A 24-YEAR-OLD WOMAN with a history of guttate psoriasis, for which she was taking adalimumab, presented with a 2-week history of diffuse papules and plaques on her neck, back, torso, and upper and lower extremities (FIGURE 1). She said that the lesions were pruritic and seemed similar to those that erupted during past outbreaks of psoriasis—although they were more numerous and progressive. So, the patient (a nurse) decided to take her biweekly dose (40 mg) of adalimumab 1 week early. After administration, the rash significantly worsened, spreading to the rest of her trunk and extremities.

Physical exam was notable for multiple erythematous papules and plaques with central clearing and light peripheral scaling on both arms and legs, as well as her chest and back. The patient also indicated she’d adopted a stray cat 2 weeks prior. Given the patient’s pet exposure and the annular nature of the lesions, a potassium hydroxide (KOH) preparation was done.

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

The KOH preparation was positive for hyphae in 4 separate sites (trunk, left arm, left leg, and left neck), confirming the diagnosis of severe extensive tinea corporis (FIGURE 2).

Dermatophyte (tinea) infections are caused by fungi that invade and reproduce in the skin, hair, and nails. Dermatophytes, which include the genera Trichophyton, Microsporum, and Epidermophyton, are the most common cause of superficial mycotic infections. As of 2016, the worldwide prevalence of superficial mycotic infections was 20% to 25%.¹ Tinea corporis can result from contact with people, animals, or soil. Infections resulting from animal-to-human contact are often transmitted by domestic animals. In this case, the patient’s exposure was from her new cat.

Tinea corporis classically manifests as pruritic, erythematous patches or plaques with central clearing, giving it an annular appearance. The response to a tinea infection depends on the immune system of the host and can range in severity from superficial to severe.² There are 2 forms of severe dermatophytosis: invasive, which involves localized perifollicular sites or deep dermatophytosis, and extensive, which is confined to the stratum corneum but results in numerous lesions.³

The diagnosis of tinea corporis is commonly confirmed using direct microscopic examination with 10% to 20% KOH preparation, which will show branching and septate hyphal filaments.⁴

Several conditions with annular lesions comprise the differential

The findings of pruritic annular erythematous lesions on the patient’s neck, chest, trunk, and bilateral extremities led the patient to suspect this was a worsening case of her guttate psoriasis. Other possible diagnoses included pityriasis rosea, subacute cutaneous lupus erythematosus (SCLE), and secondary syphilis.

Continue to: Guttate psoriasis

Guttate psoriasis would not typically progress during treatment with adalimumab, although tumor necrosis factor (TNF) inhibitors have been associated with worsening psoriasis. Guttate psoriasis manifests with small, pink to red, scaly raindrop-shaped patches over the trunk and extremities.

Pityriasis rosea, a rash that resembles branches of a Christmas tree, was strongly considered given the appearance of the lesions on the patient’s back. It commonly manifests as round to oval lesions with a subtle advancing border and central fine scaling, similar in shape and color to the lesions seen in tinea corporis.

SCLE has been associated with use of TNF inhibitors, but our patient had no other lupus-like symptoms, such as fatigue, fever, headaches, or joint pain. SCLE lesions are often annular with raised pink to red borders similar in appearance to tinea corporis.

Secondary syphilis was ruled out in this patient because she had a negative rapid plasma reagin test. Secondary syphilis most commonly manifests with diffuse, nonpruritic pink to red-brown lesions on the palms and soles of patients. Patients often have prodromal symptoms that include fever, weight loss, myalgias, headache, and sore throat.

Terbinafine, Yes, but for how long?

Historically, terbinafine has been prescribed at 250 mg once daily for 2 weeks for extensive tinea corporis. However, recent studies in India suggest that terbinafine should be dosed at 250 mg twice daily, with longer durations of treatment, due to resistance.⁵ In the United States, it is reasonable to prescribe oral terbinafine 250 mg once daily for 4 weeks and then re-evaluate the patient in a case of extensive tinea corporis.

Other oral antifungals that can effectively treat extensive tinea corporis include itraconazole, fluconazole, and griseofulvin.¹ Itraconazole and terbinafine are equally effective and safe in the treatment of tinea corporis, although itraconazole is significantly more expensive.⁶ Furthermore, a recent study found that combination therapy with oral terbinafine and itraconazole is as safe as monotherapy and is an option when terbinafine resistance is suspected.⁷

Our patient was initially started on oral terbinafine 250 mg/d. After the first dose, the patient requested a change in medication because there was no improvement in the rash. The patient was then prescribed oral fluconazole 300 mg daily and the tinea cleared after 2 months of daily therapy. (We surmise the treatment course may have been prolonged due to the possible immunosuppressant effects of adalimumab.) At the completion of treatment for the tinea corporis, the patient was restarted on adalimumab 40 mg biweekly for her psoriasis. 

A 24-YEAR-OLD WOMAN with a history of guttate psoriasis, for which she was taking adalimumab, presented with a 2-week history of diffuse papules and plaques on her neck, back, torso, and upper and lower extremities (FIGURE 1). She said that the lesions were pruritic and seemed similar to those that erupted during past outbreaks of psoriasis—although they were more numerous and progressive. So, the patient (a nurse) decided to take her biweekly dose (40 mg) of adalimumab 1 week early. After administration, the rash significantly worsened, spreading to the rest of her trunk and extremities.

Physical exam was notable for multiple erythematous papules and plaques with central clearing and light peripheral scaling on both arms and legs, as well as her chest and back. The patient also indicated she’d adopted a stray cat 2 weeks prior. Given the patient’s pet exposure and the annular nature of the lesions, a potassium hydroxide (KOH) preparation was done.

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

The KOH preparation was positive for hyphae in 4 separate sites (trunk, left arm, left leg, and left neck), confirming the diagnosis of severe extensive tinea corporis (FIGURE 2).

Dermatophyte (tinea) infections are caused by fungi that invade and reproduce in the skin, hair, and nails. Dermatophytes, which include the genera Trichophyton, Microsporum, and Epidermophyton, are the most common cause of superficial mycotic infections. As of 2016, the worldwide prevalence of superficial mycotic infections was 20% to 25%.¹ Tinea corporis can result from contact with people, animals, or soil. Infections resulting from animal-to-human contact are often transmitted by domestic animals. In this case, the patient’s exposure was from her new cat.

Tinea corporis classically manifests as pruritic, erythematous patches or plaques with central clearing, giving it an annular appearance. The response to a tinea infection depends on the immune system of the host and can range in severity from superficial to severe.² There are 2 forms of severe dermatophytosis: invasive, which involves localized perifollicular sites or deep dermatophytosis, and extensive, which is confined to the stratum corneum but results in numerous lesions.³

The diagnosis of tinea corporis is commonly confirmed using direct microscopic examination with 10% to 20% KOH preparation, which will show branching and septate hyphal filaments.⁴

Several conditions with annular lesions comprise the differential

The findings of pruritic annular erythematous lesions on the patient’s neck, chest, trunk, and bilateral extremities led the patient to suspect this was a worsening case of her guttate psoriasis. Other possible diagnoses included pityriasis rosea, subacute cutaneous lupus erythematosus (SCLE), and secondary syphilis.

Continue to: Guttate psoriasis

Guttate psoriasis would not typically progress during treatment with adalimumab, although tumor necrosis factor (TNF) inhibitors have been associated with worsening psoriasis. Guttate psoriasis manifests with small, pink to red, scaly raindrop-shaped patches over the trunk and extremities.

Pityriasis rosea, a rash that resembles branches of a Christmas tree, was strongly considered given the appearance of the lesions on the patient’s back. It commonly manifests as round to oval lesions with a subtle advancing border and central fine scaling, similar in shape and color to the lesions seen in tinea corporis.

SCLE has been associated with use of TNF inhibitors, but our patient had no other lupus-like symptoms, such as fatigue, fever, headaches, or joint pain. SCLE lesions are often annular with raised pink to red borders similar in appearance to tinea corporis.

Secondary syphilis was ruled out in this patient because she had a negative rapid plasma reagin test. Secondary syphilis most commonly manifests with diffuse, nonpruritic pink to red-brown lesions on the palms and soles of patients. Patients often have prodromal symptoms that include fever, weight loss, myalgias, headache, and sore throat.

Terbinafine, Yes, but for how long?

Historically, terbinafine has been prescribed at 250 mg once daily for 2 weeks for extensive tinea corporis. However, recent studies in India suggest that terbinafine should be dosed at 250 mg twice daily, with longer durations of treatment, due to resistance.⁵ In the United States, it is reasonable to prescribe oral terbinafine 250 mg once daily for 4 weeks and then re-evaluate the patient in a case of extensive tinea corporis.

Other oral antifungals that can effectively treat extensive tinea corporis include itraconazole, fluconazole, and griseofulvin.¹ Itraconazole and terbinafine are equally effective and safe in the treatment of tinea corporis, although itraconazole is significantly more expensive.⁶ Furthermore, a recent study found that combination therapy with oral terbinafine and itraconazole is as safe as monotherapy and is an option when terbinafine resistance is suspected.⁷

Our patient was initially started on oral terbinafine 250 mg/d. After the first dose, the patient requested a change in medication because there was no improvement in the rash. The patient was then prescribed oral fluconazole 300 mg daily and the tinea cleared after 2 months of daily therapy. (We surmise the treatment course may have been prolonged due to the possible immunosuppressant effects of adalimumab.) At the completion of treatment for the tinea corporis, the patient was restarted on adalimumab 40 mg biweekly for her psoriasis. 

A 24-YEAR-OLD WOMAN with a history of guttate psoriasis, for which she was taking adalimumab, presented with a 2-week history of diffuse papules and plaques on her neck, back, torso, and upper and lower extremities (FIGURE 1). She said that the lesions were pruritic and seemed similar to those that erupted during past outbreaks of psoriasis—although they were more numerous and progressive. So, the patient (a nurse) decided to take her biweekly dose (40 mg) of adalimumab 1 week early. After administration, the rash significantly worsened, spreading to the rest of her trunk and extremities.

Physical exam was notable for multiple erythematous papules and plaques with central clearing and light peripheral scaling on both arms and legs, as well as her chest and back. The patient also indicated she’d adopted a stray cat 2 weeks prior. Given the patient’s pet exposure and the annular nature of the lesions, a potassium hydroxide (KOH) preparation was done.

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

The KOH preparation was positive for hyphae in 4 separate sites (trunk, left arm, left leg, and left neck), confirming the diagnosis of severe extensive tinea corporis (FIGURE 2).

Dermatophyte (tinea) infections are caused by fungi that invade and reproduce in the skin, hair, and nails. Dermatophytes, which include the genera Trichophyton, Microsporum, and Epidermophyton, are the most common cause of superficial mycotic infections. As of 2016, the worldwide prevalence of superficial mycotic infections was 20% to 25%.¹ Tinea corporis can result from contact with people, animals, or soil. Infections resulting from animal-to-human contact are often transmitted by domestic animals. In this case, the patient’s exposure was from her new cat.

Tinea corporis classically manifests as pruritic, erythematous patches or plaques with central clearing, giving it an annular appearance. The response to a tinea infection depends on the immune system of the host and can range in severity from superficial to severe.² There are 2 forms of severe dermatophytosis: invasive, which involves localized perifollicular sites or deep dermatophytosis, and extensive, which is confined to the stratum corneum but results in numerous lesions.³

The diagnosis of tinea corporis is commonly confirmed using direct microscopic examination with 10% to 20% KOH preparation, which will show branching and septate hyphal filaments.⁴

Several conditions with annular lesions comprise the differential

The findings of pruritic annular erythematous lesions on the patient’s neck, chest, trunk, and bilateral extremities led the patient to suspect this was a worsening case of her guttate psoriasis. Other possible diagnoses included pityriasis rosea, subacute cutaneous lupus erythematosus (SCLE), and secondary syphilis.

Continue to: Guttate psoriasis

Guttate psoriasis would not typically progress during treatment with adalimumab, although tumor necrosis factor (TNF) inhibitors have been associated with worsening psoriasis. Guttate psoriasis manifests with small, pink to red, scaly raindrop-shaped patches over the trunk and extremities.

Pityriasis rosea, a rash that resembles branches of a Christmas tree, was strongly considered given the appearance of the lesions on the patient’s back. It commonly manifests as round to oval lesions with a subtle advancing border and central fine scaling, similar in shape and color to the lesions seen in tinea corporis.

SCLE has been associated with use of TNF inhibitors, but our patient had no other lupus-like symptoms, such as fatigue, fever, headaches, or joint pain. SCLE lesions are often annular with raised pink to red borders similar in appearance to tinea corporis.

Secondary syphilis was ruled out in this patient because she had a negative rapid plasma reagin test. Secondary syphilis most commonly manifests with diffuse, nonpruritic pink to red-brown lesions on the palms and soles of patients. Patients often have prodromal symptoms that include fever, weight loss, myalgias, headache, and sore throat.

Terbinafine, Yes, but for how long?

Historically, terbinafine has been prescribed at 250 mg once daily for 2 weeks for extensive tinea corporis. However, recent studies in India suggest that terbinafine should be dosed at 250 mg twice daily, with longer durations of treatment, due to resistance.⁵ In the United States, it is reasonable to prescribe oral terbinafine 250 mg once daily for 4 weeks and then re-evaluate the patient in a case of extensive tinea corporis.

Other oral antifungals that can effectively treat extensive tinea corporis include itraconazole, fluconazole, and griseofulvin.¹ Itraconazole and terbinafine are equally effective and safe in the treatment of tinea corporis, although itraconazole is significantly more expensive.⁶ Furthermore, a recent study found that combination therapy with oral terbinafine and itraconazole is as safe as monotherapy and is an option when terbinafine resistance is suspected.⁷

Our patient was initially started on oral terbinafine 250 mg/d. After the first dose, the patient requested a change in medication because there was no improvement in the rash. The patient was then prescribed oral fluconazole 300 mg daily and the tinea cleared after 2 months of daily therapy. (We surmise the treatment course may have been prolonged due to the possible immunosuppressant effects of adalimumab.) At the completion of treatment for the tinea corporis, the patient was restarted on adalimumab 40 mg biweekly for her psoriasis. 

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

THE CASE

A 52-year-old man requested medicine to help him with erectile dysfunction. After obtaining a medical history and performing a physical exam, the family physician (FP) asked for more details about the patient’s situation. He reported that his wife, who had recently seen the same FP for counseling related to her frustrations with her husband, was uninterested in sex. He then added that he was having an affair with a 32-year-old female co-worker and wanted to improve his sexual function.

He admitted to feeling guilty about this situation and was conflicted about whether to end the affair. He also stated that since the affair, his insomnia had worsened, he was drinking more alcohol, and he was having migraine headaches. As the FP for both patients, and with the knowledge that the wife was worried about possible infidelity, the physician felt some level of conflict about the situation. The following is a discussion of the issues that this patient encounter raised.

DISCUSSION

Issues related to infidelity are common to both men and women. They are also common in same-sex relationships; in general, however, lesbian couples have fewer outside partners, whereas gay men are more likely to seek variety by having multiple partners.¹

It is widely understood that successfully committed couples spend quality time together, emphasize each other’s strengths, show respect, accept influence, and nurture their friendship. However, many couples experience infidelity at some time in the course of their marriage. It is difficult to put an exact estimate on rates of infidelity due to problems with research methodology, inaccurate reporting, and a lack of agreement on a definition for infidelity.² General categories of infidelity include emotional only, sexual only, and combined sexual and emotional infidelity.^3,4 In terms of sexual infidelity, one study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.⁵ However, other studies suggest that women are closing the “sexual infidelity” gap and engaging in sexual affairs at a similar rate to men.⁶ There are websites that, in fact, have made it easier for married individuals to engage in affairs.

Reasons for infidelity. Men and women often have different motives in engaging in infidelity. In general, men’s motivations are more often related to sexual dissatisfaction and women’s to emotional dissatisfaction.^7,8 However, infidelity may not always be the result of marital unhappiness.

Some studies suggest that the presence of opportunity may override the positive aspects of a relationship.⁹ Opportunity is heightened in the work environment, as reflected by the finding that 50% of infidelity occurs in the office.¹⁰ Research suggests that all relationships may be vulnerable to infidelity if the right opportunities present themselves.¹¹

In general, health care providers are encouraged to use caution in generalizing about infidelity, as the subject is extremely complex, nuanced, and difficult to measure with exactitude.¹²

Continue to: The impact of infidelity

The impact of infidelity on couples varies due to factors such as the pre-morbid health of the marriage,¹³ the depth of involvement with the affair partner,¹⁴ and pre-­existing attitudes about infidelity.¹³

Infidelity is a common cause of divorce in America. However, in a sample, Schneider et al¹⁵ found that despite initial threats to leave the marriage after infidelity, less than one-quarter of partners divorced. Other studies have found that disclosure of the infidelity and a commitment to work on the marriage may be an essential component of healing.¹⁶

One study found that 25% of married men and 15% of married women admitted to having had extramarital sex at least once during their relationship.

Emotionally focused couples therapy, with its emphasis on attachment and bonding, may hold promise for helping couples successfully work through the trauma brought on by extramarital relationships.¹⁷ Psychologist and infidelity researcher Shirley Glass found that of the two-thirds of couples who chose to stay together after an affair, 80% of them reported a better marriage after treatment.¹¹

Initial steps to take, and questions to ask

Both male and female patients need to feel comfortable surfacing sexual concerns with their clinicians. In this case, the concerns of the husband are interwoven with broader marital issues, which are the source of emotional and psychosomatic distress. His decision regarding his affair carried with it potentially life-altering consequences for his wife, 3 children, and affair partner and her family. It also raised ethical issues for the FP, who was providing care to both the husband and the wife. Appropriate care requires that a physician in this situation

• demonstrate a nonjudgmental approach
• clarify personal ethics in response to patient behaviors
• maintain confidentiality
• apply an ethical framework to resolve value dilemmas
• avoid actions that would be harmful to patients.

Interviewing can help to elicit information that may be clarifying not only to the physician but also to the patient. When interviewing a patient such as the one in this case, it would be wise to ask:

• How long has the affair been going on?
• Why is the patient engaging in the affair?
• Is abuse (emotional or physical) a factor in the marriage?
• Does the patient still have feelings for their spouse? Does the patient want to work on the marriage?
• Has the patient talked to a friend or therapist about the situation?
• Would the patient be willing to talk to a therapist?

Continue to: Ethical and legal considerations

Some therapists espouse the view that being “neutral” in the presence of an affair is as much a value judgment as taking one side or the other. In the presence of emotional or physical abuse, it might indeed be best to support a marital separation. However, in other situations when there are young children involved and the patient is undecided about what to do, the FP can discuss the pros and cons of working on a marriage that suffers from more treatable types of disrepair (ie, stress, disconnection, repetitive arguments).

Provision of care. If the patient is unwilling to end the affair, the physician needs to decide whether they feel ethically at ease with prescribing sexually enhancing performance medication, given that the patient’s wife is also a patient. A physician in this situation might feel that they are betraying the wife by providing such medications to the husband. In such cases, it might be appropriate to refer the husband to a colleague.

