A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

A 59-year-old woman presented to our clinic with a large asymptomatic facial rash that had developed several months earlier. The rash had been slowly growing but did not change day to day. Her past medical history was significant for hypertension, hyperlipidemia, and cutaneous lymphoma, which was localized to her arms. She denied the use of any new products, including hair or facial products, nail polish, or any new medications.

Initially, she was presumed (by an outside provider) to have rosacea, and she received treatment with doxycycline 100 mg/d for 2 months. However, the rash did not improve.

Physical examination revealed a large erythematous rash involving her cheeks, nose, and periocular area with no other significant findings (FIGURE).

A biopsy of her right cheek was performed.

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

Following the biopsy of her right cheek, a histopathologic analysis demonstrated an atypical lymphocytic infiltrate positive for CD3 and CD4. These histopathologic features led to a diagnosis of recurrent mycosis fungoides (MF), a type of cutaneous lymphoma. (Our patient’s cutaneous lymphoma had been in remission for a year following local radiotherapy.)

MF is the most common type of cutaneous lymphoma, with an incidence of 6.4 to 9.6 cases per million people in the United States.¹ There are also 2 rare subtypes of MF: the psoriasiform and palmoplantar forms. Psoriasiform MF presents with psoriasis-like plaques, while palmoplantar MF initially ­presents on the palms and soles.

Patients with classic MF typically present with patches and plaques—with the late evolution of tumors—on non–sun-exposed areas.¹ Our patient’s clinical presentation was atypical because the rash manifested on a sun-exposed area of her body.

MF and other cutaneous lymphomas should always be part of the differential diagnosis for an unexplained persistent rash, especially in a patient with a history of MF. The development of lymphomas is thought to be a stepwise process through which chronic antigenic stimulation results in an accumulation of genetic mutations that then cause cells to undergo clonal expansion and, ultimately, malignant transformation. Genetic, environmental, and immunologic factors that contribute to the disease pathogenesis have been identified.²

Once clinical features point toward MF, the diagnosis can be further differentiated from other benign inflammatory mimics with a biopsy demonstrating cerebriform lymphocytes homing toward the epidermis, monoclonal expansion of T cells, and defective apoptosis.³

Continue to: Differential includes rosacea and seborrheic dermatitis

The diagnosis of MF can be difficult as it often imitates other benign inflammatory ­conditions.

Rosacea manifests as an erythematous facial rash but usually spares the nasolabial folds and eyelids. There are several forms, including ocular (featuring swollen and irritated conjunctiva), erythematotelangiectatic (with visible blood vessels), and papulopustular (with acneic lesions). Over time, the skin may develop a thickened, bumpy texture, referred to as phymatous rosacea.⁴ A history of acute worsening with exposure to certain hot or spicy foods, alcohol, or ultraviolet light suggests a diagnosis of rosacea.

Seborrheic dermatitis classically presents as yellow scaling on a mildly erythematous base and often involves nasolabial folds and eyebrows. Seborrheic dermatitis can be associated with human immunodeficiency virus, Parkinson’s disease, and other chronic medical conditions.

Allergic contact dermatitis can look identical to MF, but in our case, there was no new allergen in the history. A thorough history regarding new medications, creams, and household supplies is integral to differentiating this diagnosis.

Misdiagnosis can lead to advanced-stage disease

This case of persistent facial erythema, originally treated as rosacea, highlights the importance of having a low threshold of suspicion of MF, especially in a patient with a prior history of MF. A recent study by Kelati et al³ indicated that certain subtypes of MF are easily misdiagnosed and treated as psoriasis or eczema respectively for an average of 10.5 years.³ These years of misdiagnosis are significantly correlated with the development of advanced-stage MF, which is more difficult to treat.³

Continue to: Treatment with topical desonide and mechlorethamine

There are multiple treatment options for MF, depending on the stage, starting with topical therapies and advancing to systemic therapies in more advanced stages. Topical treatments include steroids, nitrogen mustard, and retinoids.⁵ Our patient was referred to a multidisciplinary lymphoma clinic, where topical treatment was initiated with desonide cream .05% and mechlorethamine gel .016%. Our patient experienced a 50% improvement in skin involvement at 3 months.

As MF progresses to more advanced ­stages, treatment often combines skin-­directed therapies with systemic immunomodulators, biologics, radiation, and total skin electron beam therapy.⁶ TSEBT is a low-dose full-body radiation treatment that targets the skin surface and therefore effectively treats cutaneous lymphoma. Although TSEBT is usually well tolerated, there have been documented acute and chronic adverse effects, including dermatitis, alopecia, peripheral edema, cutaneous malignancies, and infertility in men.⁷

While the use of topical desonide and mechlorethamine was initially favored over radiation due to eyelid involvement, our patient developed new patches on her legs 11 months after her initial visit. When ­biopsies indicated MF with large cell transformation, she received 1 course of low-dose TSEBT (12 Gy), with complete response noted at the 2 month follow-up.

CORRESPONDENCE
Lucia Seminario-Vidal, MD, PhD, Department of Dermatology and Cutaneous Surgery, 13330 USF Laurel Drive, Tampa, FL 33612; [email protected]

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

Family physicians try to base treatment decisions on the very best available evidence from randomized trials and other high-quality studies. Very often, however, the evidence is not conclusive. Family physicians are confronted with questions about a wide variety of treatments that may or may not be effective. The classic example for me is the use of chondroitin sulfate/glucosamine for knee osteoarthritis. The preponderance of evidence tells us it is not effective, but one long-term clinical trial did find some benefit.¹ And some patients swear by it!

In this issue of JFP, we have 2 articles that fall into this category: 1 by Hahn about the treatment of asthma with macrolides and the other by Sorsby et al about use of positive airway pressure (PAP) for obstructive sleep apnea (OSA).

The article by Hahn is an extensive literature review regarding the effectiveness of macrolides for asthma. Despite 2 meta-analyses and many clinical trials, the results are not conclusive; but they are highly suggestive that macrolides may benefit patients with new-onset asthma and severe asthma that does not respond completely to mainstream treatments. Why don't we have conclusive evidence? Because the right studies have not been done. Most studies of macrolides for asthma have not focused on these 2 groups, so any treatment effect may have been diluted by including patients not likely to respond.

Why don't we have conclusive evidence? Because the right studies have not been done.

The issue with PAP, also known as CPAP (or continuous positive airway pressure), for the treatment of OSA is different. In this case, the question is: What conditions and outcomes are improved by use of PAP? Studies strongly support that PAP is effective in reducing daytime sleepiness and motor vehicle accidents associated with OSA. Most of us had high hopes that PAP also would reduce the adverse cardiovascular outcomes associated with OSA. But the results of large randomized trials have not found a protective effective.

Enthusiasts argue that the studies have not been of sufficient duration and that the participants did not use their PAP devices long enough each night. Some follow-up studies have suggested a protective effective when the device is used for many years, but those studies have the major flaw of volunteer bias, meaning those who adhere to any treatment have better health outcomes than those who do not adhere.

What should you do when there is uncertainty regarding effectiveness? Use shared decision making: What does the patient want to do after you have explained the possible benefits and harms?

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

A 4-week-old term boy presented to the emergency department (ED) with recurrent bilious emesis. He had a history of neonatal abstinence syndrome, related to his mother’s use of Subutex (a form of suboxone that is considered safer during pregnancy) for her opioid addiction, and a Ladd procedure at Day 7 of life for intestinal malrotation with volvulus. He had been discharged from the hospital 4 days earlier, after recovery from surgery.

He had been doing well until the prior evening, when he developed “yellow-green” emesis and appeared to have intermittent abdominal pain. His parents said that he was refusing to take formula and he’d had frequent bilious emesis. They also noted he’d had 1 wet diaper in the past 12 hours and appeared “sleepier” than usual.

In the ED, the patient was listless, with thin and tremulous extremities. His fontanelle was flat, and his pupils were equal, round, and reactive. His mucous membranes were dry, skin was mottled, and capillary refill was delayed. His cardiopulmonary exam was normal. His abdomen was soft, mildly distended, and diffusely tender to palpation, with well-healing laparotomy scars. His reflexes were normal, with slightly increased tone. No bruising was noted.

