordant expression, that is, active IL-23 pathway in the lesional skin but not in the synovium,” the authors wrote.

When researchers then stratified patients according to how much synovial inflammation they had, they found that patients who had higher scores also showed higher expression of genes for IL-12B and IL-23R, but not IL-23A, despite showing no other major clinical differences.

The authors also looked at the protein expression levels for IL-23p40, IL-23p19 and IL-23R, and found that while the percentage of cells positive for these proteins was significantly higher in lesional, compared with nonlesional skin, it was also higher in the synovium among patients with more inflammation.

“Except for the LIKERT patient score, we did not detect other significant correlations between IL-23 axis expression and clinical parameters at baseline, suggesting that patients with comparable disease severity may have, in fact, heterogeneous histopathological features and expression of drug targets within the diseased synovium,” they wrote.

More selective expression of IL-23 in synovium

Commenting on the findings, the authors highlighted that the expression of targets for anti-TNF was much more homogeneous across skin and synovial tissue, but the IL-23A/IL-12B/IL-23R genes generally showed higher levels of expression in lesional skin. compared with either nonlesional skin or synovium. However, even within the synovium, expression of these genes varied enormously, from levels similar to those seen in paired lesional skin to levels well below those.

“It is plausible to speculate that an overall higher presence of IL-23 in the psoriatic skin supports the concept of a generally better response in terms of skin manifestations, including almost complete clearance of psoriatic lesions,” Dr. Nerviani said in an interview. “While, on the other hand, the more selective expression of IL-23 in the synovium, namely in histologically more inflamed synovium characterized by immune cells infiltration, may explain the overall more modest success to meet stringent response criteria in the joints.“

Of particular significance was the observation that IL-12B and IL-23R transcription levels were higher in patients with higher levels of synovial tissue inflammation.

“We confirmed that IL-23 axis expression relates to the synovial histopathology not only in PsA at different stages of the disease, including early treatment-naive patients, but also in the early phase of RA, investigated as disease control,” they wrote.

Dr. Nerviani said the results could inform a more tailored “precision medicine” approach to treating patients with psoriatic arthritis.

“While randomized synovial biopsy–driven clinical trials are now a reality in rheumatoid arthritis, in psoriatic arthritis, these kinds of studies have not been performed yet but may become actual in the future,” she said. “An in-depth characterization of the synovial tissue represents the first essential step towards addressing current unmet clinical needs and, potentially, changing our practice.”

However, she stressed that the study was not powered to test the correlation between the expression level of these pathways in disease tissue and clinical response to treatment.

“Further dedicated clinical trials should be designed to look at the relationship between synovial pathology and molecular characteristics, and response to targeted treatment to address this question,” Dr. Nerviani said.

The study was supported by the Queen Mary University of London and the Fondazione Ceschina, and in part by grants from Versus Arthritis. No conflicts of interest were declared.

SOURCE: Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

Nerviani A et al. Ann Rheum Dis. 2020 Nov 26. doi: 10.1136/annrheumdis-2020-218186.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

For B-cell malignancies, synthetic lethality is a viable treatment approach, according to preliminary clinical trial data with once-daily oral DTRM-555. The triple combination therapy, DTRM-555, combines a Bruton’s tyrosine kinase (BTK) inhibitor, a mammalian target of rapamycin (mTOR) inhibitor and pomalidomide, an immunomodulatory imide drug (IMiD), according to Anthony R. Mato, MD, in a presentation at the annual meeting of the American Society of Hematology, which was held virtually.
 

Richter’s transformation, a rare event

Dr. Mato’s phase 1 clinical trial included 13 patients with Richter’s transformation (RT) and 11 with diffuse large B-cell lymphoma (DLBCL). Richter’s transformation, a rare event occurring in 5%-7% of chronic lymphocytic leukemia (CLL) cases, has no clear standard of care and universally poor outcomes (overall survival, 3-12 months) once it becomes refractory to anthracycline-based chemotherapy, according to Dr. Mato.

Despite great progress in treating DLBCL, cure rates with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), the standard of care, are in the 50%-60% range and much lower (30%-40%) with poor-risk features. Furthermore, most (60%-70%) patients receiving autologous stem cell transplant or CAR-T still require additional lines of therapy.