In all cases of infidelity, however, it is wise to discuss safe-sex practices in order to limit the risk of transmitting a sexually transmitted infection (STI) to the spouse (or affair partner) and offer testing for STIs.

Confidentiality. Despite feelings the physician might have about betraying the wife’s trust by providing the performance-enhancing medicine to the husband, there is very little justification for revealing the affair to the wife. In general, confidentiality can only be broken if there is a high level of imminent danger associated with nondisclosure. The physician needs to realize the serious legal implications of breaking confidentiality in this situation, as such disclosure may prompt the initiation of divorce proceedings.

Real-world recommendations

Check your own biases. Infidelity can trigger a whole host of emotional reactions in physicians based on their own personal and professional history. It is important to be aware of such emotions and if sufficiently triggered, discuss the case with a colleague.

Continue to: Encourage bibliotherapy and marriage therapy

Encourage bibliotherapy and marriage therapy. The conversation might go something like this:

“I would recommend you do some reading about infidelity. If you are interested in working on your marriage, you might want to consider a couples counselor who can help you. Research shows that while such counseling can help couples work through infidelity, disclosure needs to occur as part of that process. Research also indicates that about two-thirds of marriages stay together after the revelation of an affair and that such couples can experience healing if they commit to a therapeutic process. If you are unsure how you want to proceed, it might be helpful for you to explore your situation with an individual therapist. What would you like to do next?”

There are also written resources that the patient might find helpful; see “3 bibliotherapy resources for infidelity” for recommendations.

Referral to an individual or marriage counselor is warranted if the patient wants to work through the issues alone or with their partner. Disclosure of infidelity may not always be necessary for successful reconciliation if the affair has ended. A marriage therapist to whom you refer needs to be competent in working with infidelity.

Our patient. At the completion of the initial consultation—and after a discussion focused on the issues described, including encouragement to seek counseling—the FP acceded to the patient’s request for sexual performance-enhancing medication.

Continue to: The patient returned a few months...

The patient returned a few months later. His wife had found texts between him and his affair partner and told the patient that they had to enter into couples therapy or she was going to file for divorce. The patient told his physician that he had ended the extramarital relationship and was working on his marriage with a qualified marriage therapist; however, he felt lingering feelings of loss, discomfort in the workplace, and confusion about his choices. The physician was supportive and encouraged him to share these feelings, if possible, with an individual therapist or to find a friend who could listen while being supportive of his marriage. The physician also offered his services as a sounding board.

A year later, the patient had found another job and was still working on his marriage.

THE TAKEAWAY

This case underscores the importance of some basic health care tenets. It reminds us that maintaining patient confidentiality is paramount, and that nonjudgmental interviewing can help us to help our patients navigate challenging situations. The particulars of this case also highlight the importance of referring patients out for individual or marriage counseling and making a referral to a colleague when a situation makes us feel as if we are betraying a patient’s trust.

CORRESPONDENCE
David C. Slawson, MD, 2001 Vail Avenue, Suite 400B, Mercy Medical Plaza, Charlotte, NC 28207; [email protected]

Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.

“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”

Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.

This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.

“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.

Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.

The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.

Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.

The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.

But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.

Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.

“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”

Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”

How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.

“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”

If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”

If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”

The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.

Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.

It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”

Dr. Greene and Dr. Hantel reported no relevant disclosures.

Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.

“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”

Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.

This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.

“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.

Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.

The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.

Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.

The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.

But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.

Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.

“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”

Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”

How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.

“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”

If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”

If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”

The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.

Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.

It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”

Dr. Greene and Dr. Hantel reported no relevant disclosures.

Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.

“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”

Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.

This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.

“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.

Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.

The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.

Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.

The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.

But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.

Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.

“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”

Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”

How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.

“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”

If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”

If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”

The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.

Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.

It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”

Dr. Greene and Dr. Hantel reported no relevant disclosures.

In April 2022, the US Preventive Services Task Force (USPSTF) issued new recommendations for the use of aspirin to prevent cardiovascular disease (CVD).¹ These recommendations differ markedly from those issued in 2016.

First, for individuals ages 40 through 59 years who have a ≥ 10% 10-year risk of CVD, the decision to initiate low-dose aspirin to prevent CVD is selective. This is in contrast to the 2016 recommendation that advised offering aspirin to any individual ages 50 to 59 whose 10-year risk of CVD was ≥ 10% and whose life expectancy was at least 10 years (TABLE).

Second, according to the new recommendations, individuals who are ages 60 years and older should not initiate low-dose aspirin for the primary prevention of CVD. Previously, selected individuals ages 60 to 69 could be advised to take low-dose aspirin.

The 2016 recommendations also considered the potential benefit of aspirin for preventing colorectal cancer. The 2022 recommendations are silent on this topic, because the USPSTF now concludes that the evidence is insufficient to form an opinion about it.

Important details to keep in mind

These new recommendations pertain to those without signs or symptoms of CVD or known CVD. They do not apply to the use of aspirin for harm reduction or tertiary prevention in those with known CVD. Moreover, the recommendations address the initiation of aspirin at the suggested dose of 81 mg/d, not the continuation of it by those already using it (more on this later). The tool recommended for calculating 10-year CVD risk is the one developed by the American College of Cardiology (ACC) and the American Heart Association (AHA) (www.cvriskcalculator.com).

An ongoing controversy. Daily low-dose aspirin for the prevention of CVD has been controversial for decades. The TABLE shows how USPSTF recommendations on this topic have changed from 2009 to the present. In 2009, the recommendations were primarily based on 2 studies; today, they are based on 13 studies and a microsimulation to estimate the benefits and harms of aspirin prophylaxis at different patient ages.² This increase in the quantity of the evidence, as well as the elevation in quality, has led to much more nuanced and conservative recommendations. These new recommendations from the USPSTF align much more closely with those of the ACC and the AHA, differing only on the upper age limit at which aspirin initiation should be discouraged (60 years for the USPSTF, 70 for ACC/AHA).

Advise aspirin use selectively per the USPSTF recommendations

Several issues must be addressed when considering daily aspirin use for those ages 40 through 59 years (C recommendation; see TABLE for grade definitions):

• Risk of bleeding is elevated with past or current peptic ulcer disease, diabetes, smoking, high blood pressure, and the use of anti-inflammatory medications, steroids, and anticoagulants.
• The harms from bleeding complications tend to occur early in the use of aspirin and can include gastrointestinal bleeding, intracranial bleeding, and hemorrhagic stroke.
• The higher the 10-year CVD risk, the greater the benefit from low-dose aspirin.
• Benefits of aspirin for the prevention of CVD increase with the number of years of use.
• If an individual has been taking low-dose aspirin without complications, a reasonable age to discontinue its use is 75 years because little incremental benefit occurs with use after that age.

Continue to: More on low-dose aspirin benefits and harms

More on low-dose aspirin benefits and harms. What exactly is the absolute benefit and harm from daily low-dose aspirin use for primary prevention of CVD? As one might expect, it varies by age. Researchers used a microsimulation model to examine updated clinical data from systematic reviews. Looking at life years gained, the largest benefit was in men with a 10-year CVD risk of 20% and aspirin initiated between the ages of 40 and 49.³ This resulted in 52.4 lifetime years gained per 1000 people.³ The results from a meta-analysis of 11 studies, published in the evidence report, found an absolute reduction in major CVD events of 0.4% (number needed to treat = 250) and an absolute increase in major bleeds of 0.5% (number needed to harm = 200).² There was no reduction found for CVD-related or all-cause deaths.

One reason for the increased caution on using aspirin as primary prevention for CVD is the role that statins now play in reducing CVD risk, a factor not accounted for in the studies assessed. It is unknown if the addition of aspirin to statins is beneficial. Remember that the USPSTF recommends the use of a low- to moderate-dose statin in those ages 40 to 75 years if they have one or more CVD risk factors and a 10-year CVD risk ≥ 10%.⁴

How aspirin use might change. The use of aspirin for CVD prevention is widespread. One analysis estimates that one-third of those ages 50 years and older are using aspirin for CVD prevention, including 45% of those older than 75.⁵ If the recommendations from the USPSTF are widely adopted, there could be a gradual decrease in aspirin use for primary prevention with little or no effect on overall population health. Other interventions such as smoking prevention, weight reduction, high blood pressure control, and targeted use of statins—if more widely used—would contribute to the downward trend in CVD deaths that has occurred over the past several decades, with fewer complications caused by regular aspirin use.

Take-home message

Follow these steps when caring for adults ages 40 years and older who do not have known CVD:

1. Assess their 10-year CVD risk using the ACC/AHA tool. If the risk is ≥ 10%:

• Discuss the use of a low- or ­moderate-dose statin if they are age 75 years or younger.
• Discuss the potential for benefit and harm of low-dose aspirin if they are between the ages of 40 and 59 years.
• Mention to those taking daily low-dose aspirin that it has low benefit if continued after age 75.

2. Perform these interventions:

• Screen for hypertension and high cholesterol.
• Screen for type 2 diabetes and pre-diabetes in patients up to age 70 years who are overweight or obese.
• Ask about smoking.
• Measure body mass index.
• Offer preventive interventions when any of these CVD risks are found.

In April 2022, the US Preventive Services Task Force (USPSTF) issued new recommendations for the use of aspirin to prevent cardiovascular disease (CVD).¹ These recommendations differ markedly from those issued in 2016.

First, for individuals ages 40 through 59 years who have a ≥ 10% 10-year risk of CVD, the decision to initiate low-dose aspirin to prevent CVD is selective. This is in contrast to the 2016 recommendation that advised offering aspirin to any individual ages 50 to 59 whose 10-year risk of CVD was ≥ 10% and whose life expectancy was at least 10 years (TABLE).

Second, according to the new recommendations, individuals who are ages 60 years and older should not initiate low-dose aspirin for the primary prevention of CVD. Previously, selected individuals ages 60 to 69 could be advised to take low-dose aspirin.

The 2016 recommendations also considered the potential benefit of aspirin for preventing colorectal cancer. The 2022 recommendations are silent on this topic, because the USPSTF now concludes that the evidence is insufficient to form an opinion about it.

Important details to keep in mind

These new recommendations pertain to those without signs or symptoms of CVD or known CVD. They do not apply to the use of aspirin for harm reduction or tertiary prevention in those with known CVD. Moreover, the recommendations address the initiation of aspirin at the suggested dose of 81 mg/d, not the continuation of it by those already using it (more on this later). The tool recommended for calculating 10-year CVD risk is the one developed by the American College of Cardiology (ACC) and the American Heart Association (AHA) (www.cvriskcalculator.com).

An ongoing controversy. Daily low-dose aspirin for the prevention of CVD has been controversial for decades. The TABLE shows how USPSTF recommendations on this topic have changed from 2009 to the present. In 2009, the recommendations were primarily based on 2 studies; today, they are based on 13 studies and a microsimulation to estimate the benefits and harms of aspirin prophylaxis at different patient ages.² This increase in the quantity of the evidence, as well as the elevation in quality, has led to much more nuanced and conservative recommendations. These new recommendations from the USPSTF align much more closely with those of the ACC and the AHA, differing only on the upper age limit at which aspirin initiation should be discouraged (60 years for the USPSTF, 70 for ACC/AHA).

Advise aspirin use selectively per the USPSTF recommendations

Several issues must be addressed when considering daily aspirin use for those ages 40 through 59 years (C recommendation; see TABLE for grade definitions):

• Risk of bleeding is elevated with past or current peptic ulcer disease, diabetes, smoking, high blood pressure, and the use of anti-inflammatory medications, steroids, and anticoagulants.
• The harms from bleeding complications tend to occur early in the use of aspirin and can include gastrointestinal bleeding, intracranial bleeding, and hemorrhagic stroke.
• The higher the 10-year CVD risk, the greater the benefit from low-dose aspirin.
• Benefits of aspirin for the prevention of CVD increase with the number of years of use.
• If an individual has been taking low-dose aspirin without complications, a reasonable age to discontinue its use is 75 years because little incremental benefit occurs with use after that age.

Continue to: More on low-dose aspirin benefits and harms

More on low-dose aspirin benefits and harms. What exactly is the absolute benefit and harm from daily low-dose aspirin use for primary prevention of CVD? As one might expect, it varies by age. Researchers used a microsimulation model to examine updated clinical data from systematic reviews. Looking at life years gained, the largest benefit was in men with a 10-year CVD risk of 20% and aspirin initiated between the ages of 40 and 49.³ This resulted in 52.4 lifetime years gained per 1000 people.³ The results from a meta-analysis of 11 studies, published in the evidence report, found an absolute reduction in major CVD events of 0.4% (number needed to treat = 250) and an absolute increase in major bleeds of 0.5% (number needed to harm = 200).² There was no reduction found for CVD-related or all-cause deaths.

One reason for the increased caution on using aspirin as primary prevention for CVD is the role that statins now play in reducing CVD risk, a factor not accounted for in the studies assessed. It is unknown if the addition of aspirin to statins is beneficial. Remember that the USPSTF recommends the use of a low- to moderate-dose statin in those ages 40 to 75 years if they have one or more CVD risk factors and a 10-year CVD risk ≥ 10%.⁴

How aspirin use might change. The use of aspirin for CVD prevention is widespread. One analysis estimates that one-third of those ages 50 years and older are using aspirin for CVD prevention, including 45% of those older than 75.⁵ If the recommendations from the USPSTF are widely adopted, there could be a gradual decrease in aspirin use for primary prevention with little or no effect on overall population health. Other interventions such as smoking prevention, weight reduction, high blood pressure control, and targeted use of statins—if more widely used—would contribute to the downward trend in CVD deaths that has occurred over the past several decades, with fewer complications caused by regular aspirin use.

Take-home message

Follow these steps when caring for adults ages 40 years and older who do not have known CVD:

1. Assess their 10-year CVD risk using the ACC/AHA tool. If the risk is ≥ 10%:

• Discuss the use of a low- or ­moderate-dose statin if they are age 75 years or younger.
• Discuss the potential for benefit and harm of low-dose aspirin if they are between the ages of 40 and 59 years.
• Mention to those taking daily low-dose aspirin that it has low benefit if continued after age 75.

2. Perform these interventions:

• Screen for hypertension and high cholesterol.
• Screen for type 2 diabetes and pre-diabetes in patients up to age 70 years who are overweight or obese.
• Ask about smoking.
• Measure body mass index.
• Offer preventive interventions when any of these CVD risks are found.

In April 2022, the US Preventive Services Task Force (USPSTF) issued new recommendations for the use of aspirin to prevent cardiovascular disease (CVD).¹ These recommendations differ markedly from those issued in 2016.

First, for individuals ages 40 through 59 years who have a ≥ 10% 10-year risk of CVD, the decision to initiate low-dose aspirin to prevent CVD is selective. This is in contrast to the 2016 recommendation that advised offering aspirin to any individual ages 50 to 59 whose 10-year risk of CVD was ≥ 10% and whose life expectancy was at least 10 years (TABLE).

Second, according to the new recommendations, individuals who are ages 60 years and older should not initiate low-dose aspirin for the primary prevention of CVD. Previously, selected individuals ages 60 to 69 could be advised to take low-dose aspirin.

The 2016 recommendations also considered the potential benefit of aspirin for preventing colorectal cancer. The 2022 recommendations are silent on this topic, because the USPSTF now concludes that the evidence is insufficient to form an opinion about it.

Important details to keep in mind

These new recommendations pertain to those without signs or symptoms of CVD or known CVD. They do not apply to the use of aspirin for harm reduction or tertiary prevention in those with known CVD. Moreover, the recommendations address the initiation of aspirin at the suggested dose of 81 mg/d, not the continuation of it by those already using it (more on this later). The tool recommended for calculating 10-year CVD risk is the one developed by the American College of Cardiology (ACC) and the American Heart Association (AHA) (www.cvriskcalculator.com).

An ongoing controversy. Daily low-dose aspirin for the prevention of CVD has been controversial for decades. The TABLE shows how USPSTF recommendations on this topic have changed from 2009 to the present. In 2009, the recommendations were primarily based on 2 studies; today, they are based on 13 studies and a microsimulation to estimate the benefits and harms of aspirin prophylaxis at different patient ages.² This increase in the quantity of the evidence, as well as the elevation in quality, has led to much more nuanced and conservative recommendations. These new recommendations from the USPSTF align much more closely with those of the ACC and the AHA, differing only on the upper age limit at which aspirin initiation should be discouraged (60 years for the USPSTF, 70 for ACC/AHA).

Advise aspirin use selectively per the USPSTF recommendations

Several issues must be addressed when considering daily aspirin use for those ages 40 through 59 years (C recommendation; see TABLE for grade definitions):

• Risk of bleeding is elevated with past or current peptic ulcer disease, diabetes, smoking, high blood pressure, and the use of anti-inflammatory medications, steroids, and anticoagulants.
• The harms from bleeding complications tend to occur early in the use of aspirin and can include gastrointestinal bleeding, intracranial bleeding, and hemorrhagic stroke.
• The higher the 10-year CVD risk, the greater the benefit from low-dose aspirin.
• Benefits of aspirin for the prevention of CVD increase with the number of years of use.
• If an individual has been taking low-dose aspirin without complications, a reasonable age to discontinue its use is 75 years because little incremental benefit occurs with use after that age.

Continue to: More on low-dose aspirin benefits and harms

More on low-dose aspirin benefits and harms. What exactly is the absolute benefit and harm from daily low-dose aspirin use for primary prevention of CVD? As one might expect, it varies by age. Researchers used a microsimulation model to examine updated clinical data from systematic reviews. Looking at life years gained, the largest benefit was in men with a 10-year CVD risk of 20% and aspirin initiated between the ages of 40 and 49.³ This resulted in 52.4 lifetime years gained per 1000 people.³ The results from a meta-analysis of 11 studies, published in the evidence report, found an absolute reduction in major CVD events of 0.4% (number needed to treat = 250) and an absolute increase in major bleeds of 0.5% (number needed to harm = 200).² There was no reduction found for CVD-related or all-cause deaths.

One reason for the increased caution on using aspirin as primary prevention for CVD is the role that statins now play in reducing CVD risk, a factor not accounted for in the studies assessed. It is unknown if the addition of aspirin to statins is beneficial. Remember that the USPSTF recommends the use of a low- to moderate-dose statin in those ages 40 to 75 years if they have one or more CVD risk factors and a 10-year CVD risk ≥ 10%.⁴

How aspirin use might change. The use of aspirin for CVD prevention is widespread. One analysis estimates that one-third of those ages 50 years and older are using aspirin for CVD prevention, including 45% of those older than 75.⁵ If the recommendations from the USPSTF are widely adopted, there could be a gradual decrease in aspirin use for primary prevention with little or no effect on overall population health. Other interventions such as smoking prevention, weight reduction, high blood pressure control, and targeted use of statins—if more widely used—would contribute to the downward trend in CVD deaths that has occurred over the past several decades, with fewer complications caused by regular aspirin use.