An acute abdominal series, including an AP view chest x-ray (FIGURE 1), was obtained to rule out recurrent volvulus, free air, or small bowel obstruction.

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

The chest x-ray (FIGURE 1) showed multiple bilateral posterior rib fractures concerning for nonaccidental trauma (NAT). The remaining acute abdominal series films (not shown) revealed the reason for his bilious emesis: a partial bowel obstruction related to his surgical procedure. Review of x-rays obtained for peripherally inserted central catheter line confirmation during his previous admission (FIGURE 2) revealed that the rib fractures had been present at that time but had been overlooked.

This case illustrates the importance of considering NAT in the differential diagnosis of any sick infant. There are an estimated 700,000 cases of child abuse and neglect and 600 fatalities per year in the United States.^1,2 The differential diagnosis for fracture or bruising in infants includes accidental trauma, bony abnormalities (eg, osteogenesis imperfecta), bleeding disorders, and trauma from medical procedures such as CPR or surgery.¹

Ask these questions, look beyond that single bruise

When evaluating for NAT, the history and physical exam are crucial. It is essential to ask if there were any witnesses, establish who was caring for the child, and investigate any delays in seeking medical evaluation.¹ During the exam, undress the child and examine every inch of skin, looking for bruising or abrasions, especially on the face, ear, neck, and oral cavity.

Any bruising in a nonambulatory infant should raise suspicion for NAT. One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.³ Fundoscopic exam with photographs should be completed to evaluate for retinal hemorrhage.

One study showed that more than half of infants with a single bruise had additional injuries identified upon further work-up.

Additional work-up should include a skeletal survey for all children younger than 24 months² in addition to computed tomography (CT) or magnetic resonance imaging of the head, complete blood count, and a coagulation panel. If there is concern for abdominal trauma, a complete metabolic panel and lipase test may be useful.⁴ If liver function tests show elevated liver enzymes (> 80 IU/L), abdominal CT with contrast is indicated.⁴

Continue to: Research has underscored...

Research has underscored the importance of screening siblings and other contacts of abused children. In particular, the twin of an abused child has a much higher risk for abuse.⁵ A skeletal survey should be obtained in contacts (< 24 months) of abused children—regardless of their physical exam findings.⁵

Management depends on injury type

The management of children with NAT depends on the injuries. Once these injuries are addressed, the next step is to determine the safest place for the infant/child to be discharged. The involvement of local social workers and Child Protective Services (CPS) is pivotal for this determination.²

Our patient. To treat the partial small bowel obstruction noted on an abdominal CT, the patient received intravenous fluids and nasogastric tube decompression. However, due to ongoing distension and high nasogastric tube output, the patient was taken to the operating room for an exploratory laparotomy. An adhesive band in the right lower quadrant was found to be causing the obstruction and was lysed.

We consulted CPS and social workers about the rib fractures identified on x-ray. We considered osteogenesis imperfecta as a possible cause, but genetic testing was negative. The ophthalmology exam was negative for retinal hemorrhages. A bone scan confirmed posterior rib fractures with no other injuries. CPS was unable to confirm that the fractures had not been sustained while the child was an inpatient, so it was ultimately determined that the patient should be discharged home with his parents with supervision.

CORRESPONDENCE 
Anne Huyler, MD, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102; [email protected]

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

THE CASE

A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.

The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.

The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.

The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.

THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx

The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.

The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.

DISCUSSION

Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.¹ Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.

Continue to: Safety of nonroal estrogen therapy

Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.¹ Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.²

Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.^3-6

Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.⁶ In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.⁷

THE TAKEAWAY

All members of a patient’s household— including pets— may be subject to unintentional secondary exposure to topical estrogen formulations and thus, experience adverse effects.

Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.

CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; [email protected].

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?

Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.^2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.⁴

Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.^5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.⁵ However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.⁶

STUDY SUMMARY

Mifepristone before misoprostol improves efficacy for early pregnancy loss

The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.¹

This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone Tx prior to vaginal misoprostol administration in the medical management of early pregnancy loss.

Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.

Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.

Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.

Continue to: Demographics

Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.

Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.

WHAT’S NEW

A high-quality RCT demonstrates improved efficacy

Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.^1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.

CAVEATS

Would a placebo group—or other forms of misoprostol—change the results?

The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.

Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.⁷ It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.

Continue to: CHALLENGES TO IMPLEMENTATION

FDA restrictions limit availability of mifepristone

The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) ­restrictions, stipulating that a health provider be specially certified for prescribing; ­dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.⁸

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Two pneumococcal vaccines are licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax, Merck]). The recommendations for using these vaccines in adults ages ≥ 19 years are arguably among the most complicated and confusing of all vaccine recommendations made by the Advisory Committee on Immunization Practices (ACIP).

In June 2019, things got even more complicated with ACIP’s unusual decision to change the previous recommendation on the routine use of PCV13 in adults ≥ 65 years. The new recommendation states that PCV13 should be used in immunocompetent older adults only after individual clinical decision making. The recommendation for routine use of PPSV23 remains unchanged. This Practice Alert explains the reasoning behind this change and its practical implications.

How we got to where we are now

Nearly 20 years ago, PCV was introduced into the child immunization schedule in the United States as a 7-valent vaccine (PCV7). In 2010, it was modified to include 13 antigens. And in 2012, the use of PCV13 was expanded to include adults with immunocompromising conditions.¹ In 2014, PCV13 was recommended as an addition to PPSV23 for adults ≥ 65 years.² However, with this recommendation, ACIP noted that the incidence of invasive pneumococcal disease in the elderly had been declining since the introduction of PCV7 use in children in the year 2000 (FIGURE 1³), presumably due to the decreased transmission of pneumococcal infections from children to older adults.

Because it was unclear in 2014 how much added benefit PCV13 would offer older adults, ACIP voted to restudy the issue after 4 years. At the June 2019 ACIP meeting, the results of an interim analysis were presented. ACIP concluded that routine use of PCV13 in immunocompetent adults ≥ 65 years adds little population-wide public health benefit given the vaccine’s routine use among children and immunocompromised adults (FIGURE 2³).

ACIP had 3 options in formulating its recommendations.

• Recommend the vaccine for routine use universally or among designated high-risk groups.
• Do not recommend the vaccine.
• Recommend the vaccine only for specific patients after individualized clinical decision making.

The last option—the one ACIP decided on—applies when a safe and immunogenic vaccine has been approved by the Food and Drug Administration and may be beneficial for (or desired by) individuals even though it does not meet criteria for routine universal or targeted use.

Practical issues

ACIP recommendations for the use of PCV13 and PPSV23 in adults vary according to 3 categories of health status: immunocompetent patients with underlying medical conditions; those with functional or anatomic asplenia; and immunocompromised individuals (TABLE¹). Those in the latter 2 categories should receive both PCV13 and PPSV23 and be revaccinated once with PPSV23 before the age of 65 (given 5 years after the first dose). For immunocompetent individuals with underlying medical conditions, only those with cerebral spinal fluid leaks or cochlear implants should receive both PCV13 and PPSV23, although revaccination with PPSV23 before the age of 65 is not recommended.

Continue to: Prior to the recent change...

Prior to the recent change, ACIP recommended both PCV13 and PPSV23 for those ≥ 65 years. Now, PCV13 is not recommended routinely for immunocompetent adults ≥ 65 years; however, individuals in this age group who have chronic underlying medical conditions may receive PCV13 after consulting with their physician. PPSV23 is still recommended for all adults in this age group. Recommendations for those with immunocompromising conditions are also unchanged.

3 sentences summarize change in ­vaccine intervals. Another source of confusion is the recommended intervals in administering the 2 vaccines when both are indicated. The current guidance has been simplified and can be summarized in 3 sentences⁴:

• When both PCV13 and PPSV23 are indicated, give PCV13 before PPSV23.
• For patients ≥ 65 years, separate the vaccines by 12 months or more—­regardless of which vaccine is administered first.
• For patients who are 19 to 64 years of age, separate the vaccines by ≥ 8 weeks.