The “synthetic lethality” (SL) strategy, which has become a focus of cancer treatment in the last decade, identifies multiple disease primary aberrant and compensatory pathways and then inhibits them together in a manner lethal to cell survival. Preclinical studies have shown low doses of a BTK inhibitor/mTOR inhibitor/IMiD to synergistically kill malignant B cells. DTRM-555 is an optimized, oral, once-daily triplet combination of a novel and clinically differentiated irreversible BTK inhibitor (DTRM-12), everolimus and pomalidomide, Dr. Mato explained.

Individuals (38% women) included in the trial had a median of 2 (1-10) prior lines of therapy, with a CD20 monoclonal antibody as one of them in all cases, and 83% with R-CHOP. All patients had life expectancy >12 weeks, with 0-1 performance status and adequate organ and hematologic function.

DTRM-12 plasma concentrations, Dr. Mato noted, were unaffected by coadministration with everolimus with or without pomalidomide.
 

Manageable adverse events

Among adverse events, neutropenia (grade 3-4, 33%/21%) and thrombocytopenia (grade 3-4, 29%/8%) were most common. One patient had grade 4 leukopenia (4%). No patients discontinued treatment on account of adverse events, however, and nonhematologic adverse event rates were low, without grade 4 events. Eight different grade 3 adverse events (atrial fibrillation [with prior history], diarrhea, hyponatremia pneumonia, pulmonary opportunistic infection, rash maculopapular, rash acneiform, skin ulceration) were reported, each in one patient. Pharmacokinetic data supported once-daily dosing for DTRM-12, with an estimated half-life of 5-9 hours that was comparable with that of once-daily ibrutinib, and longer than that of other agents of the same class. The recommended phase 2 dose going forward was 200 mg for DTRM-12, 5 mg for everolimus and 2 mg for pomalidomide.
 

Favorable responses

In efficacy analysis for 22 evaluable patients (11 in the RT group, 11 in the DLBCL ), there was 1 complete response in the RT group and 2 in the DLBCL group, with partial responses in 4 and 3, respectively, giving overall response rates of 46% in the RT group and 45% in the DLBCL group. Two and four patients, respectively, in the RT and DLBCL groups, had stable disease, Dr. Mato said, and most patients (71%) had SPD (sum of the product of the diameters) lymph node reductions, with lymph node reductions of 50% or more in 43%.

“Encouraging clinical activity was observed in high-risk, heavily pretreated Richter’s transformation and diffuse large B-cell lymphoma patients,” Dr. Mato concluded. He also noted that the main safety findings were “expected and manageable.”

The session moderator, Chaitra S. Ujjani, MD, of the Seattle Health Care Alliance, asked if the DTRM-555 regimen should be considered definitive therapy in patients who are responding, or if moving on to cellular therapies or a consolidative approach should be considered.

“If they are responding, it is reasonable to consider consolidating with a cellular therapy at this point in time,” Dr. Mato replied. He did observe, however, that many of the included patients had tried experimental therapies, including cellular therapy. “Without [data from] a much larger patient population and longer-term follow-up, I think that, for responding patients with a durable remission who have a [chimeric antigen receptor] T or transplant option, these, at the least, have to be discussed with them.”

To an additional question as to whether any of the subjects had prior exposure to BTK inhibitors, Dr. Mato responded, “There is a high exposure to BTK inhibitors, and almost universally these patients were progressors. So again, this is supportive of the hypothesis that hitting multiple pathways simultaneously is somewhat different from hitting just BTK by itself, even in the setting of progression.”

A DTRM-555 triple fixed-dose combination tablet is under development, and a double fixed-dose tablet (DTRM-505) is ready for the ongoing phase 2 U.S. study (NCT04030544) among patients with relapsed/refractory CLL or non-Hodgkin lymphoma (RT, DLBCL or transformed follicular lymphoma) with prior exposure to a novel agent.

Dr. Mato, disclosed consultancy and research funding relationships with multiple pharmaceutical and biotechnology companies.

SOURCE: Mato AR et al. ASH 2020, Abstract 126.

A wrist-worn device that uses machine learning accurately detects different seizure types. The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.

The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.

Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
 

An advance in detecting seizure types

Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.

Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.

The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.

With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.

The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.

When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.

The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.

“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.  

The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”

The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.

He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.

The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
 

‘Important milestone’

Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.

Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.

“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”

However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”

In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.

The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A wrist-worn device that uses machine learning accurately detects different seizure types. The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.

The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.

Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
 

An advance in detecting seizure types

Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.

Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.

The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.

With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.

The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.

When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.

The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.

“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.  

The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”

The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.

He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.

The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
 

‘Important milestone’

Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.

Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.

“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”

However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”

In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.