Take-home message

Follow these steps when caring for adults ages 40 years and older who do not have known CVD:

1. Assess their 10-year CVD risk using the ACC/AHA tool. If the risk is ≥ 10%:

• Discuss the use of a low- or ­moderate-dose statin if they are age 75 years or younger.
• Discuss the potential for benefit and harm of low-dose aspirin if they are between the ages of 40 and 59 years.
• Mention to those taking daily low-dose aspirin that it has low benefit if continued after age 75.

2. Perform these interventions:

• Screen for hypertension and high cholesterol.
• Screen for type 2 diabetes and pre-diabetes in patients up to age 70 years who are overweight or obese.
• Ask about smoking.
• Measure body mass index.
• Offer preventive interventions when any of these CVD risks are found.

The group of disorders known as sickle cell disease (SCD) is one of the more common genetic hemoglobinopathies. Homozygous production of the S variant of hemoglobin (Hb) in red blood cells (RBCs) results in profound sickling under conditions of physiologic stress, a condition known as Hb SS disease. People with Hb SS disease are at risk of chronic hemolytic anemia, tissue ischemia that causes vaso-occlusive pain syndrome, and other vaso-occlusive complications.¹ They also experience a > 20-year reduction in life expectancy, compared to age-matched controls; onset of risk of early death is usually after age 25 years.

People with heterozygous expression of the Hb S variant—that is, from one parent, and expression of Hb A from the other parent—are said to have sickle cell trait (SCT). They typically do not have symptoms of SCD, although they can experience vaso-occlusive pain under severe physiologic stress and suffer sudden death more often than age-matched controls. People who are heterozygous for Hb S but have another hemoglobinopathy (eg, sickle β⁰ thalassemia) might have milder SCD, with fewer symptoms, or might have severe sickle cell anemia (SCA).

Alleviating the harsh burden of illness. All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability; the same loss is true for their caregivers. Such loss, when combined with time spent in the health care system, can be catastrophic.^2,3 But this loss can be mitigated with access to regular, comprehensive health care that includes the steps described here to detect SCD early and reduce the likelihood of complications.^4,5

To begin, TABLE 1⁶ lists typical laboratory findings and classifications in patients who are homozygous or heterozygous for Hb S, and therefore experience more severe Hb SS disease or milder SCD, respectively.

Who should be screened for hemoglobinopathy?

Because of the presence of the fetal Hb (Hb F) in newborns and infants, clinical signs of Hb SS before age 2 months are uncommon. Neonatal clinical laboratory testing is necessary for prompt identification of Hb SS; universal screening is now required by all states (although parents can opt out by claiming a religious exemption). A positive test result requires confirmatory testing: most often, Hb electrophoresis or DNA testing.

All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability. But this loss can be mitigated with access to regular, comprehensive health care.

A confirmed positive homozygous (Hb SS) or heterozygous (Hb S) result is reported to the patient’s identified medical home for subsequent management. Thus, pediatric patients with SCD can be identified, and prophylactic treatment initiated, as early as possible. Later in the patient’s life, repeat screening for SCD and SCT is recommended at the initiation of pregnancy care⁷ and prior to the start of high-intensity physical training, as occurs in college and professional athletics and in certain branches of the military.⁸

Putting prevention into practice

Some of the recommendations we make to prevent complications of SCD are directed only at patients with severe disease—ie, those who have Hb SS SCD or sickle β⁰ thalassemia (SCA); the rest apply to all patients with SCD (TABLE 2^6,9). (For patients with SCT, follow guidelines as you would for patients who do not have SCD, unless otherwise noted.)

Continue to: In addition, keep in mind...

In addition, keep in mind that preventive recommendations made by the US Preventive Services Task Force (Exhibit 5 in the Expert Panel Report)⁶ apply to all patients with SCD and SCT.

Prevention of invasive pneumococcal disease

All patients with SCD are assumed to have lifelong splenic dysfunction that begins in childhood. This is particularly true for those with SCA. In the absence of vaccination, the lifetime incidence of pneumococcal bacteremia resulting in serious complications is as high as 16% in SCD.¹⁰ In multiple randomized clinical trials, prophylactic penicillin dosing has proved beneficial in these patients, demonstrating a decrease in the risk of (1) pneumococcal infection and (2) early death during the study period, with minimal adverse effects.⁵

Prophylactic penicillin dosing should be initiated during infancy in patients with SCA. From ages 3 months to 3 years, the dosage of penicillin V is 125 mg twice daily; from 3 to 5 years, 250 mg twice daily. After age 5 years, the decision to continue penicillin is individualized, with consideration of prior severe pneumococcal infection and general preventive health maintenance. Penicillin-allergic patients can be given erythromycin. All patients with SCD who have had surgical splenectomy should be placed on antibiotic prophylaxis (ie, penicillin as dosed above).⁵

The polyvalent pneumococcal vaccine has resulted in significant protection against invasive pneumococcal disease; mortality from pneumococcal disease among patients with SCD who are younger than 14 years has decreased dramatically since the vaccine was introduced.⁶ For all patients with SCD, the standard PCV13 series should be administered beginning at age 6 weeks. A 2-dose series of the PPSV23 vaccine, which includes more Streptococcus pneumoniae serotypes than the PCV13 vaccine, should be administered beginning at age 2 years or 8 weeks after completion of the PCV13 series, whichever comes first.

Prevention of flu, COVID-19, and other vaccine-preventable illness

Influenza. Beginning at age 6 months, all patients with SCD should receive inactivated influenza vaccine annually at the beginning of the influenza season. Avoid using the live attenuated vaccine (Flumist) because of an associated increased risk of severe or complicated infection.¹¹

Continue to: COVID-19, caused by severe...

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is especially problematic in patients with SCD¹²; infection causes mortality at a rate as high as 7%.⁵ The SARS-CoV-2 mRNA vaccine series is potentially lifesaving for these patients.¹² In addition, at times of high community prevalence, make an effort to minimize patients’ exposure to SARS-CoV-2, by providing telemedicine visits.

Follow the immunization schedule. Patients with SCD should receive all standard recommended vaccinations (ie, those recommended by the Advisory Committee on Immunization Practices.^a) Inactivated virus vaccines are preferred in SCD, when available. For patients who are behind on vaccinations, use a standard vaccine catch-up schedule.

Screening and prevention of complications such as stroke

Determining the risk of stroke. Patients with SCA who are not monitored have a 10% to 11% lifetime prevalence of stroke.^5,6,10 An abnormal transcranial Doppler (TCD) study (defined as a time-averaged mean maximum velocity ≥ 200 cm/s in the distal internal carotid artery or proximal middle cerebral artery) is predictive of a 40% risk of stroke in patients with SCA. With chronic transfusion therapy, a 92% reduction in the risk of stroke is achievable.¹⁰

All patients with SCA should undergo annual screening with TCD ultrasonography from ages 2 to 16 years.⁶ Those who have an abnormal TCD study should receive chronic transfusion therapy. Screening is not recommended for patients with SCD or SCT.

Other complications. Screen and manage as follows:

• Proteinuria. Left untreated, SCD can affect the kidneys and lead to renal failure. Annual screening for proteinuria is recommended beginning at age 10 years, with referral when the test is positive and reproducible.
• Lung disease and cardiovascular disease. Screening for progression of lung disease and for cardiovascular disease is not recommended in asymptomatic patients with SCD, except through the history.
• Blood pressure screening and management of hypertension are based on Joint National Committee (JNC 8) guidelines.¹³
• Screening for ocular complications by an eye care provider is recommended beginning at age 10 years.

TABLE 2^6,9 summarizes recommendations on the prevention and early detection of complications of SCD.

Continue to: Pregnancy planning

The Centers for Disease Control and Prevention recommends that a “reproductive life plan” be part of every person’s health journey (TABLE 2).^6,9 The plan is especially relevant for female patients who have a known heritable concern, such as SCD, in which a pregnancy is more likely to be complicated by growth restriction, preterm delivery, and fetal demise. These risks are reduced—but not eliminated—with intensive surveillance of the pregnancy. Pregnancy in patients with SCD is also more likely to be complicated by preeclampsia, venous thromboembolism, infection, and maternal death.

Other recommendations:

• Every patient with SCD should receive genetic counselling before conceiving, when possible.
• Pregnancy should be considered high risk in women who have SCD, and monitored as such.
• Women with SCD can use any method of contraception—none of which put them at increased risk of complications, compared to the general population. Rather, it is pregnancy that puts them at greater risk of morbidity and mortality in every age group.

Ambulatory management of acute complications

Vaso-occlusive pain crisis. The hallmark of SCD is the acute pain crisis. Almost all patients with SCD (and the occasional patient with SCT) will experience a pain crisis. In more affluent countries, management of an acute pain crisis almost always includes opioid analgesia.⁶

For the most part, pain crises manifest in a predictable pattern. Although patients with SCD might have acute pain, other causes of acute pain, such as an acute intra-abdominal process or (in older patients) a cardiac process, should be considered as well.

Prophylactic penicillin dosing has proved beneficial in patients with sickle cell disease, demonstrating a decrease in the risk of pneumococcal infection.

For patients having a vaso-occlusive pain crisis, achieving rapid analgesia is key to management. Ready availability of narcotics, at home or under observation, prevents subsequent hospitalization; nonsteroidal anti-inflammatory drugs can be used as adjuvant treatment in patients without contraindications.^5,6 An individualized treatment plan, including access to analgesia at an appropriate dosage, should be negotiated, and adhered to, by the patient and the care team.

Continue to: Rapid access to higher-level care...

Rapid access to higher-level care, including parenteral analgesia, is important if outpatient management is desired. In addition, escalation to a higher level of care should occur if there is hypoxia (or another reason to suspect acute chest syndrome [ACS; discussed in a bit]) or dehydration that requires parenteral therapy. Use of nondrug therapy, such as heat, should be encouraged. The care team should work with the patient’s school or employer to negotiate time away through the federal Family Medical Leave Act of 1993, or other means, because a pain crisis is not a planned event.

Fever. Because of the risk of serious infection as a consequence of functional asplenia, fever is particularly worrisome in patients with SCA and problematic in patients with SCD. The increased risk begins as the physiologic level of Hb F declines beginning at age 2 months.

ACS, characterized by a combination of respiratory symptoms or new infiltrates, often manifests initially with fever, and can progress rapidly to death if treatment is delayed. The initial signs and symptoms may be subtle; suspicion should remain high in any patient with respiratory symptoms who is newly hypoxic, even those who do not have fever. Osteomyelitis, another febrile illness, is also potentially life threatening if not treated promptly.

All patients with SCD whose body temperature is > 101.3 °F should be evaluated with appropriate clinical laboratory testing (complete blood count; inflammatory markers, such as C-reactive protein; basic chemistry parameters; and other tests as indicated, including serum lactate and urine culture), blood culture, and chest radiography. Empiric parenteral antibiotics are required until the patient is known to be nonbacteremic, regardless of vaccination status. Outpatient follow-up and even outpatient management with ceftriaxone can be offered in select circumstances (eg, if the patient so desires or is nontoxic, and if close follow-up can be assured).¹⁴ If ACS is a possibility based on symptoms or radiographic findings, outpatient management is not an option.

Anemia. Patients with SCA, and some with SCD, have an Hb level that is chronically, sometimes critically, low. A baseline Hb level should be established for a patient with SCD and then monitored periodically. A drop in the Hb level > 2 g/dL from baseline (or an initial Hb level of 6 g/dL if the baseline is unknown) constitutes acute anemia. Patients in whom anemia has been diagnosed should be emergently evaluated for acute splenic sequestration, an aplastic episode, a delayed hemolytic transfusion reaction, ACS, or infection, and should be treated appropriately.

Continue to: Simple transfusion can be used...

Simple transfusion can be used in an acute setting to restore and maintain Hb at a safe level. Iron overload and formation of RBC alloantigen are associated with multiple transfusions; once either of these conditions is established, subsequent transfusion therapy can be harmful. Care must be taken to prescribe transfusion appropriately; ­leukocyte-depleted RBCs should be used when available.

It is important to define specific goals of transfusion to optimize its use. Patients who have received multiple transfusions should have enhanced monitoring for bloodborne infection, such as hepatitis C virus. Acute aplastic crises are caused by parvovirus B19; when other members of the household who have SCD are present, they should be monitored for this viral infection with serial measurement of Hb and white blood cell count.⁶

Other acute problems. Should stroke, acute renal failure, priapism, or hepatobiliary complications develop, evaluate the patient rapidly and refer them to the appropriate care team for management.

Management of chronic complications

Chronic pain is a problem for many patients with SCD. The etiology of this symptom should be investigated fully because a vaso-occlusive crisis is characterized by acute pain. Avascular necrosis or ulcers due to chronic vaso-­occlusion should be managed definitively when possible. Adjuvant therapy for chronic pain, such as heat or massage, should be encouraged.

Administer the standard PCV13 series for all patients with sickle cell disease beginning at age 6 weeks.

In some patients, chronic pain without objective findings develops over time and becomes unresponsive to nonopioid pharmacotherapy. Such patients might require chronic opioid therapy, the need for which is dictated by the ability of the patient to perform their activities of daily living. For patients who require long-term daily narcotic drugs, best practices—obtaining informed consent, using registries and contracts, random drug testing, and providing naloxone [Narcan] for overdose emergency use—should be employed.¹⁵

Continue to: Chronic anemia

Chronic anemia can be managed with transfusion when elevating the Hb level is required (eg, preoperatively, to prevent stroke, to manage priapism). For some patients, ongoing transfusion is required; care should be taken to avoid iron overload and hemolysis due to antibody formation. Ongoing surveillance for these complications is required.⁶

Other chronic problems. Patients with SCD who develop avascular necrosis, vaso-occlusive ulcers, pulmonary hypertension, renal disease, recurrent priapism, or ophthalmologic complications should be co-­managed with a care team.⁶

Pharmacotherapy and SCA

A principal goal in the management of patients with SCA is prevention of vaso-­occlusive events, including ACS and acute pain crises.

Hydroxyurea, a key component of SCA treatment, is a ribonucleotide reductase inhibitor that increases the level of Hb F, thus reducing the absolute number of symptomatic vaso-occlusive events and increasing arterial blood flow. It is most useful for patients who have multiple crises. The drug prolongs survival and reduces the need for transfusion and hospitalization.^4,5

Hydroxyurea can be started in patients at age 9 months; blood testing should be performed at the start of treatment and the dosage titrated based on blood counts. Initial blood work includes:

• Hb level;
• Hb electrophoresis with the quantitative percentage of Hb F;
• complete blood count with differential and reticulocyte counts;
• chemistry profile (electrolytes, lactate dehydrogenase, total protein, albumin, total bilirubin);
• liver function tests (aspartate aminotransferase, alanine aminotransferase);
• measurement of renal function (blood urea nitrogen, creatinine);
• serum vitamin B₁₂ and folate;
• serum iron, total iron-binding capacity, and ferritin;
• hepatitis B, hepatitis C, and parvovirus B19 antigen; and
• serologic testing for HIV.

Continue to: Testing should also...

Testing should also include a pregnancy test for postmenarchal females because hydroxyurea is in US Food and Drug Administration pregnancy risk category X.

Avoid hydroxyurea in lactating women; dose the drug renally in the setting of renal disease. Because hydroxyurea has a high rate of serious adverse effects and drug-drug interactions, it should be offered in conjunction with an individualized care plan.

Hydroxyurea can also be offered to patients with other forms of SCD who have recurrent vaso-occlusive symptoms.

Two newer medications improve oxygen delivery in patients with SCD. Voxelotor, approved in 2019, works to reduce Hb S polymerization by binding to the alpha chain of Hb S and, subsequently, increasing its oxygen affinity. The drug is generally well tolerated and can be used in patients with SCD who are ≥ 12 years.¹⁶ Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule located on endothelial cells and activated platelets. The efficacy of crizanlizumab was demonstrated in the SUSTAIN trial, in which it reduced vaso-occlusive pain in patients ≥ 16 years.¹⁷

All of these medications have a narrow toxic–therapeutic window. They should therefore be administered with the participation of a multidisciplinary care team.

Continue to: The need to coordinated, comprehensive care

Patients with SCD report how challenging their disease is. All patients with SCD are more likely than age-matched counterparts to experience loss, including workdays for disability, educational potential, workdays for caregivers of affected children, and time spent in the hospital or the emergency department.^4,5 These losses, with the concomitant stress associated with chronic illness and the struggle to manage recurrent pain crises and chronic complications, are often overwhelming.

SARS-CoV-2 infection causes mortality as high as 7% in patients with sickle cell disease; the mRNA vaccine series is potentially lifesaving for them.

Comprehensive care can, as we have illustrated in this discussion, mitigate these losses. Such care should include extensive education, genetic counseling, infection prevention, pain management, and implementation of evidence-based management guidelines.^3,4,6 Patients with SCD report that their illness outlook would be better with

• greater provider knowledge of SCD,
• destigmatization of narcotics for SCD vaso-occlusive pain management,
• optimal coordination among members of the health care team, and
• improved transportation for appointments.

Patients also report that barriers associated with the unique US health care financing system are often insurmountable. As patients with SCD live longer, improved care management should focus on reducing these barriers and enhancing their quality of life.^2,18,19

CORRESPONDENCE
Robert Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama College of Medicine, 1601 Center Street, 2N, Mobile, AL 36604; perkins@health. southalabama.edu

The group of disorders known as sickle cell disease (SCD) is one of the more common genetic hemoglobinopathies. Homozygous production of the S variant of hemoglobin (Hb) in red blood cells (RBCs) results in profound sickling under conditions of physiologic stress, a condition known as Hb SS disease. People with Hb SS disease are at risk of chronic hemolytic anemia, tissue ischemia that causes vaso-occlusive pain syndrome, and other vaso-occlusive complications.¹ They also experience a > 20-year reduction in life expectancy, compared to age-matched controls; onset of risk of early death is usually after age 25 years.

People with heterozygous expression of the Hb S variant—that is, from one parent, and expression of Hb A from the other parent—are said to have sickle cell trait (SCT). They typically do not have symptoms of SCD, although they can experience vaso-occlusive pain under severe physiologic stress and suffer sudden death more often than age-matched controls. People who are heterozygous for Hb S but have another hemoglobinopathy (eg, sickle β⁰ thalassemia) might have milder SCD, with fewer symptoms, or might have severe sickle cell anemia (SCA).

Alleviating the harsh burden of illness. All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability; the same loss is true for their caregivers. Such loss, when combined with time spent in the health care system, can be catastrophic.^2,3 But this loss can be mitigated with access to regular, comprehensive health care that includes the steps described here to detect SCD early and reduce the likelihood of complications.^4,5

To begin, TABLE 1⁶ lists typical laboratory findings and classifications in patients who are homozygous or heterozygous for Hb S, and therefore experience more severe Hb SS disease or milder SCD, respectively.

Who should be screened for hemoglobinopathy?