Advice on repeating the PPSV23 vaccine also can be summarized in 3 sentences¹:

• When a repeat PPSV23 dose is indicated, give it at least 5 years after the first dose.
• Administer no more than 2 doses before age 65.
• For an individual older than 65, only 1 dose should be administered and it should be done at least 5 years after a previous PPSV23 dose.

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

Obstructive sleep apnea (OSA) is a common cause of daytime sleepiness, and severe OSA is a risk factor for hypertension, cardiovascular events, atrial fibrillation (AF), insulin resistance, cognitive impairment, motor vehicle crashes, adverse pregnancy outcomes, and overall mortality.^1-8 The hazard ratio for mortality for patients with severe OSA may be as high as 3.8.⁵

OSA is diagnosed by the apnea-hypopnea index (AHI), defined as the number of apnea or hypopnea events per hour as determined by polysomnography. An AHI score ≤ 5 is considered normal; > 5 to ≤ 15 is mild; > 15 to < 30 is moderate; and ≥ 30 is severe. Most studies of OSA treatment use reduction of AHI as the measure of treatment effectiveness, and several types of treatment improve AHI.

In family medicine, we generally want to know whether treatment of OSA will improve outcomes of significance to patients. A recent systematic review of evidence for the US Preventive Services Task Force found that it was unclear whether OSA treatment improved most health outcomes, including mortality, cardiovascular events, or motor vehicle crashes.⁶ Several other organizations have published guidelines regarding OSA treatment; these guidelines are reviewed in the TABLE.^9-13

This article summarizes the current evidence surrounding the effect of treatment of OSA on outcomes of significance to patients. While multiple treatments have been advocated for patients with OSA, positive airway pressure (PAP) is the most widely used and studied and is recommended as standard treatment by most guidelines.^9-13 Most available evidence about patient-oriented outcomes involves treatment with PAP; where there is evidence about the effect of other OSA treatments on a particular outcome, that evidence is also summarized.

Benefits of OSA treatment

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment of their OSA with PAP or oral appliances (OAs), and might benefit from hypoglossal nerve stimulation or other surgical treatment. PAP is probably more effective than OAs in patients who use it ≥ 4 hours/night, but it is more difficult to comply with PAP.¹⁴

Evidence that treatment of asymptomatic OSA benefits other medical conditions is often conflicting. Given the low risk of treatment, it is reasonable to consider offering a trial of treatment, preferably with PAP, to asymptomatic patients with moderate-to-severe OSA and certain comorbidities, including obesity, resistant hypertension, high cardiovascular risk, congestive heart failure (CHF), AF, diabetes that is difficult to ­control, and pregnancy. Such patients should be strongly encouraged to use PAP ≥ 4 hours/night, and should be advised that benefits may not be immediately apparent.

Treatment of OSA improves daytime sleepiness

Daytime sleepiness is typically measured with the Epworth Sleepiness Scale (ESS), a self-­administered questionnaire assessing a person’s level of drowsiness and propensity to fall asleep in 8 different daytime situations. Each situation is scored between 0 (would never doze) and 3 (high chance of dozing), with the scores then totaled to provide an overall score between 0 and 24. A score > 10 is considered abnormal.

Continue to: Treament of OSA...

Treatment of OSA with either PAP or OAs significantly improves ESS scores, with PAP being more effective.¹³ The difference appears to widen in patients with greater daytime sleepiness; in other words, patients with greater daytime sleepiness will gain even greater benefit from PAP, both overall and when compared with OAs.¹⁵

Patients with OSA who have excessive daytime sleepiness can gain substantial symptomatic benefit from treatment with positive airway pressure or oral appliances.

One randomized trial of an intensive lifestyle modification program for patients with OSA failed to show improvement in the ESS in the intention-to-treat analysis, but did demonstrate a 2.4-point greater reduction in ESS scores in those patients who successfully followed the program (achieving weight loss).¹⁶ Surgical treatments for OSA, such as uvulopalatopharyngoplasty or maxillary advancement, have been shown in some (but not all) studies to improve ESS scores; the different types of surgical treatment and the heterogeneity of studies prevents estimation of effect size.¹⁷ A meta-analysis of case series studies of hypoglossal nerve stimulation reported a mean improvement of 4.5 points on the ESS;¹⁸ comparison with other interventions is lacking.

Improved quality of life

Both PAP and OAs have been shown to improve sleep-related quality of life in patients with OSA. However, while the improvement is statistically significant, the effect size is small.¹⁴

That could be said of a study by Lewis et al.¹⁹ These researchers randomized patients with moderate-to-severe OSA and known coronary artery disease (CAD) or at least 3 risk factors for CAD to receive PAP, nocturnal oxygen, or lifestyle education.¹⁹ The patients randomized to receive PAP improved vitality scores by only 3.6 points on a 100-point scale; this was significantly better statistically than the improvement achieved by those randomized to lifestyle education. Smaller improvements were noted in depression, social function, and general health. Patients who had more daytime sleepiness at baseline had greater improvements in function.¹⁹

Cognitive function findings are mixed

In a systematic review published in 2004, Aloia et al⁴ found measurable impairments on neuropsychological tests of global cognitive functioning, attention/vigilance, executive functioning, memory, psychomotor function, and constructional abilities in patients with OSA. The results of treatment studies (all but 1 using PAP) were mixed. No studies showed improvement in psychomotor speed or language, and studies disagreed on whether treatment produced benefits in global cognition, attention, or executive functions.⁴

Continue to: Findings of more recent studies...

Findings of more recent studies remain mixed. A 3-month Spanish trial of PAP in older adults with severe OSA showed improvement in 2 of 4 neuropsychological tests of cognitive function; this was a secondary outcome measure.²⁰ The PREDICT trial in the United Kingdom demonstrated a reduction in daytime sleepiness but no improvement in cognitive function in PAP-treated older adults with OSA but without dementia over a 1-year period.²¹

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.

In contrast, a French long-term study of adults ages ≥ 65 years with severe (but not necessarily symptomatic) OSA showed better maintenance of memory performance; these results must be interpreted with caution, however, because the study was not randomized, controlled, or blinded, and the results were not adjusted for potential confounders.²² The severity of OSA may influence the impact of PAP treatment on cognitive function.

The prevalence of OSA in patients with dementia is high, and more severe dementia is associated with more severe OSA.²³ Although it is intuitive that disrupted sleep may worsen cognitive function, and that treatment could improve it, minimal benefit on cognitive function was shown by neuropsychological testing in patients with Alzheimer’s disease and OSA treated with continuous positive airway pressure (CPAP) vs sham CPAP in 1 small short-term randomized trial.²³

In another study of patients with Alzheimer’s disease, this time an observational (nonrandomized, non-controlled, single-blind) study of patients who also had severe symptomatic OSA, researchers followed the patients for 3 years and found a significant delay in median annual cognitive decline of 1.5 points per year on the Mini-Mental Status Examination in patients treated with PAP compared with those who did not receive PAP treatment.²⁴

Hypertension: Small but positive results

A meta-analysis of PAP use in patients with OSA and resistant hypertension (defined as inadequate control while taking at least 3 ­antihypertensive agents or control requiring at least 4 agents) documented significant blood pressure (BP) lowering, with a pooled estimate of -7.21 mm Hg systolic and -4.99 mm Hg diastolic.²⁵ The decrease in BP was demonstrated in both sleepy and non-sleepy subjects.

Continue to: Multiple studies have...

Multiple studies have shown a small reduction in BP readings (generally about 2 mm Hg) with PAP treatment in nonresistant hypertensive patients with OSA who are sleepy.²⁶ Conversely, the literature is mixed on whether treatment of non-sleepy patients with OSA reduces BP. One long-term study demonstrated a small (1.89 mm Hg systolic, 2.19 mm Hg diastolic) BP reduction effect of PAP in non-sleepy subjects with OSA.²⁷ Similarly, research has shown mandibular advancement devices to lower BP in patients with OSA, in a range similar to that achieved with PAP.²⁸ Whether very small reductions in BP improve important clinical outcomes such as stroke or heart disease is unknown.