The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A wrist-worn device that uses machine learning accurately detects different seizure types. The new findings have the potential to revolutionize the management of patients with epilepsy, according to the researchers. “We have set a first benchmark for automatic detection of a variety of epileptic seizures using wearable sensors and deep-learning algorithms. In other words, we have shown for the first time that it’s possible to do this,” said study investigator Jianbin Tang, MA, data science project lead, IBM Research Australia, Victoria.

The findings were presented at the American Epilepsy Society’s annual meeting, held online this year because of the COVID-19 pandemic.

Accurate monitoring of seizures is important for assessing risk, injury prevention, and treatment response evaluation. Currently, video EEG is the gold standard for seizure detection, but it requires a hospital stay, is often costly, and can be stigmatizing, said Mr. Tang.
 

An advance in detecting seizure types

Recent advances in non-EEG wearable devices show promise in detecting generalized onset tonic-clonic and focal to bilateral tonic-clonic seizures, but it’s not clear if they have the ability to detect other seizure types. “We hope to fill this gap by expanding wearable seizure detection to additional seizure types,” said Mr. Tang.

Seizure tracking outside the hospital setting largely “relies on manually annotated family and patient reports, which often can be unreliable due to missed seizures and problems recalling seizures,” he said.

The study included 75 children (44% were female; mean age was 11.1 years) admitted to a long-term EEG monitoring unit at a single center for a 24-hour stay. Patients wore the detector on the ankle or wrist. The device continuously collected data on functions such as sweating, heart rate, movement, and temperature.

With part of the dataset, researchers trained deep-learning algorithms to automatically detect seizure segments. They then validated the performance of the detection algorithms on the remainder of the dataset.

The analysis was based on data from 722 epileptic seizures of all types including focal and generalized, motor and nonmotor. Seizures occurred throughout the day and during the night while patients were awake or asleep.

When a seizure is detected, the system triggers a real-time alert and will store the information about the detected seizure in a repository, said Mr. Tang.

The signals were initially stored in the wristband and then securely uploaded to the Cloud. From there, the signal files were downloaded by the investigators for analysis and interpretation. All data were entirely anonymized and de-identified. Researchers used Area Under Curve–Receiver Operating Characteristic (AUC-ROC) to assess performance.

“Our best performing detection models reach an AUC-ROC of 67.59%, which represents a decent performance level,” said Mr. Tang. “There certainly is room for performance improvement and we are already working on this,” he added.  

The device performed “better than chance,” which is a “standard technical term” in the field of machine learning and is “the first hurdle any machine-learning model needs to take to be considered useful.” The investigators noted that such automatic seizure detection “is feasible across a broad spectrum of epileptic seizure types,” said Mr. Tang. “This is a first and has not been shown before.”

The study suggests that the noninvasive wearable device could be used at home, at school, and in other everyday settings outside the clinic. “This could one day provide patients, caregivers, and clinicians with reliable seizure reports,” said Mr. Tang.

He said he believes the device might be especially useful in detecting frequent or subtle seizures, which are easy to miss. Patients requiring medication evaluation and rescue medication and those at risk of status epilepticus may be good candidates.

The researchers don’t expect wearable technology to totally replace EEG but see it as “a useful complementary tool to track seizures continuously at times or in settings where EEG monitoring is not available,” said Mr. Tang.
 

‘Important milestone’

Commenting on the research, Benjamin H. Brinkmann, PhD, associate professor of neurology at the Mayo Clinic in Rochester, Minn., said the investigators “have done very good work applying state of the art machine learning techniques” to the “important problem” of accurately detecting seizures.

Dr. Brinkmann is part of the Epilepsy Foundation–sponsored “My Seizure Gauge” project that’s evaluating various wearable devices, including the Empatica E4 wristband and the Fitbit Charge 3, to determine what measurements are needed for reliable seizure forecasting.

“Previously, no one knew whether seizure prediction was possible with these devices, and the fact that this group was able to achieve ‘better-than-chance’ prediction accuracy is an important milestone.”

However, he emphasized that there is still a great deal of work to be done to determine, for example, if seizure prediction with these devices can be accurate enough to be clinically useful. “For example, if the system generates too many false-positive predictions, patients won’t use it.”

In addition, the findings need to be replicated and recordings extended to 6 months or more to determine whether they are helpful to patients long term and in the home environment, said Dr. Brinkmann.

The investigators and Dr. Brinkmann have disclosed having no relevant financial relationships.

A version of this article originally appeared on Medscape.com.