Because of the presence of the fetal Hb (Hb F) in newborns and infants, clinical signs of Hb SS before age 2 months are uncommon. Neonatal clinical laboratory testing is necessary for prompt identification of Hb SS; universal screening is now required by all states (although parents can opt out by claiming a religious exemption). A positive test result requires confirmatory testing: most often, Hb electrophoresis or DNA testing.

All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability. But this loss can be mitigated with access to regular, comprehensive health care.

A confirmed positive homozygous (Hb SS) or heterozygous (Hb S) result is reported to the patient’s identified medical home for subsequent management. Thus, pediatric patients with SCD can be identified, and prophylactic treatment initiated, as early as possible. Later in the patient’s life, repeat screening for SCD and SCT is recommended at the initiation of pregnancy care⁷ and prior to the start of high-intensity physical training, as occurs in college and professional athletics and in certain branches of the military.⁸

Putting prevention into practice

Some of the recommendations we make to prevent complications of SCD are directed only at patients with severe disease—ie, those who have Hb SS SCD or sickle β⁰ thalassemia (SCA); the rest apply to all patients with SCD (TABLE 2^6,9). (For patients with SCT, follow guidelines as you would for patients who do not have SCD, unless otherwise noted.)

Continue to: In addition, keep in mind...

In addition, keep in mind that preventive recommendations made by the US Preventive Services Task Force (Exhibit 5 in the Expert Panel Report)⁶ apply to all patients with SCD and SCT.

Prevention of invasive pneumococcal disease

All patients with SCD are assumed to have lifelong splenic dysfunction that begins in childhood. This is particularly true for those with SCA. In the absence of vaccination, the lifetime incidence of pneumococcal bacteremia resulting in serious complications is as high as 16% in SCD.¹⁰ In multiple randomized clinical trials, prophylactic penicillin dosing has proved beneficial in these patients, demonstrating a decrease in the risk of (1) pneumococcal infection and (2) early death during the study period, with minimal adverse effects.⁵

Prophylactic penicillin dosing should be initiated during infancy in patients with SCA. From ages 3 months to 3 years, the dosage of penicillin V is 125 mg twice daily; from 3 to 5 years, 250 mg twice daily. After age 5 years, the decision to continue penicillin is individualized, with consideration of prior severe pneumococcal infection and general preventive health maintenance. Penicillin-allergic patients can be given erythromycin. All patients with SCD who have had surgical splenectomy should be placed on antibiotic prophylaxis (ie, penicillin as dosed above).⁵

The polyvalent pneumococcal vaccine has resulted in significant protection against invasive pneumococcal disease; mortality from pneumococcal disease among patients with SCD who are younger than 14 years has decreased dramatically since the vaccine was introduced.⁶ For all patients with SCD, the standard PCV13 series should be administered beginning at age 6 weeks. A 2-dose series of the PPSV23 vaccine, which includes more Streptococcus pneumoniae serotypes than the PCV13 vaccine, should be administered beginning at age 2 years or 8 weeks after completion of the PCV13 series, whichever comes first.

Prevention of flu, COVID-19, and other vaccine-preventable illness

Influenza. Beginning at age 6 months, all patients with SCD should receive inactivated influenza vaccine annually at the beginning of the influenza season. Avoid using the live attenuated vaccine (Flumist) because of an associated increased risk of severe or complicated infection.¹¹

Continue to: COVID-19, caused by severe...

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is especially problematic in patients with SCD¹²; infection causes mortality at a rate as high as 7%.⁵ The SARS-CoV-2 mRNA vaccine series is potentially lifesaving for these patients.¹² In addition, at times of high community prevalence, make an effort to minimize patients’ exposure to SARS-CoV-2, by providing telemedicine visits.

Follow the immunization schedule. Patients with SCD should receive all standard recommended vaccinations (ie, those recommended by the Advisory Committee on Immunization Practices.^a) Inactivated virus vaccines are preferred in SCD, when available. For patients who are behind on vaccinations, use a standard vaccine catch-up schedule.

Screening and prevention of complications such as stroke

Determining the risk of stroke. Patients with SCA who are not monitored have a 10% to 11% lifetime prevalence of stroke.^5,6,10 An abnormal transcranial Doppler (TCD) study (defined as a time-averaged mean maximum velocity ≥ 200 cm/s in the distal internal carotid artery or proximal middle cerebral artery) is predictive of a 40% risk of stroke in patients with SCA. With chronic transfusion therapy, a 92% reduction in the risk of stroke is achievable.¹⁰

All patients with SCA should undergo annual screening with TCD ultrasonography from ages 2 to 16 years.⁶ Those who have an abnormal TCD study should receive chronic transfusion therapy. Screening is not recommended for patients with SCD or SCT.

Other complications. Screen and manage as follows:

• Proteinuria. Left untreated, SCD can affect the kidneys and lead to renal failure. Annual screening for proteinuria is recommended beginning at age 10 years, with referral when the test is positive and reproducible.
• Lung disease and cardiovascular disease. Screening for progression of lung disease and for cardiovascular disease is not recommended in asymptomatic patients with SCD, except through the history.
• Blood pressure screening and management of hypertension are based on Joint National Committee (JNC 8) guidelines.¹³
• Screening for ocular complications by an eye care provider is recommended beginning at age 10 years.

TABLE 2^6,9 summarizes recommendations on the prevention and early detection of complications of SCD.

Continue to: Pregnancy planning

The Centers for Disease Control and Prevention recommends that a “reproductive life plan” be part of every person’s health journey (TABLE 2).^6,9 The plan is especially relevant for female patients who have a known heritable concern, such as SCD, in which a pregnancy is more likely to be complicated by growth restriction, preterm delivery, and fetal demise. These risks are reduced—but not eliminated—with intensive surveillance of the pregnancy. Pregnancy in patients with SCD is also more likely to be complicated by preeclampsia, venous thromboembolism, infection, and maternal death.

Other recommendations:

• Every patient with SCD should receive genetic counselling before conceiving, when possible.
• Pregnancy should be considered high risk in women who have SCD, and monitored as such.
• Women with SCD can use any method of contraception—none of which put them at increased risk of complications, compared to the general population. Rather, it is pregnancy that puts them at greater risk of morbidity and mortality in every age group.

Ambulatory management of acute complications

Vaso-occlusive pain crisis. The hallmark of SCD is the acute pain crisis. Almost all patients with SCD (and the occasional patient with SCT) will experience a pain crisis. In more affluent countries, management of an acute pain crisis almost always includes opioid analgesia.⁶

For the most part, pain crises manifest in a predictable pattern. Although patients with SCD might have acute pain, other causes of acute pain, such as an acute intra-abdominal process or (in older patients) a cardiac process, should be considered as well.

Prophylactic penicillin dosing has proved beneficial in patients with sickle cell disease, demonstrating a decrease in the risk of pneumococcal infection.

For patients having a vaso-occlusive pain crisis, achieving rapid analgesia is key to management. Ready availability of narcotics, at home or under observation, prevents subsequent hospitalization; nonsteroidal anti-inflammatory drugs can be used as adjuvant treatment in patients without contraindications.^5,6 An individualized treatment plan, including access to analgesia at an appropriate dosage, should be negotiated, and adhered to, by the patient and the care team.

Continue to: Rapid access to higher-level care...

Rapid access to higher-level care, including parenteral analgesia, is important if outpatient management is desired. In addition, escalation to a higher level of care should occur if there is hypoxia (or another reason to suspect acute chest syndrome [ACS; discussed in a bit]) or dehydration that requires parenteral therapy. Use of nondrug therapy, such as heat, should be encouraged. The care team should work with the patient’s school or employer to negotiate time away through the federal Family Medical Leave Act of 1993, or other means, because a pain crisis is not a planned event.

Fever. Because of the risk of serious infection as a consequence of functional asplenia, fever is particularly worrisome in patients with SCA and problematic in patients with SCD. The increased risk begins as the physiologic level of Hb F declines beginning at age 2 months.

ACS, characterized by a combination of respiratory symptoms or new infiltrates, often manifests initially with fever, and can progress rapidly to death if treatment is delayed. The initial signs and symptoms may be subtle; suspicion should remain high in any patient with respiratory symptoms who is newly hypoxic, even those who do not have fever. Osteomyelitis, another febrile illness, is also potentially life threatening if not treated promptly.

All patients with SCD whose body temperature is > 101.3 °F should be evaluated with appropriate clinical laboratory testing (complete blood count; inflammatory markers, such as C-reactive protein; basic chemistry parameters; and other tests as indicated, including serum lactate and urine culture), blood culture, and chest radiography. Empiric parenteral antibiotics are required until the patient is known to be nonbacteremic, regardless of vaccination status. Outpatient follow-up and even outpatient management with ceftriaxone can be offered in select circumstances (eg, if the patient so desires or is nontoxic, and if close follow-up can be assured).¹⁴ If ACS is a possibility based on symptoms or radiographic findings, outpatient management is not an option.

Anemia. Patients with SCA, and some with SCD, have an Hb level that is chronically, sometimes critically, low. A baseline Hb level should be established for a patient with SCD and then monitored periodically. A drop in the Hb level > 2 g/dL from baseline (or an initial Hb level of 6 g/dL if the baseline is unknown) constitutes acute anemia. Patients in whom anemia has been diagnosed should be emergently evaluated for acute splenic sequestration, an aplastic episode, a delayed hemolytic transfusion reaction, ACS, or infection, and should be treated appropriately.

Continue to: Simple transfusion can be used...

Simple transfusion can be used in an acute setting to restore and maintain Hb at a safe level. Iron overload and formation of RBC alloantigen are associated with multiple transfusions; once either of these conditions is established, subsequent transfusion therapy can be harmful. Care must be taken to prescribe transfusion appropriately; ­leukocyte-depleted RBCs should be used when available.

It is important to define specific goals of transfusion to optimize its use. Patients who have received multiple transfusions should have enhanced monitoring for bloodborne infection, such as hepatitis C virus. Acute aplastic crises are caused by parvovirus B19; when other members of the household who have SCD are present, they should be monitored for this viral infection with serial measurement of Hb and white blood cell count.⁶

Other acute problems. Should stroke, acute renal failure, priapism, or hepatobiliary complications develop, evaluate the patient rapidly and refer them to the appropriate care team for management.

Management of chronic complications

Chronic pain is a problem for many patients with SCD. The etiology of this symptom should be investigated fully because a vaso-occlusive crisis is characterized by acute pain. Avascular necrosis or ulcers due to chronic vaso-­occlusion should be managed definitively when possible. Adjuvant therapy for chronic pain, such as heat or massage, should be encouraged.

Administer the standard PCV13 series for all patients with sickle cell disease beginning at age 6 weeks.

In some patients, chronic pain without objective findings develops over time and becomes unresponsive to nonopioid pharmacotherapy. Such patients might require chronic opioid therapy, the need for which is dictated by the ability of the patient to perform their activities of daily living. For patients who require long-term daily narcotic drugs, best practices—obtaining informed consent, using registries and contracts, random drug testing, and providing naloxone [Narcan] for overdose emergency use—should be employed.¹⁵

Continue to: Chronic anemia

Chronic anemia can be managed with transfusion when elevating the Hb level is required (eg, preoperatively, to prevent stroke, to manage priapism). For some patients, ongoing transfusion is required; care should be taken to avoid iron overload and hemolysis due to antibody formation. Ongoing surveillance for these complications is required.⁶

Other chronic problems. Patients with SCD who develop avascular necrosis, vaso-occlusive ulcers, pulmonary hypertension, renal disease, recurrent priapism, or ophthalmologic complications should be co-­managed with a care team.⁶

Pharmacotherapy and SCA

A principal goal in the management of patients with SCA is prevention of vaso-­occlusive events, including ACS and acute pain crises.

Hydroxyurea, a key component of SCA treatment, is a ribonucleotide reductase inhibitor that increases the level of Hb F, thus reducing the absolute number of symptomatic vaso-occlusive events and increasing arterial blood flow. It is most useful for patients who have multiple crises. The drug prolongs survival and reduces the need for transfusion and hospitalization.^4,5

Hydroxyurea can be started in patients at age 9 months; blood testing should be performed at the start of treatment and the dosage titrated based on blood counts. Initial blood work includes:

• Hb level;
• Hb electrophoresis with the quantitative percentage of Hb F;
• complete blood count with differential and reticulocyte counts;
• chemistry profile (electrolytes, lactate dehydrogenase, total protein, albumin, total bilirubin);
• liver function tests (aspartate aminotransferase, alanine aminotransferase);
• measurement of renal function (blood urea nitrogen, creatinine);
• serum vitamin B₁₂ and folate;
• serum iron, total iron-binding capacity, and ferritin;
• hepatitis B, hepatitis C, and parvovirus B19 antigen; and
• serologic testing for HIV.

Continue to: Testing should also...

Testing should also include a pregnancy test for postmenarchal females because hydroxyurea is in US Food and Drug Administration pregnancy risk category X.

Avoid hydroxyurea in lactating women; dose the drug renally in the setting of renal disease. Because hydroxyurea has a high rate of serious adverse effects and drug-drug interactions, it should be offered in conjunction with an individualized care plan.

Hydroxyurea can also be offered to patients with other forms of SCD who have recurrent vaso-occlusive symptoms.

Two newer medications improve oxygen delivery in patients with SCD. Voxelotor, approved in 2019, works to reduce Hb S polymerization by binding to the alpha chain of Hb S and, subsequently, increasing its oxygen affinity. The drug is generally well tolerated and can be used in patients with SCD who are ≥ 12 years.¹⁶ Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule located on endothelial cells and activated platelets. The efficacy of crizanlizumab was demonstrated in the SUSTAIN trial, in which it reduced vaso-occlusive pain in patients ≥ 16 years.¹⁷

All of these medications have a narrow toxic–therapeutic window. They should therefore be administered with the participation of a multidisciplinary care team.

Continue to: The need to coordinated, comprehensive care

Patients with SCD report how challenging their disease is. All patients with SCD are more likely than age-matched counterparts to experience loss, including workdays for disability, educational potential, workdays for caregivers of affected children, and time spent in the hospital or the emergency department.^4,5 These losses, with the concomitant stress associated with chronic illness and the struggle to manage recurrent pain crises and chronic complications, are often overwhelming.

SARS-CoV-2 infection causes mortality as high as 7% in patients with sickle cell disease; the mRNA vaccine series is potentially lifesaving for them.

Comprehensive care can, as we have illustrated in this discussion, mitigate these losses. Such care should include extensive education, genetic counseling, infection prevention, pain management, and implementation of evidence-based management guidelines.^3,4,6 Patients with SCD report that their illness outlook would be better with

• greater provider knowledge of SCD,
• destigmatization of narcotics for SCD vaso-occlusive pain management,
• optimal coordination among members of the health care team, and
• improved transportation for appointments.

Patients also report that barriers associated with the unique US health care financing system are often insurmountable. As patients with SCD live longer, improved care management should focus on reducing these barriers and enhancing their quality of life.^2,18,19

CORRESPONDENCE
Robert Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama College of Medicine, 1601 Center Street, 2N, Mobile, AL 36604; perkins@health. southalabama.edu

The group of disorders known as sickle cell disease (SCD) is one of the more common genetic hemoglobinopathies. Homozygous production of the S variant of hemoglobin (Hb) in red blood cells (RBCs) results in profound sickling under conditions of physiologic stress, a condition known as Hb SS disease. People with Hb SS disease are at risk of chronic hemolytic anemia, tissue ischemia that causes vaso-occlusive pain syndrome, and other vaso-occlusive complications.¹ They also experience a > 20-year reduction in life expectancy, compared to age-matched controls; onset of risk of early death is usually after age 25 years.

People with heterozygous expression of the Hb S variant—that is, from one parent, and expression of Hb A from the other parent—are said to have sickle cell trait (SCT). They typically do not have symptoms of SCD, although they can experience vaso-occlusive pain under severe physiologic stress and suffer sudden death more often than age-matched controls. People who are heterozygous for Hb S but have another hemoglobinopathy (eg, sickle β⁰ thalassemia) might have milder SCD, with fewer symptoms, or might have severe sickle cell anemia (SCA).

Alleviating the harsh burden of illness. All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability; the same loss is true for their caregivers. Such loss, when combined with time spent in the health care system, can be catastrophic.^2,3 But this loss can be mitigated with access to regular, comprehensive health care that includes the steps described here to detect SCD early and reduce the likelihood of complications.^4,5

To begin, TABLE 1⁶ lists typical laboratory findings and classifications in patients who are homozygous or heterozygous for Hb S, and therefore experience more severe Hb SS disease or milder SCD, respectively.

Who should be screened for hemoglobinopathy?

Because of the presence of the fetal Hb (Hb F) in newborns and infants, clinical signs of Hb SS before age 2 months are uncommon. Neonatal clinical laboratory testing is necessary for prompt identification of Hb SS; universal screening is now required by all states (although parents can opt out by claiming a religious exemption). A positive test result requires confirmatory testing: most often, Hb electrophoresis or DNA testing.

All patients with SCD are more likely than age-matched counterparts to experience income loss because of their disability. But this loss can be mitigated with access to regular, comprehensive health care.

A confirmed positive homozygous (Hb SS) or heterozygous (Hb S) result is reported to the patient’s identified medical home for subsequent management. Thus, pediatric patients with SCD can be identified, and prophylactic treatment initiated, as early as possible. Later in the patient’s life, repeat screening for SCD and SCT is recommended at the initiation of pregnancy care⁷ and prior to the start of high-intensity physical training, as occurs in college and professional athletics and in certain branches of the military.⁸

Putting prevention into practice

Some of the recommendations we make to prevent complications of SCD are directed only at patients with severe disease—ie, those who have Hb SS SCD or sickle β⁰ thalassemia (SCA); the rest apply to all patients with SCD (TABLE 2^6,9). (For patients with SCT, follow guidelines as you would for patients who do not have SCD, unless otherwise noted.)

Continue to: In addition, keep in mind...

In addition, keep in mind that preventive recommendations made by the US Preventive Services Task Force (Exhibit 5 in the Expert Panel Report)⁶ apply to all patients with SCD and SCT.

Prevention of invasive pneumococcal disease

All patients with SCD are assumed to have lifelong splenic dysfunction that begins in childhood. This is particularly true for those with SCA. In the absence of vaccination, the lifetime incidence of pneumococcal bacteremia resulting in serious complications is as high as 16% in SCD.¹⁰ In multiple randomized clinical trials, prophylactic penicillin dosing has proved beneficial in these patients, demonstrating a decrease in the risk of (1) pneumococcal infection and (2) early death during the study period, with minimal adverse effects.⁵

Prophylactic penicillin dosing should be initiated during infancy in patients with SCA. From ages 3 months to 3 years, the dosage of penicillin V is 125 mg twice daily; from 3 to 5 years, 250 mg twice daily. After age 5 years, the decision to continue penicillin is individualized, with consideration of prior severe pneumococcal infection and general preventive health maintenance. Penicillin-allergic patients can be given erythromycin. All patients with SCD who have had surgical splenectomy should be placed on antibiotic prophylaxis (ie, penicillin as dosed above).⁵

The polyvalent pneumococcal vaccine has resulted in significant protection against invasive pneumococcal disease; mortality from pneumococcal disease among patients with SCD who are younger than 14 years has decreased dramatically since the vaccine was introduced.⁶ For all patients with SCD, the standard PCV13 series should be administered beginning at age 6 weeks. A 2-dose series of the PPSV23 vaccine, which includes more Streptococcus pneumoniae serotypes than the PCV13 vaccine, should be administered beginning at age 2 years or 8 weeks after completion of the PCV13 series, whichever comes first.