CV risk: Again, findings are mixed

The SAVE study is the largest randomized investigation of the effect of treatment of OSA with PAP for secondary prevention of cardiovascular events.²⁹ The trial involved 2717 adults with cardiovascular disease, moderate-to-severe OSA, and minimal sleepiness, and had as its primary composite endpoint death from cardiovascular causes, myocardial infarction (MI), stroke, hospitalization for unstable angina, heart failure, or transient ischemic attack. Patients with severe daytime sleepiness or severe hypoxemia were excluded. The study found no difference between PAP and usual care in the primary outcome, despite a significant reduction in the AHI from a mean of 29 at baseline to 3.7 with PAP treatment.

Similarly, a randomized controlled trial (RCT) of 725 patients with non-sleepy OSA failed to show a reduction in cardiovascular events or in the development of hypertension.³⁰ Peker et al³¹ randomized 244 adults with recently revascularized coronary artery disease and OSA without daytime sleepiness to auto-­titrating CPAP or usual care and did not find a statistically significant difference in revascularization, MI, stroke, or cardiovascular mortality; however, those patients who were compliant with CPAP for ≥ 4 hours/night did have a statistically significant reduction in the combined endpoint.

In contrast, a trial of patients with first-ever stroke and moderate-to-severe OSA who were randomized to early nasal CPAP or usual care demonstrated better 5-year cardiovascular survival for the patients in the CPAP group, and a trend toward better cardiovascular event-free survival.³² Degree of daytime sleepiness was not stated in this study.

A recent meta-analysis of RCTs failed to find a reduction in major adverse cardiovascular events (MACE) in patients with moderate-to-severe OSA treated with PAP.³³ In this study, subgroup analysis documented benefit in patients who were adherent with PAP for ≥ 4 hours/night. A larger meta-analysis, however, did not find a reduction in MACE even in the adherent subgroup.³⁴

Continue to: AF and OSA

OSA is an independent risk factor for AF, approximately doubling the risk.³⁵ A review of 10,132 patients with AF (1841 with OSA) in a large observational study demonstrated no difference in outcomes of all-cause mortality, first hospitalization, major bleeding, or major cardiovascular events in OSA patients who were or were not treated with PAP. The PAP-treated patients did have a slightly lower (16% vs 18%) risk of worsening of AF over 2 years.³⁶ Overall, AF patients with OSA had more symptoms and higher admission rates, but no difference in overall mortality or MACE. Observational studies have suggested that PAP treatment of OSA facilitates maintenance of normal sinus rhythm after cardioversion and after ablation.³⁷

CHF: Results look promising

In one small study, 24 patients with heart failure with reduced ejection fraction who were optimally medically treated were randomized to receive PAP or sham PAP for 1 month.³⁸ The treatment group demonstrated reduced systolic BP, reduced end systolic dimension, and significant improvement in ejection fraction from 25 ± 2.8% to 33.8 ± 2.4%.

OSA Tx improves insulin sensitivity

OSA is associated with impaired glucose tolerance, and PAP treatment of OSA has been documented to improve insulin sensitivity.^39,40 An efficacy study utilizing PAP in a laboratory setting for 8 hours/night demonstrated significant reduction in fasting blood sugar and a reduction in the dawn phenomenon (an increase in early morning fasting glucose as a result of rebound from hypoglycemia during sleep).³⁹ A 2015 meta-analysis of short-term studies also showed improvement in insulin sensitivity in OSA patients treated with PAP, but failed to find any reduction in A_1C or in body mass index.⁴⁰

All-cause mortality: Difference in findings between short- and long-term studies

Yu et al’s³⁴ meta-analysis of 10 RCTs involving 7266 participants found no difference in mortality in treated (vs no treatment or sham treatment) OSA patients. This was true even in the more adherent subgroup. These studies were relatively short-term, with the longest mean follow-up being 68 months.

Offer a trial of treatment with PAP to asymptomatic patients with moderate-to-severe OSA and comorbidities, such as obesity, resistant hypertension, CHF, atrial fibrillation, and diabetes.

However, several longer-term population-based studies have suggested that OSA treatment improves all-cause mortality. An 18-year follow-up of a Wisconsin cohort documented dramatically increased mortality in patients with severe sleep apnea; mortality was even higher when patients treated with PAP were removed from the analysis, suggesting that PAP treatment was protective, mainly for cardiovascular death.⁵

Continue to: A Danish registry...

A Danish registry documented that patients treated with CPAP had higher rates of comorbidities before and during treatment; when these comorbidities were controlled, men ages ≥ 60 years had improved survival when treated with CPAP. There was no survival benefit in women.⁴¹

Strongly encourage patients to use PAP ≥ 4 hours/night and to recognize that benefits may not be immediately apparent.

A recent analysis—the Sleep Heart Health Study—followed patients with obesity and severe OSA for a mean of 11.1 years and calculated a hazard ratio for all-cause mortality associated with prescribed PAP therapy of 0.58 (95% confidence interval [CI], ­0.35-0.96) after propensity matching.⁴² The difference in mortality appeared 6 to 7 years after PAP therapy was prescribed. This delay may explain the failure of shorter-term studies to demonstrate evidence of benefit.

OSA Tx reduces motor vehicle crashes

Drowsy driving is widely accepted as a risk for motor vehicle crashes. Successful treatment of OSA with PAP has been shown to improve driving performance on a driving simulator.⁴³ An analysis of 15 studies similarly demonstrated a significant reduction in driving accidents (incident rate ratio [IRR] = 0.45) and in near-miss accidents (IRR = 0.23) in patients with OSA treated with CPAP.⁴⁴

Pulmonary hypertension: OSA Tx lowers pulmonary arterial pressure

Patients with OSA have higher than expected rates of pulmonary arterial hypertension—as high as 22%—documented by pulmonary artery catheterization findings.⁴⁵ A meta-analysis of studies that examined the effect of PAP in patients with OSA and coexisting pulmonary hypertension but without other overt pulmonary or cardiac disease found significant reductions in pulmonary artery pressure.⁴⁶ Whether this finding translates into improved patient-­oriented outcomes is unknown.

OSA and pregnancy outcomes

A national cohort study demonstrated that OSA is an independent risk factor for multiple adverse pregnancy outcomes, including gestational diabetes, hypertensive disorders in pregnancy, intrauterine growth retardation, and stillbirth.⁷ OSA was also associated with the rare serious adverse outcomes of congestive heart failure, cardiomyopathy, and pulmonary embolism.⁷ There is little evidence to date with which to determine whether treatment of OSA improves outcomes, but PAP treatment is documented to be safe in pregnant women.⁸

CORRESPONDENCE 
Stephen C. Sorsby, MD, MHA, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 530, Little Rock, AR 72205; [email protected].

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]

SAN ANTONIO – A proprietary oral fixed-dose, triple-antibiotic combination pill offers a promising new approach to the treatment of Crohn’s disease, David Y. Graham, MD, declared at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

In the phase 3 MAP US trial, patients with Crohn’s disease who were randomized to the fixed-dose combination of 45 mg rifabutin, 95 mg clarithromycin, and 10 mg clofazimine, known for now as RHB-104, experienced significantly higher rates of clinical remission and improvement in inflammation as assessed endoscopically and via biomarkers, compared with placebo-treated controls, reported Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

RHB-104 is effective against Mycobacterium avium paratuberculosis (MAP) – and therein hangs a tale.

“MAP has been considered as a possible cause of Crohn’s disease since the disease was described by Crohn in 1932,” the gastroenterologist noted. “These randomized trial data provide further evidence suggesting an important role for MAP or similar microorganisms in the pathogenesis of Crohn’s disease.”

For Dr. Graham, this is a case of deja vu all over again. More than a quarter century ago he was lead author of a highly influential randomized, controlled trial which established that treatment with antibiotics directed against Helicobacter pylori cured peptic ulcer disease. As such, he became internationally recognized as a key figure in the resultant revolution in peptic ulcer treatment. He hears an echo of that earlier transformative change in the MAP US results.

“This is either an additional therapy or it’s the beginning of a paradigm shift. I mean, I see this as we’re standing at the same place now as we were standing with Helicobacter pylori 30 years ago, when the question was: Have we found something that we can eradicate and change the natural history of the disease and cure it? You can say this [MAP-directed therapy] is going in that direction, but it certainly hasn’t gotten to the point of proof yet. The results have to be reproduced,” he said.

The MAP US trial included 331 patients with moderate to severely active Crohn’s disease at 92 sites who had failed to achieve an adequate response with conventional therapies. Participants were randomized double blind to twice-daily RHB-104 or placebo for 52 weeks. Those not in remission at 26 weeks could opt for open-label RHB-104. Background concomitant treatment with corticosteroids, tumor necrosis factor inhibitors, and immunosuppressives was permitted.

The primary outcome was clinical remission as defined by a Crohn’s Disease Activity Index (CDAI) score below 150 at week 26. This was achieved in 36.7% of the active treatment group and 23% of controls, a highly significant difference. The clinical remission rates at week 16 were 42.2% and 29.1%, respectively. At week 26, 44% of RHB-104-treated patients had achieved at least a 100-point reduction in CDAI score, compared with baseline, as did 30.9% of controls. The key symptom score provided by the sum of the abdominal pain and bowel movement components of the CDAI was significantly lower in the RHB-104 group than in controls from week 16 on.

The remission rate at week 26 in the group on RHB-104 was similarly favorable regardless of whether or not they were on anti–tumor necrosis factor therapy.

“This suggests that RHB-104 can be used effectively and safely as an adjunct treatment to other medications to enhance the response to medical therapy,” according to Dr. Graham, who was principal investigator for MAP US.

The composite endpoint of clinical remission plus at least a 50% reduction from baseline in fecal calprotectin or C-reactive protein was achieved in 21.1% of the RHB-104 group and 9.1% of controls at week 26, and by 16.9% on RHB-104 and 7.9% on placebo at week 52.

In the 35 patients who underwent endoscopy at week 26, a 50% or greater reduction in the Simple Endoscopic Score in Crohn’s Disease was documented in 28.6% of patients on RHB-104 versus 4.8% of controls.

Durable remission, defined as a CDAI score below 150 at all study visits from week 16 to week 52, was achieved in 18.7% of the RHB-104 group, compared with 8.5% of controls.

The side effect profiles of RHB-104 and placebo were similar, with no serious adverse events recorded in the 52-week study. An increase in the QT interval on ECG was noted in the RHB-104 group from week 4 on, but it wasn’t associated with any clinical findings. Further study of this ECG finding is underway.

Several audience members rose to urge caution in interpreting the MAP US data.

“We must adhere to Koch’s postulates before we make conclusions about causative agents of an infectious disease, and I didn’t see those data here. So I look forward to a future presentation that shares that,” one gastroenterologist commented.

“I haven’t seen any data here that shows Mycobacterium was present in these patients,” noted another.

Dr. Graham replied that MAP US was a hypothesis-driven clinical trial: Crohn’s disease has much in common with an inflammatory bowel disease occurring in ruminant animals, where RHB-104 has shown treatment efficacy.

“This is a Mycobacterium avium organism, so it’s not something you’re going to cure in 2 weeks or 2 months. But the question is, do you have an effect on the disease, and the answer in MAP US was unquestionably yes. It’s very positive data to further pursue the hypothesis, but the study doesn’t provide a definitive answer,” he said.

Dr. Graham reported serving as a consultant to RedHill Biopharma, the study sponsor.

[email protected]

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.^1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.³

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.

This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.

3 cases to consider

CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.

Outcome. Mr. D has remained free of symptoms of ­asthma for more than 20 years.

CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.

Outcome. Casey was able to resume normal physical ­activities, including competitive swimming.

CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.

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Continue to: Outcome...

Outcome. Ms. S’s symptoms resolved completely within months.

Evidence of benefit of macrolides in asthma

These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma

Meta-analysis. Reiter et al⁴ performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV₁) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.

Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and ­procedures.”

Cochrane meta-analysis. Kew et al⁵ performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported

• no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
• significant effects of macrolides for asthma symptoms and FEV₁.

Continue to: Two within-study subgroup...

Some patients with asthma who respond to azithromycin experience persistent improvement after antibiotic treatment.

Two within-study subgroup analyses showed a possible benefit of macrolides for non-­eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al⁵ noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.

Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.

Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.⁶ Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.² Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.²

Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials^7,8 that were not included in the cited meta-analyses, along with other evidence,² point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.

Clinical trial in adults. Gibson et al⁷ conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.⁹

Continue to: Azithromycin reduced the frequency...

Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).

There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.

Other evidence¹⁰ indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).

Pediatric clinical trial. Stokholm et al⁸ performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.

Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).

Continue to: No differences between...

No differences between the randomized groups were observed in clinical adverse ­effects.

Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in ­individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).^10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little¹² or no¹³ short-term benefit; however, these negative findings have been ­hypothesized to be the result of selection bias.¹⁴

Other evidence is worth examining

Other studies not included in the meta-­analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.

Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)¹⁵ is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.

However, many eligible subjects, whom the principal investigator believed were ­ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose¹⁶ (OL cohort only, Level 2 study: controlled, nonrandomized, ­nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.

Continue to: The less severely...

The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.

There is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.

Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”¹⁵

Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).¹⁷ Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.

Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).

These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.¹⁷ Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.

Continue to: Physicians should also note...

Physicians should also note the landmark trial of azithromycin in severe, smoking-­associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).¹⁸

Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.¹⁹ A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.

Rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.

Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.

Tx recommendations: When to consider azithromycin

Randomized⁷ and nonrandomized¹⁵ evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).

It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.¹¹ Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).¹⁰

Continue to: Do biomarkers predict response?

Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended²⁰ but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.

So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma²¹) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.³ The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.²² Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this ­recommendation).

Acute bronchitis and asthma-onset ­associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.²³ However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.²³ Several other matters are worth noting:

• C pneumoniae-specific IgA²³ and IgE²⁴ are promising biomarkers that deserve further investigation.
• M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.^21,25
• Noneosinophilic severe asthma is another potential predictive characteristic.²⁶ The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial⁷ reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.

Potential for harm withlong-term macrolide use?

Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 1^27,28 and discussed below).²⁹

Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.³⁰ In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.^31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.^31,32 The major clinical “side ­effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.^31,32

Continue to: Antibiotic resistance

Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens³³; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.³⁴ There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.³³

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.³⁵ In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups^31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.^8,36

Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.

Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in ­every 4000 administrations.²⁷ Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.³⁷ There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population^38,39 or when azithromycin is coadministered with a LABA.³

Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).³² In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32 (2.8%) of 1142 patients with COPD treated daily for 1 year.¹⁸

Continue to: Physicians who prescribe...

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.⁴⁰ Nevertheless:

• Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
• Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of ­azithromycin.
• The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.⁴⁰

Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.² A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.⁴¹ Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.^42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.⁴¹

In the long run, azithromycin was 10 to 20 times as cost effective as the other 3 therapeutic options for improving asthma qualityof-life outcomes.

Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.^42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.⁴⁴

Consider a trial of azithromycin for patients who have new-onset asthma.

What about cost?

Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS¹⁵—costs about as much as 1 ICS and LABA combination inhaler. Using published results,^15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.

Continue to: Recommendations to reflect on for your practice

Table 2^7,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients

• whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
• who have new-onset asthma.

At press time, the European Respiratory Journal published a patient-level meta-analysis that demonstrates that maintenance use of azithromycin decreases exacerbations in adults with asthma. To learn more, go to https://erj.ersjournals.com/content/54/5/1901381

Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.

*Data available from the author upon request. See “Correspondence,” at end of article.

CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.^1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.³

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.

This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.

3 cases to consider

CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.

Outcome. Mr. D has remained free of symptoms of ­asthma for more than 20 years.

CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.

Outcome. Casey was able to resume normal physical ­activities, including competitive swimming.

CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.

[polldaddy:10475438]

Continue to: Outcome...

Outcome. Ms. S’s symptoms resolved completely within months.

Evidence of benefit of macrolides in asthma

These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma

Meta-analysis. Reiter et al⁴ performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV₁) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.

Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and ­procedures.”