Prevention of flu, COVID-19, and other vaccine-preventable illness

Influenza. Beginning at age 6 months, all patients with SCD should receive inactivated influenza vaccine annually at the beginning of the influenza season. Avoid using the live attenuated vaccine (Flumist) because of an associated increased risk of severe or complicated infection.¹¹

Continue to: COVID-19, caused by severe...

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is especially problematic in patients with SCD¹²; infection causes mortality at a rate as high as 7%.⁵ The SARS-CoV-2 mRNA vaccine series is potentially lifesaving for these patients.¹² In addition, at times of high community prevalence, make an effort to minimize patients’ exposure to SARS-CoV-2, by providing telemedicine visits.

Follow the immunization schedule. Patients with SCD should receive all standard recommended vaccinations (ie, those recommended by the Advisory Committee on Immunization Practices.^a) Inactivated virus vaccines are preferred in SCD, when available. For patients who are behind on vaccinations, use a standard vaccine catch-up schedule.

Screening and prevention of complications such as stroke

Determining the risk of stroke. Patients with SCA who are not monitored have a 10% to 11% lifetime prevalence of stroke.^5,6,10 An abnormal transcranial Doppler (TCD) study (defined as a time-averaged mean maximum velocity ≥ 200 cm/s in the distal internal carotid artery or proximal middle cerebral artery) is predictive of a 40% risk of stroke in patients with SCA. With chronic transfusion therapy, a 92% reduction in the risk of stroke is achievable.¹⁰

All patients with SCA should undergo annual screening with TCD ultrasonography from ages 2 to 16 years.⁶ Those who have an abnormal TCD study should receive chronic transfusion therapy. Screening is not recommended for patients with SCD or SCT.

Other complications. Screen and manage as follows:

• Proteinuria. Left untreated, SCD can affect the kidneys and lead to renal failure. Annual screening for proteinuria is recommended beginning at age 10 years, with referral when the test is positive and reproducible.
• Lung disease and cardiovascular disease. Screening for progression of lung disease and for cardiovascular disease is not recommended in asymptomatic patients with SCD, except through the history.
• Blood pressure screening and management of hypertension are based on Joint National Committee (JNC 8) guidelines.¹³
• Screening for ocular complications by an eye care provider is recommended beginning at age 10 years.

TABLE 2^6,9 summarizes recommendations on the prevention and early detection of complications of SCD.

Continue to: Pregnancy planning

The Centers for Disease Control and Prevention recommends that a “reproductive life plan” be part of every person’s health journey (TABLE 2).^6,9 The plan is especially relevant for female patients who have a known heritable concern, such as SCD, in which a pregnancy is more likely to be complicated by growth restriction, preterm delivery, and fetal demise. These risks are reduced—but not eliminated—with intensive surveillance of the pregnancy. Pregnancy in patients with SCD is also more likely to be complicated by preeclampsia, venous thromboembolism, infection, and maternal death.

Other recommendations:

• Every patient with SCD should receive genetic counselling before conceiving, when possible.
• Pregnancy should be considered high risk in women who have SCD, and monitored as such.
• Women with SCD can use any method of contraception—none of which put them at increased risk of complications, compared to the general population. Rather, it is pregnancy that puts them at greater risk of morbidity and mortality in every age group.

Ambulatory management of acute complications

Vaso-occlusive pain crisis. The hallmark of SCD is the acute pain crisis. Almost all patients with SCD (and the occasional patient with SCT) will experience a pain crisis. In more affluent countries, management of an acute pain crisis almost always includes opioid analgesia.⁶

For the most part, pain crises manifest in a predictable pattern. Although patients with SCD might have acute pain, other causes of acute pain, such as an acute intra-abdominal process or (in older patients) a cardiac process, should be considered as well.

Prophylactic penicillin dosing has proved beneficial in patients with sickle cell disease, demonstrating a decrease in the risk of pneumococcal infection.

For patients having a vaso-occlusive pain crisis, achieving rapid analgesia is key to management. Ready availability of narcotics, at home or under observation, prevents subsequent hospitalization; nonsteroidal anti-inflammatory drugs can be used as adjuvant treatment in patients without contraindications.^5,6 An individualized treatment plan, including access to analgesia at an appropriate dosage, should be negotiated, and adhered to, by the patient and the care team.

Continue to: Rapid access to higher-level care...

Rapid access to higher-level care, including parenteral analgesia, is important if outpatient management is desired. In addition, escalation to a higher level of care should occur if there is hypoxia (or another reason to suspect acute chest syndrome [ACS; discussed in a bit]) or dehydration that requires parenteral therapy. Use of nondrug therapy, such as heat, should be encouraged. The care team should work with the patient’s school or employer to negotiate time away through the federal Family Medical Leave Act of 1993, or other means, because a pain crisis is not a planned event.

Fever. Because of the risk of serious infection as a consequence of functional asplenia, fever is particularly worrisome in patients with SCA and problematic in patients with SCD. The increased risk begins as the physiologic level of Hb F declines beginning at age 2 months.

ACS, characterized by a combination of respiratory symptoms or new infiltrates, often manifests initially with fever, and can progress rapidly to death if treatment is delayed. The initial signs and symptoms may be subtle; suspicion should remain high in any patient with respiratory symptoms who is newly hypoxic, even those who do not have fever. Osteomyelitis, another febrile illness, is also potentially life threatening if not treated promptly.

All patients with SCD whose body temperature is > 101.3 °F should be evaluated with appropriate clinical laboratory testing (complete blood count; inflammatory markers, such as C-reactive protein; basic chemistry parameters; and other tests as indicated, including serum lactate and urine culture), blood culture, and chest radiography. Empiric parenteral antibiotics are required until the patient is known to be nonbacteremic, regardless of vaccination status. Outpatient follow-up and even outpatient management with ceftriaxone can be offered in select circumstances (eg, if the patient so desires or is nontoxic, and if close follow-up can be assured).¹⁴ If ACS is a possibility based on symptoms or radiographic findings, outpatient management is not an option.

Anemia. Patients with SCA, and some with SCD, have an Hb level that is chronically, sometimes critically, low. A baseline Hb level should be established for a patient with SCD and then monitored periodically. A drop in the Hb level > 2 g/dL from baseline (or an initial Hb level of 6 g/dL if the baseline is unknown) constitutes acute anemia. Patients in whom anemia has been diagnosed should be emergently evaluated for acute splenic sequestration, an aplastic episode, a delayed hemolytic transfusion reaction, ACS, or infection, and should be treated appropriately.

Continue to: Simple transfusion can be used...

Simple transfusion can be used in an acute setting to restore and maintain Hb at a safe level. Iron overload and formation of RBC alloantigen are associated with multiple transfusions; once either of these conditions is established, subsequent transfusion therapy can be harmful. Care must be taken to prescribe transfusion appropriately; ­leukocyte-depleted RBCs should be used when available.

It is important to define specific goals of transfusion to optimize its use. Patients who have received multiple transfusions should have enhanced monitoring for bloodborne infection, such as hepatitis C virus. Acute aplastic crises are caused by parvovirus B19; when other members of the household who have SCD are present, they should be monitored for this viral infection with serial measurement of Hb and white blood cell count.⁶

Other acute problems. Should stroke, acute renal failure, priapism, or hepatobiliary complications develop, evaluate the patient rapidly and refer them to the appropriate care team for management.

Management of chronic complications

Chronic pain is a problem for many patients with SCD. The etiology of this symptom should be investigated fully because a vaso-occlusive crisis is characterized by acute pain. Avascular necrosis or ulcers due to chronic vaso-­occlusion should be managed definitively when possible. Adjuvant therapy for chronic pain, such as heat or massage, should be encouraged.

Administer the standard PCV13 series for all patients with sickle cell disease beginning at age 6 weeks.

In some patients, chronic pain without objective findings develops over time and becomes unresponsive to nonopioid pharmacotherapy. Such patients might require chronic opioid therapy, the need for which is dictated by the ability of the patient to perform their activities of daily living. For patients who require long-term daily narcotic drugs, best practices—obtaining informed consent, using registries and contracts, random drug testing, and providing naloxone [Narcan] for overdose emergency use—should be employed.¹⁵

Continue to: Chronic anemia

Chronic anemia can be managed with transfusion when elevating the Hb level is required (eg, preoperatively, to prevent stroke, to manage priapism). For some patients, ongoing transfusion is required; care should be taken to avoid iron overload and hemolysis due to antibody formation. Ongoing surveillance for these complications is required.⁶

Other chronic problems. Patients with SCD who develop avascular necrosis, vaso-occlusive ulcers, pulmonary hypertension, renal disease, recurrent priapism, or ophthalmologic complications should be co-­managed with a care team.⁶

Pharmacotherapy and SCA

A principal goal in the management of patients with SCA is prevention of vaso-­occlusive events, including ACS and acute pain crises.

Hydroxyurea, a key component of SCA treatment, is a ribonucleotide reductase inhibitor that increases the level of Hb F, thus reducing the absolute number of symptomatic vaso-occlusive events and increasing arterial blood flow. It is most useful for patients who have multiple crises. The drug prolongs survival and reduces the need for transfusion and hospitalization.^4,5

Hydroxyurea can be started in patients at age 9 months; blood testing should be performed at the start of treatment and the dosage titrated based on blood counts. Initial blood work includes:

• Hb level;
• Hb electrophoresis with the quantitative percentage of Hb F;
• complete blood count with differential and reticulocyte counts;
• chemistry profile (electrolytes, lactate dehydrogenase, total protein, albumin, total bilirubin);
• liver function tests (aspartate aminotransferase, alanine aminotransferase);
• measurement of renal function (blood urea nitrogen, creatinine);
• serum vitamin B₁₂ and folate;
• serum iron, total iron-binding capacity, and ferritin;
• hepatitis B, hepatitis C, and parvovirus B19 antigen; and
• serologic testing for HIV.

Continue to: Testing should also...

Testing should also include a pregnancy test for postmenarchal females because hydroxyurea is in US Food and Drug Administration pregnancy risk category X.

Avoid hydroxyurea in lactating women; dose the drug renally in the setting of renal disease. Because hydroxyurea has a high rate of serious adverse effects and drug-drug interactions, it should be offered in conjunction with an individualized care plan.

Hydroxyurea can also be offered to patients with other forms of SCD who have recurrent vaso-occlusive symptoms.

Two newer medications improve oxygen delivery in patients with SCD. Voxelotor, approved in 2019, works to reduce Hb S polymerization by binding to the alpha chain of Hb S and, subsequently, increasing its oxygen affinity. The drug is generally well tolerated and can be used in patients with SCD who are ≥ 12 years.¹⁶ Crizanlizumab is a monoclonal antibody directed against P-selectin, an adhesion molecule located on endothelial cells and activated platelets. The efficacy of crizanlizumab was demonstrated in the SUSTAIN trial, in which it reduced vaso-occlusive pain in patients ≥ 16 years.¹⁷

All of these medications have a narrow toxic–therapeutic window. They should therefore be administered with the participation of a multidisciplinary care team.

Continue to: The need to coordinated, comprehensive care

Patients with SCD report how challenging their disease is. All patients with SCD are more likely than age-matched counterparts to experience loss, including workdays for disability, educational potential, workdays for caregivers of affected children, and time spent in the hospital or the emergency department.^4,5 These losses, with the concomitant stress associated with chronic illness and the struggle to manage recurrent pain crises and chronic complications, are often overwhelming.

SARS-CoV-2 infection causes mortality as high as 7% in patients with sickle cell disease; the mRNA vaccine series is potentially lifesaving for them.

Comprehensive care can, as we have illustrated in this discussion, mitigate these losses. Such care should include extensive education, genetic counseling, infection prevention, pain management, and implementation of evidence-based management guidelines.^3,4,6 Patients with SCD report that their illness outlook would be better with

• greater provider knowledge of SCD,
• destigmatization of narcotics for SCD vaso-occlusive pain management,
• optimal coordination among members of the health care team, and
• improved transportation for appointments.

Patients also report that barriers associated with the unique US health care financing system are often insurmountable. As patients with SCD live longer, improved care management should focus on reducing these barriers and enhancing their quality of life.^2,18,19

CORRESPONDENCE
Robert Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama College of Medicine, 1601 Center Street, 2N, Mobile, AL 36604; perkins@health. southalabama.edu

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Treatment with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors has made a notable dent in survival statistics for patients with metastatic renal cell carcinoma, but up to 20% of patients will only ever achieve progressive disease status and at 1 year, 20% of patients will have died from the condition.

The treatment is still superior to doublet immune checkpoint blockade therapy, shows a cohort study among patients with metastatic renal cell carcinoma published in JAMA Network Open.

The investigation also found that objective imaging responses were associated with improvement in overall survival among patients receiving either type of therapy. Led by Vishal Navani, MBBS, University of Calgary (Alta.), this was a multicenter international cohort study of 899 patients (median age 62.8 years; 74.2% male) with a histologically confirmed diagnosis of metastatic renal cell carcinoma (mRCC) nested in routine clinical practice (International Metastatic Renal Cell Carcinoma Database Consortium [IMDC]). Complete or partial responses were independently more likely with first-line VEGF inhibitor therapy (IOVE) (including axitinib-avelumab, axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab therapies) than with the first-line immuno-oncology doublet (IOIO) of ipilimumab-nivolumab (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.26-2.81; P = .002). Analysis of factors affecting responses showed they were more likely to occur in the presence of lung metastases (OR, 1.49: 95% CI, 1.01-2.20), receipt of cytoreductive nephrectomy (OR, 1.59; 95% CI, 1.04-2.43), and favorable IMDC risk.

Beyond imaging response, Dr. Navani and colleagues tested the association between objective imaging response and overall survival as a secondary endpoint. Among responders versus nonresponders, median overall survival was not estimable (95%CI, 48.2 months to not estimable) versus 31.6 months (95%CI, 24.2-41.4 months; log rank P < .001). The overall survival advantage for objective imaging response versus nonresponse persisted in both the IOIO and IOVE groups taken separately (log rank P < .001 and log rank P = .02, respectively).

A large proportion of patients (27.5%) in the IOIO group experienced progressive disease as the best overall response, with significantly reduced median overall survival of 8.4 months (95%CI, 7.2-13.0 months). In the IOVE group, by contrast, 12.2% experienced progressive disease as the best overall response, with improved median overall survival of 18.5 months (95%CI, 4.9-22.4 months).

While first-line combination therapies have brought meaningful overall survival benefits in this population, up to 20% of patients, the researchers wrote, have progressive disease as their best overall response, and all-cause mortality in clinical trials is as high as 20% at 1 year. Improving the survival curve has been hampered by the lack of biomarkers to predict objective imaging response or survival benefit with first-line therapies. Also, the association between treatment with first-line immuno-oncology combination therapies and physician-assessed objective imaging response among patients with metastatic renal cell carcinoma has remained uncharacterized. Meaningful clinical differences in the likelihood of objective imaging response based on the first-line therapy type shown in this analysis may inform therapy selection, particularly if tumor reduction is needed to inhibit life-limiting disease progression and to palliate tumor-induced symptoms.

The authors pointed out the study’s strength, citing the inclusion of a large data set from a 90% nonclinical trial population, and its limitations, which include a lack of independent blinded centralized imaging review.

They declared no relevant disclosures.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

Researchers writing in JAMA Network Open report that for patients with metastatic clear cell renal cell carcinoma, removing the kidney and its primary tumor is not associated with improved overall survival.

The finding, which was derived using instrumental variable analysis to adjust for bias due to unmeasured variables, is in contradiction to findings from prior observational data sets.

“These observational studies did not account for selection bias related to unmeasured confounding by surgical indication, and as such, their results may not accurately reflect the effectiveness of the intervention,” wrote the authors, led by Nicholas H. Chakiryan, MD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.

The primary outcome analysis using conventional adjustments for selection bias in the final study population of 12,766 patients (median age 63 years, 68% male, 88% White) found cytoreductive nephrectomy performed in 5,005 patients (39%) to be associated with a significant overall survival benefit (multivariable Cox proportional hazards regression: hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.47-0.51; propensity score matching: HR, 0.48; 95%CI, 0.46-0.50). Analysis using instrumental variable estimates, however, did not demonstrate an association between cytoreductive nephrectomy and overall survival (HR, 0.92; 95%CI, 0.78-1.09). “This discrepancy likely reflects the fact that surgical indication for cytoreductive nephrectomy is primarily driven by factors that are not commonly measured or available in observational data sets,” wrote Dr. Chakiryan and colleagues.

For metastatic clear cell renal cell carcinoma (ccRCC) surgical candidates lacking poor-risk disease, cytoreductive nephrectomy has been a clinical standard for decades. Several large observational studies conducted during the current postcytokine, tyrosine kinase–inhibiting targeted therapy era have demonstrated that cytoreductive nephrectomy continues to offer substantial overall survival benefit. These studies did not, however, account for selection bias related to unmeasured confounding by surgical indication.

The researchers identified 12,766 cases of ccRCC from the National Cancer Database, which includes more than 70% of incident cancer cases diagnosed in the United States, from Jan. 1, 2006, to Dec. 31, 2016. Their primary objective was to assess the effect of cytoreductive nephrectomy on overall survival for patients with metastatic ccRCC using instrumental variable analysis to adjust for unmeasured confounding and to compare these results with those generated by conventional adjustments for selection bias.

Instrumental variables are used to control for confounding and measurement error in observational studies. In this study, increasing distance to the treating facility was a significant instrumental variable (P < .001), with an increasing proportion of patients undergoing cytoreductive nephrectomy as distance to a facility increased. “It is worth reinforcing that instrumental variable estimates reflect the outcomes of marginal patients in the sample,” the researchers noted. “In this instance, marginal patients are those whose cytoreductive nephrectomy status was primarily associated with their distance to the treating facility. Increasing distance to the treating facility was significantly associated with receipt of a cytoreductive nephrectomy, presumably because patients are more willing to travel to referral centers for complex surgical care with a limited number of visits, as opposed to receipt of systemic therapy that requires frequent visits for an indefinite period and can be effectively administered locally.”

“Consistent with contemporary level 1 evidence, instrumental variable analysis demonstrated that cytoreductive nephrectomy was not associated with improved overall survival for patients with metastatic clear cell renal cell carcinoma,” the authors concluded.

Among limitations of the analysis, they noted that instrumental variable analyses functionally compare marginal patient populations within the overall cohort, potentially limiting the generalizability of the results.