Cochrane meta-analysis. Kew et al⁵ performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported

• no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
• significant effects of macrolides for asthma symptoms and FEV₁.

Continue to: Two within-study subgroup...

Some patients with asthma who respond to azithromycin experience persistent improvement after antibiotic treatment.

Two within-study subgroup analyses showed a possible benefit of macrolides for non-­eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al⁵ noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.

Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.

Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.⁶ Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.² Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.²

Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials^7,8 that were not included in the cited meta-analyses, along with other evidence,² point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.

Clinical trial in adults. Gibson et al⁷ conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.⁹

Continue to: Azithromycin reduced the frequency...

Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).

There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.

Other evidence¹⁰ indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).

Pediatric clinical trial. Stokholm et al⁸ performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.

Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).

Continue to: No differences between...

No differences between the randomized groups were observed in clinical adverse ­effects.

Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in ­individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).^10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little¹² or no¹³ short-term benefit; however, these negative findings have been ­hypothesized to be the result of selection bias.¹⁴

Other evidence is worth examining

Other studies not included in the meta-­analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.

Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)¹⁵ is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.

However, many eligible subjects, whom the principal investigator believed were ­ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose¹⁶ (OL cohort only, Level 2 study: controlled, nonrandomized, ­nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.

Continue to: The less severely...

The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.

There is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.

Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”¹⁵

Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).¹⁷ Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.

Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).

These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.¹⁷ Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.

Continue to: Physicians should also note...

Physicians should also note the landmark trial of azithromycin in severe, smoking-­associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).¹⁸

Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.¹⁹ A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.

Rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.

Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.

Tx recommendations: When to consider azithromycin

Randomized⁷ and nonrandomized¹⁵ evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).

It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.¹¹ Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).¹⁰

Continue to: Do biomarkers predict response?

Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended²⁰ but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.

So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma²¹) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.³ The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.²² Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this ­recommendation).

Acute bronchitis and asthma-onset ­associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.²³ However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.²³ Several other matters are worth noting:

• C pneumoniae-specific IgA²³ and IgE²⁴ are promising biomarkers that deserve further investigation.
• M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.^21,25
• Noneosinophilic severe asthma is another potential predictive characteristic.²⁶ The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial⁷ reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.

Potential for harm withlong-term macrolide use?

Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 1^27,28 and discussed below).²⁹

Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.³⁰ In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.^31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.^31,32 The major clinical “side ­effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.^31,32

Continue to: Antibiotic resistance

Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens³³; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.³⁴ There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.³³

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.³⁵ In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups^31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.^8,36

Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.

Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in ­every 4000 administrations.²⁷ Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.³⁷ There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population^38,39 or when azithromycin is coadministered with a LABA.³

Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).³² In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32 (2.8%) of 1142 patients with COPD treated daily for 1 year.¹⁸

Continue to: Physicians who prescribe...

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.⁴⁰ Nevertheless:

• Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
• Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of ­azithromycin.
• The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.⁴⁰

Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.² A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.⁴¹ Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.^42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.⁴¹

In the long run, azithromycin was 10 to 20 times as cost effective as the other 3 therapeutic options for improving asthma qualityof-life outcomes.

Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.^42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.⁴⁴

Consider a trial of azithromycin for patients who have new-onset asthma.

What about cost?

Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS¹⁵—costs about as much as 1 ICS and LABA combination inhaler. Using published results,^15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.

Continue to: Recommendations to reflect on for your practice

Table 2^7,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients

• whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
• who have new-onset asthma.

At press time, the European Respiratory Journal published a patient-level meta-analysis that demonstrates that maintenance use of azithromycin decreases exacerbations in adults with asthma. To learn more, go to https://erj.ersjournals.com/content/54/5/1901381

Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.

*Data available from the author upon request. See “Correspondence,” at end of article.

CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.^1,2 Arising from that hypothesis, macrolide antibiotics have been the subject of clinical trials and other studies to determine whether these drugs are efficacious in the long-term management of asthma in adults and children. Macrolides might also have immunomodulatory and antiviral properties that can benefit patients with asthma.³

In vitro laboratory and in vivo animal models support the biologic plausibility that chronic infection is a potential cause of asthma.

This article looks at the evidence and clinical scenarios for the use of macrolides in asthma, provides proposed dosing schedules, and reviews associated concerns, including adverse effects, risk of bacterial resistance, and cost.

3 cases to consider

CASE 1 Paul D developed severe, refractory asthma at 30 years of age after an acute respiratory illness. At age 40, he was treated with 14 weekly doses of azithromycin. His asthma resolved slowly over 12 months.

Outcome. Mr. D has remained free of symptoms of ­asthma for more than 20 years.

CASE 2 Casey K developed severe wheezing at 18 months of age after an acute respiratory illness. Refractory asthma symptoms persisted until 6 years of age, at which time he was given 12 weekly doses of azithromycin. Asthma symptoms gradually resolved.

Outcome. Casey was able to resume normal physical ­activities, including competitive swimming.

CASE 3 Amy S, who had no history of respiratory problems, presented at 30 years of age with a 3-month history of wheezing and dyspnea after an acute respiratory illness. She was treated symptomatically with bronchodilators; wheezing failed to resolve. After 6 months of persistent wheezing that significantly affected her exercise capacity, Ms. S was given a diagnosis of persistent asthma and received 12 weekly doses of azithromycin.

[polldaddy:10475438]

Continue to: Outcome...

Outcome. Ms. S’s symptoms resolved completely within months.

Evidence of benefit of macrolides in asthma

These 3 cases, taken from my practice (but with names changed), demonstrate the therapeutic potential of macrolide antibiotics for patients with asthma under specific clinical circumstances. The cases are referenced again in the following examination of the literature on macrolides for asthma

Meta-analysis. Reiter et al⁴ performed a meta-analysis of 12 randomized clinical trials of macrolides for long-term management of asthma in children and adults. Prolonged treatment was defined as > 3 weeks of continuous administration of a macrolide. The pooled effect of macrolides on forced expiratory volume in 1 second (FEV₁) was not significant; however, a significant effect on peak expiratory flow, symptom scores, quality of life, and airway hyperreactivity was observed.

Comment: The study’s authors concluded: “Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and ­procedures.”

Cochrane meta-analysis. Kew et al⁵ performed a meta-analysis of 23 studies of macrolides for managing chronic asthma for the Cochrane Database of Systematic Reviews. In their review, they reported

• no significant effects of macrolides on asthma exacerbations, asthma control, quality of life, and rescue medication use; and
• significant effects of macrolides for asthma symptoms and FEV₁.

Continue to: Two within-study subgroup...

Some patients with asthma who respond to azithromycin experience persistent improvement after antibiotic treatment.

Two within-study subgroup analyses showed a possible benefit of macrolides for non-­eosinophilic asthma, defined by a predominance of neutrophils in a bronchoalveolar lavage specimen. Kew et al⁵ noted that (1) most of the evidence examined in the review was of low quality and (2) inclusion criteria, interventions, and outcomes were highly variable.

Comment: The validity of a meta-analysis depends on the validity and similarity of underlying trials. Both meta-analyses just described were characterized by (1) grouping trials of older and newer macrolides and (2) significant selection bias in the underlying trials.

Selection bias is prevalent in asthma research and is a major contributor to uncertainty: Randomized controlled trials upon which guideline treatments are based have systematically excluded > 90% of people with asthma.⁶ Exclusions include past or current smoking, the asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome, severe asthma, and acute respiratory illness; these exclusion criteria have also been applied to studies of macrolides. Importantly, patients in the excluded groups are probably those most likely to respond to a macrolide.² Pragmatic effectiveness studies (broad eligibility criteria, adequate duration of azithromycin treatment, a posttreatment observation period, and pre-specified biomarker subgroup analyses) have been recommended to address the hypothesis of what has been termed infectious asthma.²

Inconsistent evidence, the generally poor quality of underlying studies, and uncertainty about which subgroup(s) of asthma patients might benefit all contribute to a strength of recommendation of “B” for treating asthma with macrolides. Two recent randomized trials^7,8 that were not included in the cited meta-analyses, along with other evidence,² point to 2 groups of patients who are candidates for a trial of azithromycin: those with severe refractory asthma and those with new-onset asthma.

Clinical trial in adults. Gibson et al⁷ conducted a randomized, double-blind, placebo-controlled trial of azithromycin 500 mg 3 times a week or placebo for 1 year in 420 adults who had uncontrolled persistent asthma despite taking medium-to-high doses of an inhaled corticosteroid (ICS) plus a long-acting β agonist (LABA) (the AMAZES [Asthma and Macrolides: The Azithromycin Efficacy and Safety] trial; Level 1 study). The mean baseline asthma control questionnaire score was 1.5, equivalent to an Asthma Control Test (ACT) score* of 15.⁹

Continue to: Azithromycin reduced the frequency...

Azithromycin reduced the frequency of asthma exacerbations (to 1.07 per patient–year for azithromycin, compared with 1.86 per patient–year for placebo [incidence rate ratio = 0.59; 95% confidence interval (CI), 0.47-0.74]). The percentage of patients experiencing at least 1 exacerbation was reduced with azithromycin treatment (61% of patients in the placebo group experienced ≥ 1 exacerbation, compared with 44% in the azithromycin group [P < .0001; number needed to treat = 6]). Asthma quality of life was also improved by azithromycin (P = .001).

There was no significant difference between azithromycin and placebo in the overall rate of serious adverse events. Diarrhea that did not require treatment discontinuation was more common in patients treated with azithromycin (34%) than in the placebo group (19%). There was no posttreatment observation period to assess whether these azithromycin benefits waned or persisted after treatment was stopped.

Other evidence¹⁰ indicates that at least some patients who respond to azithromycin will experience persistent improvement after antibiotic treatment is completed (see CASE 1).

Pediatric clinical trial. Stokholm et al⁸ performed a randomized, double-blind, placebo-controlled trial of azithromycin in children 1 to 3 years of age who had been given a diagnosis of recurrent asthma-like symptoms (Level 1 study). Treatment was a 3-day course of azithromycin oral solution, 10 mg/kg/d, or placebo. Random allocation was performed for 158 asthma-like episodes in 72 children.

Azithromycin reduced the wheezing episode to a mean duration of 3.4 days, compared with 7.7 days for placebo (risk reduction = 63.3%; 95% CI, 56%-69.3% [P < .0001]). Effect size increased with early initiation of treatment: ie, an 83% reduction in episode duration was seen when treatment was initiated before Day 6 of the episode, compared with a 36% reduction if treatment was initiated on or after Day 6 (P < .0001).

Continue to: No differences between...

No differences between the randomized groups were observed in clinical adverse ­effects.

Comment: The brief course of azithromycin provided to patients in this trial did not have a significant impact on time to next episode of troublesome lung symptoms in ­individual children. Previous clinical observations have suggested that a longer duration of treatment (3-6 months) might be required to achieve lasting improvement or remission in selected patients with asthma (see CASE 2).^10,11 The short-term benefit of azithromycin for acute wheezing is limited to children: Two comparable acute dosing trials in adults have shown little¹² or no¹³ short-term benefit; however, these negative findings have been ­hypothesized to be the result of selection bias.¹⁴

Other evidence is worth examining

Other studies not included in the meta-­analyses of randomized controlled trials provide additional evidence to support a recommendation of a trial of azithromycin in patients with severe, refractory, or new-onset asthma.

Nonrandomized controlled evidence. AZMATICS (AZithroMycin/Asthma Trial In Community Settings)¹⁵ is the sole randomized, double-blind, placebo-controlled trial of long-term azithromycin that included a 9-month posttreatment observation period. Seventy-five participants were randomized to receive a loading dose of 600 mg of azithromycin or placebo once daily for 3 days in Week 1. They then received either azithromycin 600 mg or placebo once weekly for 11 weeks. Posttreatment observation was performed until 48 weeks after randomization.

However, many eligible subjects, whom the principal investigator believed were ­ideal candidates for randomization, declined randomization because they did not want to risk receiving placebo. To accommodate those patients, the protocol was amended to include an open-label (OL) azithromycin arm, in which each participant’s personal physician prescribed azithromycin 750 mg for 11 weeks after a loading dose¹⁶ (OL cohort only, Level 2 study: controlled, nonrandomized, ­nonblinded). The OL group had (1) a higher baseline prevalence of severe, persistent asthma (32%) than the randomized group (8%) (P = .012); and (2) worse asthma quality of life than the randomized patients (P = .023). The OL group represented selection bias attributable to patient preference.

Continue to: The less severely...

The less severely affected randomized group of the trial did not exhibit significant effects attributable to azithromycin. The more severely affected OL cohort demonstrated significant, and large, azithromycin treatment effects for asthma symptoms, asthma quality of life, and asthma control (P < .05 for both groups; number needed to treat [NNT] = 3) that persisted during the posttreatment observation period.

There is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.

Comment: The authors concluded: “Pending further randomized trials and given the relative safety of azithromycin and the significant disease burden from severe, refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents.”¹⁵

Before-and-after trial. Forty-six patients with moderate or severe chronic, persistent, stable asthma were selected as a cohort unlikely to experience spontaneous remission (ie, patients in exacerbation were excluded) (Level 2 study: prospective cohort).¹⁷ Subjects were treated for a median of 4 weeks (range, 3 to 9 weeks) with oral doxycycline, 100 mg bid; azithromycin, 1000 mg, once weekly; or erythromycin, 1000 mg/d in divided doses. Average duration of posttreatment follow-up was 6 months. All subjects were positive for antibodies to Chlamydia pneumoniae.

Four patients with diagnosed acuteC pneumoniae respiratory infection developed chronic asthma, which disappeared in each case after treatment. Of the other 42 seroreactive patients who were treated a mean of 6 years after they developed chronic asthma, 21 had either complete remission of asthma symptoms (n = 3) or major persistent clinical improvement (n = 18). Clinical improvement was more likely to occur in patients with early disease (P = .01) and before development of fixed airway obstruction (P < .01).

These results are consistent with the hypothesis that chronic infection of the lower respiratory tract contributes to the development and progression of asthma.¹⁷ Although clinical improvement was more likely in early asthma compared with asthma with fixed airway obstruction, improvement was nevertheless noted in the latter group.

Continue to: Physicians should also note...

Physicians should also note the landmark trial of azithromycin in severe, smoking-­associated COPD, which found a clinically significant benefit in reducing exacerbations and improving quality of life (NNT = 3, to prevent 1 exacerbation).¹⁸

Case series. In a prospective case series (Level 2 study: prospective cohort), 163 primary care outpatients (adolescents and adults) who had acute wheezing illnesses or chronic asthma were evaluated for C pneumoniae infection by serologic testing.¹⁹ A subgroup of this cohort also had nasopharyngeal cultures tested for C pneumoniae.

Rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.

Twenty patients (12%) were given a diagnosis of C pneumoniae infection defined by serology (n = 15), culture isolation (n = 3), or both (n = 2). Of the 20, 10 wheezed for the first time—6 of whom subsequently developed chronic asthma (n = 5) or chronic bronchitis (n = 1), with a serologic profile suggesting chronic infection. The other 10 patients who had a diagnosis of C pneumoniae infection already had a diagnosis of chronic asthma. In patients with established chronic asthma, initial serologic findings suggested chronic, rather than acute, C pneumoniae infection.

Tx recommendations: When to consider azithromycin

Randomized⁷ and nonrandomized¹⁵ evidence supports treating severely uncontrolled or refractory asthma (strength of recommendation [SOR], B); no comparable randomized trials of azithromycin have been conducted for new-onset asthma (SOR, C). Consider prescribing empiric azithromycin for patients with new-onset asthma in the context of shared decision making about potential benefits, harms, and consequences of chronic asthma (SOR, C).

It is important to note that wheezing is frequently associated with uncomplicated acute bronchitis that resolves spontaneously without antibiotic treatment.¹¹ Azithromycin treatment for new-onset asthma should therefore be reserved for patients in whom apparent uncomplicated acute bronchitis fails to resolve after 3 to 6 months, and whose illness is diagnosable as asthma (see CASE 3).¹⁰

Continue to: Do biomarkers predict response?