An analysis of trends in lung cancer screening since March 2021 when the U.S. Preventive Services Task Force (USPSTF) expanded the eligibility criteria for lung cancer screening, shows that significantly more Black men have been screened for lung cancer, but not women or undereducated people.

The eligibility for lung cancer screening was expanded in 2021 to include men and women under 50 years old and people who smoke at least one pack of cigarettes a day for the last 20 years. “

“Expansion of screening criteria is a critical first step to achieving equity in lung cancer screening for all high-risk populations, but myriad challenges remain before individuals enter the door for screening,” wrote the authors, led by Julie A. Barta, MD, Thomas Jefferson University, Philadelphia. “Health policy changes must occur simultaneously with efforts to expand community outreach, overcome logistical barriers, and facilitate screening adherence. Only after comprehensive strategies to dismantle screening barriers are identified, validated, and implemented can there be a truly equitable landscape for lung cancer screening.”

For the study, published in JAMA Open Network, researchers examined rates of centralized lung cancer screening in the Baltimore area. In addition to expanding lung cancer screening generally, there was hope that the expanded criteria might increase uptake of screening in populations that are traditionally underserved, such as African American, Hispanic, and female patients. Of 815 people screened during the study period (March-December 2021), 161 were newly eligible for screening under the 2021 criteria.

“There’s been quite a bit of work in the field demonstrating that Black men and women develop lung cancer at more advanced stages of disease, and they often are diagnosed at younger ages and have fewer pack-years of smoking. So the hypothesis was that this would reduce some of the disparities seen in lung cancer screening by making more people eligible,” Dr. Barta said in an interview.

The researchers categorized participants as those who would have been eligible for screening under the USPSTF 2013 guideline (age 55 or older, 30 or more pack-years, quit within the past 15 years), and those who would be eligible under the 2021 guideline (age 50 or older, 20 or more pack-years, quit within the past 15 years). Of the 2021 cohort, 54.5% were African American, versus 39.5% of the 2013 cohort (P = .002). There were no differences between the cohorts with respect to education level or gender.

“Although we’ve seen some encouraging improvement in terms of getting more eligible patients into our screening program, there’s still a lot of work to be done in the field,” Dr. Barta said. “Diagnosing lung cancer at earlier stages of disease is more cost effective in general for the health care system than fighting lung cancer at advanced stages, which requires more complex and multimodal and prolonged therapies.”
 

New evidence: Chest CTs for lung cancer screening reduces incidence of advanced lung cancer

In an analysis of the SEER database presented in June at the annual meeting of the American Society of Clinical Oncology, the adoption of low-dose chest computed tomography (LDCT) led to fewer diagnoses of advanced lung cancer, although these declines varied significantly by race and ethnicity. Non-Hispanic Blacks seemed to benefit the most with a 55% decline (P < .01), while Hispanics had the lowest rate of decline at 41% (P < .01). The change was recommended by USPSTF in 2013 after the National Lung Screening Trial revealed a 20% relative reduction in mortality when CT scans were used instead of chest radiography. The Centers for Medicare and Medicaid Services approved coverage of the screen in 2015.

The SEER study looked at data from 400,343 individuals from 2004-2014 (preintervention) and 2015-2018 (postintervention). The age-adjusted incidence of advanced lung cancer declined during both periods, but the decline was sharper between 2015 and 2018, with three fewer cases per 100,000 people than 2004-2014 (P < .01). Similar patterns were seen in subanalyses of males and females, non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. The relative declines were largest in women, non-Hispanic Blacks, and people who lived outside of Metropolitan areas.

During a Q&A session that followed the presentation, Robert Smith, PhD, pointed out that the bar for eligibility of lung cancer risk has been set quite high, following the eligibility criteria for clinical trials. He noted that many patients who could be eligible for screening are still missed because of a lack of clinical routines designed to identify eligible patients. “We are missing opportunities to prevent avertable lung cancer deaths,” said Dr. Smith, senior vice president of cancer screening at the American Cancer Society.

On the other hand, screening-prompted biopsies have the potential to cause harm, particularly in patients who already have lung disease, said Douglas Allen Arenberg, MD, professor at the University of Michigan, Ann Arbor. “I think that’s what scares most people is the potential downside, which is very hard to measure outside of a clinical trial,” said Dr. Arenberg, who served as a discussant for the presentation.

One way to reduce that risk is to identify biomarkers, either for screens or for incidentally-detected nodules, that have good negative predictive value. “If I had a blood test that is as good as a negative PET scan, I’m going to be much more likely to say, ‘Yeah, you’re 40 and your grandfather had lung cancer. Maybe you should get a CT. If we had that, we could screen a lot more people. Right now, I would discourage anybody who is at low risk from getting screened because when they come to me, the biggest opportunity I have to do harm is when I do a biopsy, and you always remember the ones that go wrong,” he said.

Dr. Arenberg also called for improvements in electronic medical records to better flag at-risk patients. “I think we as physicians have to demand more of the software developers that create these EMRs for us,” he said.

Another study in the same session used data from 1,391,088 patients drawn from the National Cancer Database between 2010 and 2017 to examine trends in diagnosis of stage I cancer. In 2010, 23.5% of patients were diagnosed as stage I, versus 29.1% in 2017. Stage I incidence increased from 25.8% to 31.7% in non–small cell lung cancer, but there was no statistically significant change in small cell lung cancer. As with the SEER database study, the researchers noted that the shift toward stage I diagnoses predated the recommendation of LDCT.

Dr. Arenberg suggested that the trend may come down to increased frequency of CT scans, which often collect incidental images of the lungs. He added that better access to care may also be helping to drive the change. “How much of that might have had something to do with the introduction 5 or 10 years earlier of the Affordable Care Act and people just simply having access to care and taking advantage of that?” Dr. Arenberg said.

But Dr. Arenberg said that not even screening can explain all the data. He referenced a stage shift in patients of all age groups in the National Cancer Database study, even those too young to be eligible for screening. “There’s something else going on here. It would be nice for us to understand what caused these trends, so perhaps we could accentuate that trend even more, but stage shifts are clearly occurring in lung cancer,” Dr. Arenberg said.

Dr. Barta has received grants from Genentech Health Equity Innovations Fund. Dr. Arenberg has no relevant financial disclosures. Dr. Smith’s potential disclosures could not be ascertained.

An analysis of trends in lung cancer screening since March 2021 when the U.S. Preventive Services Task Force (USPSTF) expanded the eligibility criteria for lung cancer screening, shows that significantly more Black men have been screened for lung cancer, but not women or undereducated people.

The eligibility for lung cancer screening was expanded in 2021 to include men and women under 50 years old and people who smoke at least one pack of cigarettes a day for the last 20 years. “

“Expansion of screening criteria is a critical first step to achieving equity in lung cancer screening for all high-risk populations, but myriad challenges remain before individuals enter the door for screening,” wrote the authors, led by Julie A. Barta, MD, Thomas Jefferson University, Philadelphia. “Health policy changes must occur simultaneously with efforts to expand community outreach, overcome logistical barriers, and facilitate screening adherence. Only after comprehensive strategies to dismantle screening barriers are identified, validated, and implemented can there be a truly equitable landscape for lung cancer screening.”

For the study, published in JAMA Open Network, researchers examined rates of centralized lung cancer screening in the Baltimore area. In addition to expanding lung cancer screening generally, there was hope that the expanded criteria might increase uptake of screening in populations that are traditionally underserved, such as African American, Hispanic, and female patients. Of 815 people screened during the study period (March-December 2021), 161 were newly eligible for screening under the 2021 criteria.

“There’s been quite a bit of work in the field demonstrating that Black men and women develop lung cancer at more advanced stages of disease, and they often are diagnosed at younger ages and have fewer pack-years of smoking. So the hypothesis was that this would reduce some of the disparities seen in lung cancer screening by making more people eligible,” Dr. Barta said in an interview.

The researchers categorized participants as those who would have been eligible for screening under the USPSTF 2013 guideline (age 55 or older, 30 or more pack-years, quit within the past 15 years), and those who would be eligible under the 2021 guideline (age 50 or older, 20 or more pack-years, quit within the past 15 years). Of the 2021 cohort, 54.5% were African American, versus 39.5% of the 2013 cohort (P = .002). There were no differences between the cohorts with respect to education level or gender.

“Although we’ve seen some encouraging improvement in terms of getting more eligible patients into our screening program, there’s still a lot of work to be done in the field,” Dr. Barta said. “Diagnosing lung cancer at earlier stages of disease is more cost effective in general for the health care system than fighting lung cancer at advanced stages, which requires more complex and multimodal and prolonged therapies.”
 

New evidence: Chest CTs for lung cancer screening reduces incidence of advanced lung cancer

In an analysis of the SEER database presented in June at the annual meeting of the American Society of Clinical Oncology, the adoption of low-dose chest computed tomography (LDCT) led to fewer diagnoses of advanced lung cancer, although these declines varied significantly by race and ethnicity. Non-Hispanic Blacks seemed to benefit the most with a 55% decline (P < .01), while Hispanics had the lowest rate of decline at 41% (P < .01). The change was recommended by USPSTF in 2013 after the National Lung Screening Trial revealed a 20% relative reduction in mortality when CT scans were used instead of chest radiography. The Centers for Medicare and Medicaid Services approved coverage of the screen in 2015.

The SEER study looked at data from 400,343 individuals from 2004-2014 (preintervention) and 2015-2018 (postintervention). The age-adjusted incidence of advanced lung cancer declined during both periods, but the decline was sharper between 2015 and 2018, with three fewer cases per 100,000 people than 2004-2014 (P < .01). Similar patterns were seen in subanalyses of males and females, non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. The relative declines were largest in women, non-Hispanic Blacks, and people who lived outside of Metropolitan areas.

During a Q&A session that followed the presentation, Robert Smith, PhD, pointed out that the bar for eligibility of lung cancer risk has been set quite high, following the eligibility criteria for clinical trials. He noted that many patients who could be eligible for screening are still missed because of a lack of clinical routines designed to identify eligible patients. “We are missing opportunities to prevent avertable lung cancer deaths,” said Dr. Smith, senior vice president of cancer screening at the American Cancer Society.

On the other hand, screening-prompted biopsies have the potential to cause harm, particularly in patients who already have lung disease, said Douglas Allen Arenberg, MD, professor at the University of Michigan, Ann Arbor. “I think that’s what scares most people is the potential downside, which is very hard to measure outside of a clinical trial,” said Dr. Arenberg, who served as a discussant for the presentation.

One way to reduce that risk is to identify biomarkers, either for screens or for incidentally-detected nodules, that have good negative predictive value. “If I had a blood test that is as good as a negative PET scan, I’m going to be much more likely to say, ‘Yeah, you’re 40 and your grandfather had lung cancer. Maybe you should get a CT. If we had that, we could screen a lot more people. Right now, I would discourage anybody who is at low risk from getting screened because when they come to me, the biggest opportunity I have to do harm is when I do a biopsy, and you always remember the ones that go wrong,” he said.

Dr. Arenberg also called for improvements in electronic medical records to better flag at-risk patients. “I think we as physicians have to demand more of the software developers that create these EMRs for us,” he said.

Another study in the same session used data from 1,391,088 patients drawn from the National Cancer Database between 2010 and 2017 to examine trends in diagnosis of stage I cancer. In 2010, 23.5% of patients were diagnosed as stage I, versus 29.1% in 2017. Stage I incidence increased from 25.8% to 31.7% in non–small cell lung cancer, but there was no statistically significant change in small cell lung cancer. As with the SEER database study, the researchers noted that the shift toward stage I diagnoses predated the recommendation of LDCT.

Dr. Arenberg suggested that the trend may come down to increased frequency of CT scans, which often collect incidental images of the lungs. He added that better access to care may also be helping to drive the change. “How much of that might have had something to do with the introduction 5 or 10 years earlier of the Affordable Care Act and people just simply having access to care and taking advantage of that?” Dr. Arenberg said.

But Dr. Arenberg said that not even screening can explain all the data. He referenced a stage shift in patients of all age groups in the National Cancer Database study, even those too young to be eligible for screening. “There’s something else going on here. It would be nice for us to understand what caused these trends, so perhaps we could accentuate that trend even more, but stage shifts are clearly occurring in lung cancer,” Dr. Arenberg said.

Dr. Barta has received grants from Genentech Health Equity Innovations Fund. Dr. Arenberg has no relevant financial disclosures. Dr. Smith’s potential disclosures could not be ascertained.

An analysis of trends in lung cancer screening since March 2021 when the U.S. Preventive Services Task Force (USPSTF) expanded the eligibility criteria for lung cancer screening, shows that significantly more Black men have been screened for lung cancer, but not women or undereducated people.

The eligibility for lung cancer screening was expanded in 2021 to include men and women under 50 years old and people who smoke at least one pack of cigarettes a day for the last 20 years. “

“Expansion of screening criteria is a critical first step to achieving equity in lung cancer screening for all high-risk populations, but myriad challenges remain before individuals enter the door for screening,” wrote the authors, led by Julie A. Barta, MD, Thomas Jefferson University, Philadelphia. “Health policy changes must occur simultaneously with efforts to expand community outreach, overcome logistical barriers, and facilitate screening adherence. Only after comprehensive strategies to dismantle screening barriers are identified, validated, and implemented can there be a truly equitable landscape for lung cancer screening.”

For the study, published in JAMA Open Network, researchers examined rates of centralized lung cancer screening in the Baltimore area. In addition to expanding lung cancer screening generally, there was hope that the expanded criteria might increase uptake of screening in populations that are traditionally underserved, such as African American, Hispanic, and female patients. Of 815 people screened during the study period (March-December 2021), 161 were newly eligible for screening under the 2021 criteria.

“There’s been quite a bit of work in the field demonstrating that Black men and women develop lung cancer at more advanced stages of disease, and they often are diagnosed at younger ages and have fewer pack-years of smoking. So the hypothesis was that this would reduce some of the disparities seen in lung cancer screening by making more people eligible,” Dr. Barta said in an interview.

The researchers categorized participants as those who would have been eligible for screening under the USPSTF 2013 guideline (age 55 or older, 30 or more pack-years, quit within the past 15 years), and those who would be eligible under the 2021 guideline (age 50 or older, 20 or more pack-years, quit within the past 15 years). Of the 2021 cohort, 54.5% were African American, versus 39.5% of the 2013 cohort (P = .002). There were no differences between the cohorts with respect to education level or gender.

“Although we’ve seen some encouraging improvement in terms of getting more eligible patients into our screening program, there’s still a lot of work to be done in the field,” Dr. Barta said. “Diagnosing lung cancer at earlier stages of disease is more cost effective in general for the health care system than fighting lung cancer at advanced stages, which requires more complex and multimodal and prolonged therapies.”
 

New evidence: Chest CTs for lung cancer screening reduces incidence of advanced lung cancer

In an analysis of the SEER database presented in June at the annual meeting of the American Society of Clinical Oncology, the adoption of low-dose chest computed tomography (LDCT) led to fewer diagnoses of advanced lung cancer, although these declines varied significantly by race and ethnicity. Non-Hispanic Blacks seemed to benefit the most with a 55% decline (P < .01), while Hispanics had the lowest rate of decline at 41% (P < .01). The change was recommended by USPSTF in 2013 after the National Lung Screening Trial revealed a 20% relative reduction in mortality when CT scans were used instead of chest radiography. The Centers for Medicare and Medicaid Services approved coverage of the screen in 2015.

The SEER study looked at data from 400,343 individuals from 2004-2014 (preintervention) and 2015-2018 (postintervention). The age-adjusted incidence of advanced lung cancer declined during both periods, but the decline was sharper between 2015 and 2018, with three fewer cases per 100,000 people than 2004-2014 (P < .01). Similar patterns were seen in subanalyses of males and females, non-Hispanic Whites, non-Hispanic Blacks, and Hispanics. The relative declines were largest in women, non-Hispanic Blacks, and people who lived outside of Metropolitan areas.

During a Q&A session that followed the presentation, Robert Smith, PhD, pointed out that the bar for eligibility of lung cancer risk has been set quite high, following the eligibility criteria for clinical trials. He noted that many patients who could be eligible for screening are still missed because of a lack of clinical routines designed to identify eligible patients. “We are missing opportunities to prevent avertable lung cancer deaths,” said Dr. Smith, senior vice president of cancer screening at the American Cancer Society.

On the other hand, screening-prompted biopsies have the potential to cause harm, particularly in patients who already have lung disease, said Douglas Allen Arenberg, MD, professor at the University of Michigan, Ann Arbor. “I think that’s what scares most people is the potential downside, which is very hard to measure outside of a clinical trial,” said Dr. Arenberg, who served as a discussant for the presentation.

One way to reduce that risk is to identify biomarkers, either for screens or for incidentally-detected nodules, that have good negative predictive value. “If I had a blood test that is as good as a negative PET scan, I’m going to be much more likely to say, ‘Yeah, you’re 40 and your grandfather had lung cancer. Maybe you should get a CT. If we had that, we could screen a lot more people. Right now, I would discourage anybody who is at low risk from getting screened because when they come to me, the biggest opportunity I have to do harm is when I do a biopsy, and you always remember the ones that go wrong,” he said.

Dr. Arenberg also called for improvements in electronic medical records to better flag at-risk patients. “I think we as physicians have to demand more of the software developers that create these EMRs for us,” he said.

Another study in the same session used data from 1,391,088 patients drawn from the National Cancer Database between 2010 and 2017 to examine trends in diagnosis of stage I cancer. In 2010, 23.5% of patients were diagnosed as stage I, versus 29.1% in 2017. Stage I incidence increased from 25.8% to 31.7% in non–small cell lung cancer, but there was no statistically significant change in small cell lung cancer. As with the SEER database study, the researchers noted that the shift toward stage I diagnoses predated the recommendation of LDCT.

Dr. Arenberg suggested that the trend may come down to increased frequency of CT scans, which often collect incidental images of the lungs. He added that better access to care may also be helping to drive the change. “How much of that might have had something to do with the introduction 5 or 10 years earlier of the Affordable Care Act and people just simply having access to care and taking advantage of that?” Dr. Arenberg said.

But Dr. Arenberg said that not even screening can explain all the data. He referenced a stage shift in patients of all age groups in the National Cancer Database study, even those too young to be eligible for screening. “There’s something else going on here. It would be nice for us to understand what caused these trends, so perhaps we could accentuate that trend even more, but stage shifts are clearly occurring in lung cancer,” Dr. Arenberg said.

Dr. Barta has received grants from Genentech Health Equity Innovations Fund. Dr. Arenberg has no relevant financial disclosures. Dr. Smith’s potential disclosures could not be ascertained.

Treatment with berdazimer gel, a novel, topical nitric oxide–releasing agent, significantly improved clearance of molluscum contagiosum lesions, compared with placebo, in a study of 891 individuals at 55 clinics.

Molluscum contagiosum (MC) remains a common infection that, despite being self-limiting, may persist for months or years, and is associated with quality of life concerns and the need for ongoing therapy, wrote John C. Browning, MD, of Texas Dermatology and Laser Specialists, San Antonio, and colleagues, who conducted the phase 3 randomized study.