Confirming C pneumoniae infection by bronchoscopy before beginning treatment has been recommended²⁰ but might be impractical; also, diagnostic testing for C pneumoniae is limited in availability and has potentially low sensitivity for diagnosing chronic deep lung infection.

So should you test for C pneumoniae biomarkers (or for biomarkers of Mycoplasma pneumoniae, another atypical infection implicated in the pathogenesis of asthma²¹) before initiating treatment? Azithromycin has antimicrobial, immunomodulatory, and potential antiviral properties.³ The body of evidence reviewed here indicates that the effects of macrolides on asthma might be, at least in part, antimicrobial. However, there is no direct evidence that the benefit of azithromycin in asthma is limited to patients who have positive infection biomarkers.²² Therefore, infection biomarker testing as a decision aid cannot be recommended at this time (although future research might alter this ­recommendation).

Acute bronchitis and asthma-onset ­associated with an acute lower respiratory tract infection have been statistically associated with biomarkers of C pneumoniae infection.²³ However, C pneumoniae biomarkers are also prevalent in patients who have asthma that is not associated with an infectious onset.²³ Several other matters are worth noting:

• C pneumoniae-specific IgA²³ and IgE²⁴ are promising biomarkers that deserve further investigation.
• M pneumoniae infection has also been associated with asthma and a response to antibiotic therapy.^21,25
• Noneosinophilic severe asthma is another potential predictive characteristic.²⁶ The applicability of this biomarker to primary care practice is limited, however, by the invasive nature of bronchoscopy and by the uncertain validity of the diagnostic concept: There is no guarantee that dynamic inflammatory infiltrates remain stable over a lifetime. Furthermore, the AMAZES Trial⁷ reported that azithromycin benefit was comparable in eosinophilic and noneosinophilic asthma.

Potential for harm withlong-term macrolide use?

Controversies about the role of macrolides in asthma involve uncertainty about who might benefit from treatment and the potential harms of macrolides use (TABLE 1^27,28 and discussed below).²⁹

Adverse effects. The newer macrolides azithromycin and clarithromycin offer favorable safety and tolerability profiles, compared with those of older agents.³⁰ In clinical trials of azithromycin, gastrointestinal symptoms (nausea, vomiting, abdominal pain, and diarrhea) were usually mild or moderate and rarely (< 2% of subjects) required discontinuation of study medication.^31,32Clostridium difficile diarrhea has not been reported in any of the large clinical trials, in which thousands of patients received azithromycin for 3 to 12 months.^31,32 The major clinical “side ­effects” attributable to azithromycin are a significant reduction, compared to placebo, in acute respiratory illness, bronchitis, pneumonia, and sinusitis.^31,32

Continue to: Antibiotic resistance

Antibiotic resistance. Exposure of populations to macrolides can increase the percentage of macrolide-resistant bacterial respiratory pathogens³³; policies aimed at decreasing inappropriate macrolide prescribing can significantly lower that percentage.³⁴ There is no evidence, however, of any detrimental effects of macrolide resistance in individual patients receiving azithromycin.³³

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

In trials of azithromycin for the treatment of trachoma in Africa, significantly fewer deaths occurred in villages where subjects were treated with azithromycin than in villages where azithromycin therapy was not provided.³⁵ In the United States, weekly azithromycin treatment for 3 to 12 months in adults with heart disease resulted in fewer cases of acute bronchitis and pneumonia, compared with the placebo-treated groups^31,32; similar benefit for azithromycin was seen in children who had recurrent lung infection.^8,36

Nevertheless, concern over the spread of macrolide-resistant bacteria to the surrounding community is a concern and a possibility—and should be the subject of future research.

Sudden cardiac death. In a Medicaid population, the risk of sudden cardiac death from taking a macrolide among patients at high risk of cardiovascular disease was 1 in ­every 4000 administrations.²⁷ Compare that level of risk with the 1 in 167 risk of an acute cardiovascular event in patients with COPD who start taking a LABA.³⁷ There is no detectable increase in the risk of sudden cardiac death when taking azithromycin in the general (ie, average cardiovascular risk) population^38,39 or when azithromycin is coadministered with a LABA.³

Hearing loss. An excess of 18 (< 1%) patients affected by hearing loss, 7 of whom sought medical attention, was reported among 2004 patients who had stable coronary artery disease and had been treated once weekly with azithromycin for 12 months (P = .02, compared with placebo).³² In another study, hearing test changes leading to discontinuation of azithromycin were detected in an excess of 32 (2.8%) of 1142 patients with COPD treated daily for 1 year.¹⁸

Continue to: Physicians who prescribe...

Physicians who prescribe long-term azithromycin should instruct patients to report any hearing loss.

Drug–drug interactions. Azithromycin is free of the drug–drug interactions characteristic of conventional macrolides, such as clarithromycin.⁴⁰ Nevertheless:

• Caution is advised when giving azithromycin in conjunction with coumadin or theophylline.
• Giving azithromycin with antacids that contain aluminum or magnesium salts can reduce the rate, although not the extent, of the absorption of ­azithromycin.
• The serum concentration of azithromycin is markedly increased when it is given with nelfinavir.⁴⁰

Microbiome effects. The host microbiome can have a significant effect on the risk of asthma.² A cross-sectional study indicated that lower respiratory bacterial burden is greater in patients with asthma, compared with that of healthy control subjects, and correlates with bronchial hyperresponsiveness.⁴¹ Early colonization of the infant nasopharynx, particularly with Streptococcus spp, is a predictor of asthma risk.^42,43 Bacterial pathogens in the nasopharyngeal biome at the time of upper respiratory viral infection are significant determinants of risk for the spread of infection to the lower airways, suggesting that these microorganisms contribute to the risk of persistent asthma.⁴¹

In the long run, azithromycin was 10 to 20 times as cost effective as the other 3 therapeutic options for improving asthma qualityof-life outcomes.

Investigators have speculated that, rather than increasing the risk of asthma by disrupting the “healthy” microbiome, azithromycin might be helpful in treating an “unhealthy” microbiome.^42,43 Recently, it was shown in a randomized trial that azithromycin induced a perturbation in the gut microbiota of children 14 days after randomization, although the drug did not have a long-lasting effect on the composition of gut microbiota.⁴⁴

Consider a trial of azithromycin for patients who have new-onset asthma.

What about cost?

Inhaled corticosteroids and combination formulations of an ICS and a LABA are expensive and must be taken for the long term. A 3-month course of generic azithromycin—comparable to what was used in the OL subgroup of AZMATICS¹⁵—costs about as much as 1 ICS and LABA combination inhaler. Using published results,^15,45 a pilot cost-effectiveness analysis in patients with persistent asthma compared doubling the ICS dosage, adding salmeterol, adding tiotropium, or prescribing 3 months of azithromycin. In the long run, azithromycin was 10 to 20 times as cost-effective as the other 3 therapeutic options for improving asthma quality-of-life outcomes.* However, reliable cost-effectiveness analyses require more, and better, evidence.

Continue to: Recommendations to reflect on for your practice

Table 2^7,15 outlines selected long-term (≥ 3 months) macrolide dosing schedules in the management of asthma. Consider a trial of azithromycin for your patients

• whose asthma is refractory (poorly controlled persistent asthma), despite treatment with either an ICS and LABA combination or an ICS and long-acting muscarinic antagonist combination; and
• who have new-onset asthma.

At press time, the European Respiratory Journal published a patient-level meta-analysis that demonstrates that maintenance use of azithromycin decreases exacerbations in adults with asthma. To learn more, go to https://erj.ersjournals.com/content/54/5/1901381

Last, there is no evidence for or against prescribing azithromycin for patients who have chronic asthma that is not refractory but is uncontrolled because they are not being treated according to guidelines.

*Data available from the author upon request. See “Correspondence,” at end of article.

CORRESPONDENCE
David L. Hahn, MD, MS, Department of Family Medicine & Community Health, University of Wisconsin School of Medicine & Public Health, 1100 Delaplaine Court, Madison, WI 53715; [email protected].