The infection is most common in children aged 1-14 years, and treatment may be needed in part to avoid infecting peers and family members, they said. No treatments for molluscum are currently approved by the Food and Drug Administration.

In the study, which was published in JAMA Dermatology, the researchers randomized 444 patients to berdazimer gel 10.3% and 447 to a placebo gel, applied once daily in a thin layer on all MC lesions for 12 weeks. The study was conducted at 55 clinics across the United States between Sept. 1, 2020, and July 21, 2021. The mean age of the patients was about 6.5 years (range was 0.9-49 years), and about 85% were White. Participants had 3-70 raised MC lesions; those with sexually transmitted MC or MC in the periocular area were excluded. The primary endpoint was complete clearance of MC lesions after 12 weeks of treatment. At 12 weeks, significantly more patients treated with berdazimer gel achieved complete clearance than those on vehicle (32.4% vs. 19.7%; P < .001). A total of 64 (14.4%) patients in the berdazimer group discontinued treatment because of MC clearance, compared with 40 patients (8.9%) in the vehicle group.

Most adverse events were mild or moderate, and rates of adverse events resulting in treatment discontinuation were low overall for both groups; the most common adverse events were application-site pain and erythema, which were mostly mild. Overall, 4.1% of berdazimer-treated patients and 0.7% of placebo patients discontinued the study because of adverse events.

The study findings were limited by several factors, including the small number of patients in subgroups for race, ethnicity, and age; and the lack of data on patients with sexually transmitted MC and on concomitant use with other topical MC therapies, the researchers noted.

However, the results represent the largest randomized clinical trial of berdazimer 10.3% to date, and support its potential as a first-line therapy for MC patients aged 6 months and older, according to the authors. “Berdazimer is under consideration as a first in-class therapeutic agent for MC and may provide a topical prescription alternative to other therapies used for this highly contagious and psychosocially challenging skin condition,” they said.

Having a reliable, steroid-free, safe, and efficacious medication to treat molluscum in the pediatric population, as early as age 6 months, that can be used at home would “change the whole therapeutic paradigm,” one of the study authors, Adelaide Hebert, MD, said in an interview at the Society for Pediatric Dermatology annual meeting in July, where she presented phase 2 data on berdazimer gel. “This is a common problem and the rate of infections among siblings if it goes untreated is 41%. Affected kids have a sense of isolation; they don’t get invited to swimming parties.”

The lack of a safe and effective topical therapy “has been challenging,” added Dr. Hebert, professor of dermatology and pediatrics, and chief of pediatric dermatology at the University of Texas, Houston. She noted that treatments that have been used but have not been successful include imiquimod. “I’m not impressed with tretinoin,” although it is prescribed for MC, and the most common treatment prescribed by pediatricians for molluscum – mupirocin – is “usually not effective,” she said.

Another MC treatment in trials

Another investigative treatment for molluscum contagiosum, VP-102, a drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, has been evaluated in phase 3 studies of patients with MC aged 2 years and older. The results of two phase 3 studies were published in 2020.

In May 2022, Verrica Pharmaceuticals, which is developing VP-102, announced that Food and Drug Administration approval had been delayed because of deficiencies identified at a contract manufacturing organization, and that the company was working with the agency to bring VP-102 to the market as soon as possible.

A step in the right direction

Although MC is self-resolving, cases last an average of 13.5 months, and “many families look to fast-forward their child’s experience with the infection,” Vikash S. Oza, MD, a pediatric dermatologist at New York University, New York, wrote in an editorial that accompanied the berdazimer study.

“To truly create a paradigm shift in the decision to treat MC, a therapeutic treatment would need to be developed that would lead to resolution of the infection over a short time frame (ideally, weeks) with minimal discomfort,” Dr. Oza noted. “Both VP-102 and berdazimer gel, 10.3%, have the potential to be the first-ever MC therapies approved by the U.S. Food and Drug Administration,” and families seeking to reduce MC in visible areas would welcome this option for a home therapy, he said.

However, Dr. Oza emphasized that potential barriers to widespread use of these therapies include whether the efficacy can be maintained in patients who fail to comply with daily application, and the ongoing need for office-based therapy to manage sexually transmitted MC in adults and periocular and perianal MC in children. The study was funded by Novan. Lead author Dr. Browning disclosed grants from Novan during the conduct of the study; Dr. Hebert reported grants from the University of Texas Health Science Center McGovern Medical School-Houston during the conduct of the study. Disclosures of other authors included having reported equity in Novan during the conduct of the study and receiving a grant from Novan. Dr. Oza had no financial conflicts to disclose.

Treatment with berdazimer gel, a novel, topical nitric oxide–releasing agent, significantly improved clearance of molluscum contagiosum lesions, compared with placebo, in a study of 891 individuals at 55 clinics.

Molluscum contagiosum (MC) remains a common infection that, despite being self-limiting, may persist for months or years, and is associated with quality of life concerns and the need for ongoing therapy, wrote John C. Browning, MD, of Texas Dermatology and Laser Specialists, San Antonio, and colleagues, who conducted the phase 3 randomized study.

The infection is most common in children aged 1-14 years, and treatment may be needed in part to avoid infecting peers and family members, they said. No treatments for molluscum are currently approved by the Food and Drug Administration.

In the study, which was published in JAMA Dermatology, the researchers randomized 444 patients to berdazimer gel 10.3% and 447 to a placebo gel, applied once daily in a thin layer on all MC lesions for 12 weeks. The study was conducted at 55 clinics across the United States between Sept. 1, 2020, and July 21, 2021. The mean age of the patients was about 6.5 years (range was 0.9-49 years), and about 85% were White. Participants had 3-70 raised MC lesions; those with sexually transmitted MC or MC in the periocular area were excluded. The primary endpoint was complete clearance of MC lesions after 12 weeks of treatment. At 12 weeks, significantly more patients treated with berdazimer gel achieved complete clearance than those on vehicle (32.4% vs. 19.7%; P < .001). A total of 64 (14.4%) patients in the berdazimer group discontinued treatment because of MC clearance, compared with 40 patients (8.9%) in the vehicle group.

Most adverse events were mild or moderate, and rates of adverse events resulting in treatment discontinuation were low overall for both groups; the most common adverse events were application-site pain and erythema, which were mostly mild. Overall, 4.1% of berdazimer-treated patients and 0.7% of placebo patients discontinued the study because of adverse events.

The study findings were limited by several factors, including the small number of patients in subgroups for race, ethnicity, and age; and the lack of data on patients with sexually transmitted MC and on concomitant use with other topical MC therapies, the researchers noted.

However, the results represent the largest randomized clinical trial of berdazimer 10.3% to date, and support its potential as a first-line therapy for MC patients aged 6 months and older, according to the authors. “Berdazimer is under consideration as a first in-class therapeutic agent for MC and may provide a topical prescription alternative to other therapies used for this highly contagious and psychosocially challenging skin condition,” they said.

Having a reliable, steroid-free, safe, and efficacious medication to treat molluscum in the pediatric population, as early as age 6 months, that can be used at home would “change the whole therapeutic paradigm,” one of the study authors, Adelaide Hebert, MD, said in an interview at the Society for Pediatric Dermatology annual meeting in July, where she presented phase 2 data on berdazimer gel. “This is a common problem and the rate of infections among siblings if it goes untreated is 41%. Affected kids have a sense of isolation; they don’t get invited to swimming parties.”

The lack of a safe and effective topical therapy “has been challenging,” added Dr. Hebert, professor of dermatology and pediatrics, and chief of pediatric dermatology at the University of Texas, Houston. She noted that treatments that have been used but have not been successful include imiquimod. “I’m not impressed with tretinoin,” although it is prescribed for MC, and the most common treatment prescribed by pediatricians for molluscum – mupirocin – is “usually not effective,” she said.

Another MC treatment in trials

Another investigative treatment for molluscum contagiosum, VP-102, a drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, has been evaluated in phase 3 studies of patients with MC aged 2 years and older. The results of two phase 3 studies were published in 2020.

In May 2022, Verrica Pharmaceuticals, which is developing VP-102, announced that Food and Drug Administration approval had been delayed because of deficiencies identified at a contract manufacturing organization, and that the company was working with the agency to bring VP-102 to the market as soon as possible.

A step in the right direction

Although MC is self-resolving, cases last an average of 13.5 months, and “many families look to fast-forward their child’s experience with the infection,” Vikash S. Oza, MD, a pediatric dermatologist at New York University, New York, wrote in an editorial that accompanied the berdazimer study.

“To truly create a paradigm shift in the decision to treat MC, a therapeutic treatment would need to be developed that would lead to resolution of the infection over a short time frame (ideally, weeks) with minimal discomfort,” Dr. Oza noted. “Both VP-102 and berdazimer gel, 10.3%, have the potential to be the first-ever MC therapies approved by the U.S. Food and Drug Administration,” and families seeking to reduce MC in visible areas would welcome this option for a home therapy, he said.

However, Dr. Oza emphasized that potential barriers to widespread use of these therapies include whether the efficacy can be maintained in patients who fail to comply with daily application, and the ongoing need for office-based therapy to manage sexually transmitted MC in adults and periocular and perianal MC in children. The study was funded by Novan. Lead author Dr. Browning disclosed grants from Novan during the conduct of the study; Dr. Hebert reported grants from the University of Texas Health Science Center McGovern Medical School-Houston during the conduct of the study. Disclosures of other authors included having reported equity in Novan during the conduct of the study and receiving a grant from Novan. Dr. Oza had no financial conflicts to disclose.

Treatment with berdazimer gel, a novel, topical nitric oxide–releasing agent, significantly improved clearance of molluscum contagiosum lesions, compared with placebo, in a study of 891 individuals at 55 clinics.

Molluscum contagiosum (MC) remains a common infection that, despite being self-limiting, may persist for months or years, and is associated with quality of life concerns and the need for ongoing therapy, wrote John C. Browning, MD, of Texas Dermatology and Laser Specialists, San Antonio, and colleagues, who conducted the phase 3 randomized study.

The infection is most common in children aged 1-14 years, and treatment may be needed in part to avoid infecting peers and family members, they said. No treatments for molluscum are currently approved by the Food and Drug Administration.

In the study, which was published in JAMA Dermatology, the researchers randomized 444 patients to berdazimer gel 10.3% and 447 to a placebo gel, applied once daily in a thin layer on all MC lesions for 12 weeks. The study was conducted at 55 clinics across the United States between Sept. 1, 2020, and July 21, 2021. The mean age of the patients was about 6.5 years (range was 0.9-49 years), and about 85% were White. Participants had 3-70 raised MC lesions; those with sexually transmitted MC or MC in the periocular area were excluded. The primary endpoint was complete clearance of MC lesions after 12 weeks of treatment. At 12 weeks, significantly more patients treated with berdazimer gel achieved complete clearance than those on vehicle (32.4% vs. 19.7%; P < .001). A total of 64 (14.4%) patients in the berdazimer group discontinued treatment because of MC clearance, compared with 40 patients (8.9%) in the vehicle group.

Most adverse events were mild or moderate, and rates of adverse events resulting in treatment discontinuation were low overall for both groups; the most common adverse events were application-site pain and erythema, which were mostly mild. Overall, 4.1% of berdazimer-treated patients and 0.7% of placebo patients discontinued the study because of adverse events.

The study findings were limited by several factors, including the small number of patients in subgroups for race, ethnicity, and age; and the lack of data on patients with sexually transmitted MC and on concomitant use with other topical MC therapies, the researchers noted.

However, the results represent the largest randomized clinical trial of berdazimer 10.3% to date, and support its potential as a first-line therapy for MC patients aged 6 months and older, according to the authors. “Berdazimer is under consideration as a first in-class therapeutic agent for MC and may provide a topical prescription alternative to other therapies used for this highly contagious and psychosocially challenging skin condition,” they said.

Having a reliable, steroid-free, safe, and efficacious medication to treat molluscum in the pediatric population, as early as age 6 months, that can be used at home would “change the whole therapeutic paradigm,” one of the study authors, Adelaide Hebert, MD, said in an interview at the Society for Pediatric Dermatology annual meeting in July, where she presented phase 2 data on berdazimer gel. “This is a common problem and the rate of infections among siblings if it goes untreated is 41%. Affected kids have a sense of isolation; they don’t get invited to swimming parties.”

The lack of a safe and effective topical therapy “has been challenging,” added Dr. Hebert, professor of dermatology and pediatrics, and chief of pediatric dermatology at the University of Texas, Houston. She noted that treatments that have been used but have not been successful include imiquimod. “I’m not impressed with tretinoin,” although it is prescribed for MC, and the most common treatment prescribed by pediatricians for molluscum – mupirocin – is “usually not effective,” she said.

Another MC treatment in trials

Another investigative treatment for molluscum contagiosum, VP-102, a drug-device combination of cantharidin 0.7% administered through a single-use precision applicator, has been evaluated in phase 3 studies of patients with MC aged 2 years and older. The results of two phase 3 studies were published in 2020.

In May 2022, Verrica Pharmaceuticals, which is developing VP-102, announced that Food and Drug Administration approval had been delayed because of deficiencies identified at a contract manufacturing organization, and that the company was working with the agency to bring VP-102 to the market as soon as possible.

A step in the right direction

Although MC is self-resolving, cases last an average of 13.5 months, and “many families look to fast-forward their child’s experience with the infection,” Vikash S. Oza, MD, a pediatric dermatologist at New York University, New York, wrote in an editorial that accompanied the berdazimer study.

“To truly create a paradigm shift in the decision to treat MC, a therapeutic treatment would need to be developed that would lead to resolution of the infection over a short time frame (ideally, weeks) with minimal discomfort,” Dr. Oza noted. “Both VP-102 and berdazimer gel, 10.3%, have the potential to be the first-ever MC therapies approved by the U.S. Food and Drug Administration,” and families seeking to reduce MC in visible areas would welcome this option for a home therapy, he said.

However, Dr. Oza emphasized that potential barriers to widespread use of these therapies include whether the efficacy can be maintained in patients who fail to comply with daily application, and the ongoing need for office-based therapy to manage sexually transmitted MC in adults and periocular and perianal MC in children. The study was funded by Novan. Lead author Dr. Browning disclosed grants from Novan during the conduct of the study; Dr. Hebert reported grants from the University of Texas Health Science Center McGovern Medical School-Houston during the conduct of the study. Disclosures of other authors included having reported equity in Novan during the conduct of the study and receiving a grant from Novan. Dr. Oza had no financial conflicts to disclose.

Young adults aged 15-34 years derive no significant health benefits from alcohol consumption, but moderate drinking may benefit the over-40 crowd, according to a new analysis.

The health risks and benefits of moderate alcohol consumption are complex and remain a hot topic of debate. The data suggest that small amounts of alcohol may reduce the risk of certain health outcomes over time, but increase the risk of others, wrote Dana Bryazka, MS, a researcher at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle, and colleagues, in a paper published in the Lancet.

“The amount of alcohol that minimizes health loss is likely to depend on the distribution of underlying causes of disease burden in a given population. Since this distribution varies widely by geography, age, sex, and time, the level of alcohol consumption associated with the lowest risk to health would depend on the age structure and disease composition of that population,” the researchers wrote.

“We estimate that 1.78 million people worldwide died due to alcohol use in 2020,” Ms. Bryazka said in an interview. “It is important that alcohol consumption guidelines and policies are updated to minimize this harm, particularly in the populations at greatest risk,” she said.  

“Existing alcohol consumption guidelines frequently vary by sex, with higher consumption thresholds set for males compared to females. Interestingly, with the currently available data we do not see evidence that risk of alcohol use varies by sex,” she noted.
 

Methods and results

In the study, the researchers conducted a systematic analysis of burden-weighted dose-response relative risk curves across 22 health outcomes. They used disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for the years 1990-2020 for 21 regions, including 204 countries and territories. The data were analyzed by 5-year age group, sex, and year for individuals aged 15-95 years and older. The researchers estimated the theoretical minimum risk exposure level (TMREL) and nondrinker equivalent (NDE), meaning the amount of alcohol at which the health risk equals that of a nondrinker.

One standard drink was defined as 10 g of pure alcohol, equivalent to a small glass of red wine (100 mL or 3.4 fluid ounces) at 13% alcohol by volume, a can or bottle of beer (375 mL or 12 fluid ounces) at 3.5% alcohol by volume, or a shot of whiskey or other spirits (30 mL or 1.0 fluid ounces) at 40% alcohol by volume.

Overall, the TMREL was low regardless of age, sex, time, or geography, and varied from 0 to 1.87 standard drinks per day. However, it was lowest for males aged 15-39 years (0.136 drinks per day) and only slightly higher for females aged 15-39 (0.273), representing 1-2 tenths of a standard drink.

For adults aged 40 and older without any underlying health conditions, drinking a small amount of alcohol may provide some benefits, such as reducing the risk of ischemic heart disease, stroke, and diabetes, the researchers noted. In general, for individuals aged 40-64 years, TMRELs ranged from about half a standard drink per day (0.527 drinks for males and 0.562 standard drinks per day for females) to almost two standard drinks (1.69 standard drinks per day for males and 1.82 for females). For those older than 65 years, the TMRELs represented just over 3 standard drinks per day (3.19 for males and 3.51 for females). For individuals aged 40 years and older, the distribution of disease burden varied by region, but was J-shaped across all regions, the researchers noted.

The researchers also found that those individuals consuming harmful amounts of alcohol were most likely to be aged 15-39 (59.1%) and male (76.9%).

The study findings were limited by several factors including the observational design and lack of data on drinking patterns, such as binge drinking, the researchers noted. Other limitations include the lack of data reflecting patterns of alcohol consumption during the COVID-19 pandemic, and exclusion of outcomes often associated with alcohol use, such as depression, anxiety, and dementia, that might reduce estimates of TMREL and NDE.

However, the results add to the ongoing discussion of the relationship between moderate alcohol consumption and health, the researchers said.

“The findings of this study support the development of tailored guidelines and recommendations on alcohol consumption by age and across regions and highlight that existing low consumption thresholds are too high for younger populations in all regions,” they concluded.
 

Consider individual factors when counseling patients

The takeaway message for primary care is that alcohol consumed in moderation can reduce the risk of ischemic heart disease, stroke, and diabetes, Ms. Bryazka noted. “However, it also increases the risk of many cancers, intentional and unintentional injuries, and infectious diseases like tuberculosis,” she said. “Of these health outcomes, young people are most likely to experience injuries, and as a result, we find that there are significant health risks associated with consuming alcohol for young people. Among older individuals, the relative proportions of these outcomes vary by geography, and so do the risks associated with consuming alcohol,” she explained.

“Importantly, our analysis was conducted at the population level; when evaluating risk at the individual level, it is also important to consider other factors such as the presence of comorbidities and interactions between alcohol and medications,” she emphasized.
 

Health and alcohol interaction is complicated

“These findings seemingly contradict a previous [Global Burden of Diseases, Injuries, and Risk Factors Study] estimate published in The Lancet, which emphasized that any alcohol use, regardless of amount, leads to health loss across populations,” wrote Robyn Burton, PhD, and Nick Sheron, MD, both of King’s College, London, in an accompanying comment.

However, the novel methods of weighting relative risk curves according to levels of underlying disease drive the difference in results, along with disaggregated estimates by age, sex, and region, they said.

“Across most geographical regions in this latest analysis, injuries accounted for most alcohol-related harm in younger age groups. This led to a minimum risk level of zero, or very close to zero, among individuals aged 15-39 years across all geographical regions,” which is lower than the level for older adults because of the shift in alcohol-related disease burden towards cardiovascular disease and cancers, they said. “This highlights the need to consider existing rates of disease in a population when trying to determine the total harm posed by alcohol,” the commentators wrote.

In an additional commentary, Tony Rao, MD, a visiting clinical research fellow in psychiatry at King’s College, London, noted that “the elephant in the room with this study is the interpretation of risk based on outcomes for cardiovascular disease – particularly in older people. We know that any purported health benefits from alcohol on the heart and circulation are balanced out by the increased risk from other conditions such as cancer, liver disease, and mental disorders such as depression and dementia,” Dr. Rao said. “If we are to simply draw the conclusion that older people should continue or start drinking small amounts because it protects against diseases affecting heart and circulation – which still remains controversial – other lifestyle changes or the use of drugs targeted at individual cardiovascular disorders seem like a less harmful way of improving health and wellbeing.”

Data can guide clinical practice

No previous study has examined the effect of the theoretical minimum risk of alcohol consumption by geography, age, sex, and time in the context of background disease rates, said Noel Deep, MD, in an interview.

“This study enabled the researchers to quantify the proportion of the population that consumed alcohol in amounts that exceeded the thresholds by location, age, sex, and year, and this can serve as a guide in our efforts to target the control of alcohol intake by individuals,” said Dr. Deep, a general internist in private practice in Antigo, Wisc. He also serves as chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

The first take-home message for clinicians is that even low levels of alcohol consumption can have deleterious effects on the health of patients, and patients should be advised accordingly based on the prevalence of diseases in that community and geographic area, Dr. Deep said. “Secondly, clinicians should also consider the risk of alcohol consumption on all forms of health impacts in a given population rather than just focusing on alcohol-related health conditions,” he added.

“This study provides us with the data to tailor our efforts in educating the clinicians and the public about the relationship between alcohol consumption and disease outcomes based on the observed disease rates in each population,” Dr. Deep explained. “The data should provide another reason for physicians to advise their younger patients, especially the younger males, to avoid or minimize alcohol use,” he said. The data also can help clinicians formulate public health messaging and community education to reduce harmful alcohol use, he added.

As for additional research, Dr. Deep said he would like to see data on the difference in the health-related effects of alcohol in binge-drinkers vs. those who regularly consume alcohol on a daily basis. “It would probably also be helpful to figure out what type of alcohol is being studied and the quality of the alcohol,” he said.

The study was supported by the Bill and Melinda Gates Foundation. Ms. Bryazka and colleagues had no financial conflicts to disclose. Dr. Burton disclosed serving as a consultant to the World Health Organization European Office for the Prevention and Control of Noncommunicable Diseases. Dr. Sheron had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Internal Medicine News.

The study was supported by the Bill and Melinda Gates Foundation.

Young adults aged 15-34 years derive no significant health benefits from alcohol consumption, but moderate drinking may benefit the over-40 crowd, according to a new analysis.

The health risks and benefits of moderate alcohol consumption are complex and remain a hot topic of debate. The data suggest that small amounts of alcohol may reduce the risk of certain health outcomes over time, but increase the risk of others, wrote Dana Bryazka, MS, a researcher at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle, and colleagues, in a paper published in the Lancet.

“The amount of alcohol that minimizes health loss is likely to depend on the distribution of underlying causes of disease burden in a given population. Since this distribution varies widely by geography, age, sex, and time, the level of alcohol consumption associated with the lowest risk to health would depend on the age structure and disease composition of that population,” the researchers wrote.

“We estimate that 1.78 million people worldwide died due to alcohol use in 2020,” Ms. Bryazka said in an interview. “It is important that alcohol consumption guidelines and policies are updated to minimize this harm, particularly in the populations at greatest risk,” she said.  

“Existing alcohol consumption guidelines frequently vary by sex, with higher consumption thresholds set for males compared to females. Interestingly, with the currently available data we do not see evidence that risk of alcohol use varies by sex,” she noted.
 

Methods and results

In the study, the researchers conducted a systematic analysis of burden-weighted dose-response relative risk curves across 22 health outcomes. They used disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for the years 1990-2020 for 21 regions, including 204 countries and territories. The data were analyzed by 5-year age group, sex, and year for individuals aged 15-95 years and older. The researchers estimated the theoretical minimum risk exposure level (TMREL) and nondrinker equivalent (NDE), meaning the amount of alcohol at which the health risk equals that of a nondrinker.

One standard drink was defined as 10 g of pure alcohol, equivalent to a small glass of red wine (100 mL or 3.4 fluid ounces) at 13% alcohol by volume, a can or bottle of beer (375 mL or 12 fluid ounces) at 3.5% alcohol by volume, or a shot of whiskey or other spirits (30 mL or 1.0 fluid ounces) at 40% alcohol by volume.

Overall, the TMREL was low regardless of age, sex, time, or geography, and varied from 0 to 1.87 standard drinks per day. However, it was lowest for males aged 15-39 years (0.136 drinks per day) and only slightly higher for females aged 15-39 (0.273), representing 1-2 tenths of a standard drink.

For adults aged 40 and older without any underlying health conditions, drinking a small amount of alcohol may provide some benefits, such as reducing the risk of ischemic heart disease, stroke, and diabetes, the researchers noted. In general, for individuals aged 40-64 years, TMRELs ranged from about half a standard drink per day (0.527 drinks for males and 0.562 standard drinks per day for females) to almost two standard drinks (1.69 standard drinks per day for males and 1.82 for females). For those older than 65 years, the TMRELs represented just over 3 standard drinks per day (3.19 for males and 3.51 for females). For individuals aged 40 years and older, the distribution of disease burden varied by region, but was J-shaped across all regions, the researchers noted.

The researchers also found that those individuals consuming harmful amounts of alcohol were most likely to be aged 15-39 (59.1%) and male (76.9%).

The study findings were limited by several factors including the observational design and lack of data on drinking patterns, such as binge drinking, the researchers noted. Other limitations include the lack of data reflecting patterns of alcohol consumption during the COVID-19 pandemic, and exclusion of outcomes often associated with alcohol use, such as depression, anxiety, and dementia, that might reduce estimates of TMREL and NDE.

However, the results add to the ongoing discussion of the relationship between moderate alcohol consumption and health, the researchers said.

“The findings of this study support the development of tailored guidelines and recommendations on alcohol consumption by age and across regions and highlight that existing low consumption thresholds are too high for younger populations in all regions,” they concluded.
 

Consider individual factors when counseling patients

The takeaway message for primary care is that alcohol consumed in moderation can reduce the risk of ischemic heart disease, stroke, and diabetes, Ms. Bryazka noted. “However, it also increases the risk of many cancers, intentional and unintentional injuries, and infectious diseases like tuberculosis,” she said. “Of these health outcomes, young people are most likely to experience injuries, and as a result, we find that there are significant health risks associated with consuming alcohol for young people. Among older individuals, the relative proportions of these outcomes vary by geography, and so do the risks associated with consuming alcohol,” she explained.

“Importantly, our analysis was conducted at the population level; when evaluating risk at the individual level, it is also important to consider other factors such as the presence of comorbidities and interactions between alcohol and medications,” she emphasized.
 

Health and alcohol interaction is complicated

“These findings seemingly contradict a previous [Global Burden of Diseases, Injuries, and Risk Factors Study] estimate published in The Lancet, which emphasized that any alcohol use, regardless of amount, leads to health loss across populations,” wrote Robyn Burton, PhD, and Nick Sheron, MD, both of King’s College, London, in an accompanying comment.

However, the novel methods of weighting relative risk curves according to levels of underlying disease drive the difference in results, along with disaggregated estimates by age, sex, and region, they said.

“Across most geographical regions in this latest analysis, injuries accounted for most alcohol-related harm in younger age groups. This led to a minimum risk level of zero, or very close to zero, among individuals aged 15-39 years across all geographical regions,” which is lower than the level for older adults because of the shift in alcohol-related disease burden towards cardiovascular disease and cancers, they said. “This highlights the need to consider existing rates of disease in a population when trying to determine the total harm posed by alcohol,” the commentators wrote.

In an additional commentary, Tony Rao, MD, a visiting clinical research fellow in psychiatry at King’s College, London, noted that “the elephant in the room with this study is the interpretation of risk based on outcomes for cardiovascular disease – particularly in older people. We know that any purported health benefits from alcohol on the heart and circulation are balanced out by the increased risk from other conditions such as cancer, liver disease, and mental disorders such as depression and dementia,” Dr. Rao said. “If we are to simply draw the conclusion that older people should continue or start drinking small amounts because it protects against diseases affecting heart and circulation – which still remains controversial – other lifestyle changes or the use of drugs targeted at individual cardiovascular disorders seem like a less harmful way of improving health and wellbeing.”

Data can guide clinical practice

No previous study has examined the effect of the theoretical minimum risk of alcohol consumption by geography, age, sex, and time in the context of background disease rates, said Noel Deep, MD, in an interview.

“This study enabled the researchers to quantify the proportion of the population that consumed alcohol in amounts that exceeded the thresholds by location, age, sex, and year, and this can serve as a guide in our efforts to target the control of alcohol intake by individuals,” said Dr. Deep, a general internist in private practice in Antigo, Wisc. He also serves as chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

The first take-home message for clinicians is that even low levels of alcohol consumption can have deleterious effects on the health of patients, and patients should be advised accordingly based on the prevalence of diseases in that community and geographic area, Dr. Deep said. “Secondly, clinicians should also consider the risk of alcohol consumption on all forms of health impacts in a given population rather than just focusing on alcohol-related health conditions,” he added.

“This study provides us with the data to tailor our efforts in educating the clinicians and the public about the relationship between alcohol consumption and disease outcomes based on the observed disease rates in each population,” Dr. Deep explained. “The data should provide another reason for physicians to advise their younger patients, especially the younger males, to avoid or minimize alcohol use,” he said. The data also can help clinicians formulate public health messaging and community education to reduce harmful alcohol use, he added.

As for additional research, Dr. Deep said he would like to see data on the difference in the health-related effects of alcohol in binge-drinkers vs. those who regularly consume alcohol on a daily basis. “It would probably also be helpful to figure out what type of alcohol is being studied and the quality of the alcohol,” he said.

The study was supported by the Bill and Melinda Gates Foundation. Ms. Bryazka and colleagues had no financial conflicts to disclose. Dr. Burton disclosed serving as a consultant to the World Health Organization European Office for the Prevention and Control of Noncommunicable Diseases. Dr. Sheron had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Internal Medicine News.

The study was supported by the Bill and Melinda Gates Foundation.

Young adults aged 15-34 years derive no significant health benefits from alcohol consumption, but moderate drinking may benefit the over-40 crowd, according to a new analysis.

The health risks and benefits of moderate alcohol consumption are complex and remain a hot topic of debate. The data suggest that small amounts of alcohol may reduce the risk of certain health outcomes over time, but increase the risk of others, wrote Dana Bryazka, MS, a researcher at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle, and colleagues, in a paper published in the Lancet.

“The amount of alcohol that minimizes health loss is likely to depend on the distribution of underlying causes of disease burden in a given population. Since this distribution varies widely by geography, age, sex, and time, the level of alcohol consumption associated with the lowest risk to health would depend on the age structure and disease composition of that population,” the researchers wrote.

“We estimate that 1.78 million people worldwide died due to alcohol use in 2020,” Ms. Bryazka said in an interview. “It is important that alcohol consumption guidelines and policies are updated to minimize this harm, particularly in the populations at greatest risk,” she said.  

“Existing alcohol consumption guidelines frequently vary by sex, with higher consumption thresholds set for males compared to females. Interestingly, with the currently available data we do not see evidence that risk of alcohol use varies by sex,” she noted.
 

Methods and results

In the study, the researchers conducted a systematic analysis of burden-weighted dose-response relative risk curves across 22 health outcomes. They used disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for the years 1990-2020 for 21 regions, including 204 countries and territories. The data were analyzed by 5-year age group, sex, and year for individuals aged 15-95 years and older. The researchers estimated the theoretical minimum risk exposure level (TMREL) and nondrinker equivalent (NDE), meaning the amount of alcohol at which the health risk equals that of a nondrinker.

One standard drink was defined as 10 g of pure alcohol, equivalent to a small glass of red wine (100 mL or 3.4 fluid ounces) at 13% alcohol by volume, a can or bottle of beer (375 mL or 12 fluid ounces) at 3.5% alcohol by volume, or a shot of whiskey or other spirits (30 mL or 1.0 fluid ounces) at 40% alcohol by volume.

Overall, the TMREL was low regardless of age, sex, time, or geography, and varied from 0 to 1.87 standard drinks per day. However, it was lowest for males aged 15-39 years (0.136 drinks per day) and only slightly higher for females aged 15-39 (0.273), representing 1-2 tenths of a standard drink.

For adults aged 40 and older without any underlying health conditions, drinking a small amount of alcohol may provide some benefits, such as reducing the risk of ischemic heart disease, stroke, and diabetes, the researchers noted. In general, for individuals aged 40-64 years, TMRELs ranged from about half a standard drink per day (0.527 drinks for males and 0.562 standard drinks per day for females) to almost two standard drinks (1.69 standard drinks per day for males and 1.82 for females). For those older than 65 years, the TMRELs represented just over 3 standard drinks per day (3.19 for males and 3.51 for females). For individuals aged 40 years and older, the distribution of disease burden varied by region, but was J-shaped across all regions, the researchers noted.

The researchers also found that those individuals consuming harmful amounts of alcohol were most likely to be aged 15-39 (59.1%) and male (76.9%).

The study findings were limited by several factors including the observational design and lack of data on drinking patterns, such as binge drinking, the researchers noted. Other limitations include the lack of data reflecting patterns of alcohol consumption during the COVID-19 pandemic, and exclusion of outcomes often associated with alcohol use, such as depression, anxiety, and dementia, that might reduce estimates of TMREL and NDE.

However, the results add to the ongoing discussion of the relationship between moderate alcohol consumption and health, the researchers said.

“The findings of this study support the development of tailored guidelines and recommendations on alcohol consumption by age and across regions and highlight that existing low consumption thresholds are too high for younger populations in all regions,” they concluded.
 

Consider individual factors when counseling patients

The takeaway message for primary care is that alcohol consumed in moderation can reduce the risk of ischemic heart disease, stroke, and diabetes, Ms. Bryazka noted. “However, it also increases the risk of many cancers, intentional and unintentional injuries, and infectious diseases like tuberculosis,” she said. “Of these health outcomes, young people are most likely to experience injuries, and as a result, we find that there are significant health risks associated with consuming alcohol for young people. Among older individuals, the relative proportions of these outcomes vary by geography, and so do the risks associated with consuming alcohol,” she explained.

“Importantly, our analysis was conducted at the population level; when evaluating risk at the individual level, it is also important to consider other factors such as the presence of comorbidities and interactions between alcohol and medications,” she emphasized.
 

Health and alcohol interaction is complicated

“These findings seemingly contradict a previous [Global Burden of Diseases, Injuries, and Risk Factors Study] estimate published in The Lancet, which emphasized that any alcohol use, regardless of amount, leads to health loss across populations,” wrote Robyn Burton, PhD, and Nick Sheron, MD, both of King’s College, London, in an accompanying comment.

However, the novel methods of weighting relative risk curves according to levels of underlying disease drive the difference in results, along with disaggregated estimates by age, sex, and region, they said.

“Across most geographical regions in this latest analysis, injuries accounted for most alcohol-related harm in younger age groups. This led to a minimum risk level of zero, or very close to zero, among individuals aged 15-39 years across all geographical regions,” which is lower than the level for older adults because of the shift in alcohol-related disease burden towards cardiovascular disease and cancers, they said. “This highlights the need to consider existing rates of disease in a population when trying to determine the total harm posed by alcohol,” the commentators wrote.

In an additional commentary, Tony Rao, MD, a visiting clinical research fellow in psychiatry at King’s College, London, noted that “the elephant in the room with this study is the interpretation of risk based on outcomes for cardiovascular disease – particularly in older people. We know that any purported health benefits from alcohol on the heart and circulation are balanced out by the increased risk from other conditions such as cancer, liver disease, and mental disorders such as depression and dementia,” Dr. Rao said. “If we are to simply draw the conclusion that older people should continue or start drinking small amounts because it protects against diseases affecting heart and circulation – which still remains controversial – other lifestyle changes or the use of drugs targeted at individual cardiovascular disorders seem like a less harmful way of improving health and wellbeing.”

Data can guide clinical practice

No previous study has examined the effect of the theoretical minimum risk of alcohol consumption by geography, age, sex, and time in the context of background disease rates, said Noel Deep, MD, in an interview.

“This study enabled the researchers to quantify the proportion of the population that consumed alcohol in amounts that exceeded the thresholds by location, age, sex, and year, and this can serve as a guide in our efforts to target the control of alcohol intake by individuals,” said Dr. Deep, a general internist in private practice in Antigo, Wisc. He also serves as chief medical officer and a staff physician at Aspirus Langlade Hospital in Antigo.

The first take-home message for clinicians is that even low levels of alcohol consumption can have deleterious effects on the health of patients, and patients should be advised accordingly based on the prevalence of diseases in that community and geographic area, Dr. Deep said. “Secondly, clinicians should also consider the risk of alcohol consumption on all forms of health impacts in a given population rather than just focusing on alcohol-related health conditions,” he added.

“This study provides us with the data to tailor our efforts in educating the clinicians and the public about the relationship between alcohol consumption and disease outcomes based on the observed disease rates in each population,” Dr. Deep explained. “The data should provide another reason for physicians to advise their younger patients, especially the younger males, to avoid or minimize alcohol use,” he said. The data also can help clinicians formulate public health messaging and community education to reduce harmful alcohol use, he added.

As for additional research, Dr. Deep said he would like to see data on the difference in the health-related effects of alcohol in binge-drinkers vs. those who regularly consume alcohol on a daily basis. “It would probably also be helpful to figure out what type of alcohol is being studied and the quality of the alcohol,” he said.

The study was supported by the Bill and Melinda Gates Foundation. Ms. Bryazka and colleagues had no financial conflicts to disclose. Dr. Burton disclosed serving as a consultant to the World Health Organization European Office for the Prevention and Control of Noncommunicable Diseases. Dr. Sheron had no financial conflicts to disclose. Dr. Deep had no financial conflicts to disclose, but serves on the Editorial Advisory Board of Internal Medicine News.

The study was supported by the Bill and Melinda Gates Foundation.