A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

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

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

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

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

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

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

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

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

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

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

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

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

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

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

The architecture of the glenohumeral joint makes it the most common large joint to become dislocated, accounting for approximately 45% of all dislocations. Anterior dislocation constitutes more than 95% of glenohumeral joint dislocations; posterior dislocation, only 2% to 5%.^1,2

For the family physician, determining appropriate follow-up after emergent reduction depends on several distinct variables, which we review here; subsequent treatment might involve, as we outline, physical therapy, immobilization, surgical intervention, or a combination of several modalities. Treatment decisions can make the difference between successful rehabilitation and potential disability, particularly in typically young and active patients.

Numerous mechanisms of injury

Anterior shoulder dislocations typically occur with the affected shoulder in a position of abduction and external rotation; 90% of patients are 21 to 30 years of age, and men are affected 3 times more often than women.² Unsurprisingly, athletes are affected most frequently, with the common sports-related mechanism of injury being either sudden pressure exerted on the abducted and externally rotated arm or a fall onto an outstretched hand with the arm elevated. Repetitive microtrauma from such sports as swimming, baseball, and volleyball can also lead to instability.

Bankart lesion. This tear of the anterior or inferior section of the labrum is the most characteristic lesion noted in anterior dislocations, found in 73% of first-time dislocations and 100% of recurrent dislocations.^3,4

Hills-Sachs lesion is often associated with a Bankart lesion. The Hills-Sachs lesion is an impaction fracture of the posterolateral aspect of the humeral head resulting from its displacement over the anterior lip of the glenoid. Hill-Sachs lesions are seen in 71% of first-time and recurrent dislocations.³

Less common concomitant injuries during anterior shoulder dislocation include rupture of the rotator-cuff tendons (particularly in patients older than 40 years), glenoid and proximal humerus fractures, a tear of the superior labrum (known as a “SLAP lesion”), cartilage injury, and neurovascular injury.

Posterior instability typically occurs as a result of a strong muscle contraction, as seen in electrocution or seizure; however, it can be caused by athletic trauma, particularly in football.⁵ Repetitive forces exerted on the forward-flexed and internally rotated shoulder position during blocking puts football players at increased risk of posterior instability.⁵

Continue to: Multidirectional instability

Multidirectional instability is more frequently attributable to congenital hyperlaxity of the glenohumeral joint capsule, rather than to acute injury. However, athletes can also develop capsular laxity from repetitive microtrauma to the shoulder.⁵

Emergent reduction: Prompt action needed

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort. (Typically, but not always, this is done in the emergency department.) It is crucial to have effective muscle relaxation before any attempt at reduction, to minimize the risk of iatrogenic injury to bone, cartilage, tendons, and neurovascular structures.

Muscle relaxation can be facilitated with intravenous midazolam or other agents, as specified by institutional protocol. Intra-articular lidocaine injection or intravenous fentanyl is often utilized in conjunction with the sedating agent to reduce pain and further accommodate relaxation.

Anterior reduction. Any one of several techniques can be used to perform emergent reduction of anterior shoulder dislocations, all of which have demonstrated success. The Milch technique is among the least traumatic for effective reduction.⁶ In this technique (FIGURE 1), the patient is supine; gentle but firm downward traction is applied to the humerus at the elbow of the affected arm while the arm is in abduction and external rotation. The provider can manipulate the humeral head at that point by placing a thumb in the patient’s axilla; the arm can also be further internally rotated and adducted until reduction is achieved.

Posterior reduction of a dislocation is performed while the patient is supine, with the body stabilized. Traction is applied on the adducted and internally rotated arm in conjunction with direct pressure on the posterior aspect of the humeral head (FIGURE 2).

Continue to: Follow-up actions

Follow-up actions. Before discharging the patient after reduction of a dislocation, it is essential to:

• perform post-reduction evaluation of shoulder stability at different levels of abduction
• perform a thorough neurovascular assessment
• obtain an anteroposterior (AP) radiograph to ensure proper positioning of the glenohumeral joint.

The reduced shoulder should be immobilized in a sling. The discharge plan should include pain management for several days and a follow-up appointment in 5 to 8 days with the primary care provider² (FIGURE 3).

Follow-up evaluation by the primary care provider

History. Prior to the initial examination at follow-up, obtain a comprehensive history that includes the nature of the injury and the direction of force that was placed on the shoulder. Determine whether the shoulder was reduced spontaneously or required manual reduction in the field or an emergency department. Note any associated injury sustained concurrently and the presence (or absence) of neck pain, numbness, tingling, or weakness in the affected arm.

Physical exam starts with thorough inspection of the affected shoulder, with comparison to the contralateral side, at rest and during shoulder motion. Palpation to reveal points of tenderness should include the anterior joint line, acromioclavicular joint, bicipital groove, subacromial space, acromion, and greater tuberosity.

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort.

Following inspection and palpation, assess active and passive range of motion in forward elevation, abduction, internal and external rotation at the side of the body, and internal and external rotation in shoulder abduction. Assessment might be limited by pain and apprehension, and should be performed within the patient’s comfortable range of motion.

Continue to: Once range of motion...

Once range of motion is determined, assess⁷:

• muscle power of the rotator cuff in abduction (for the supraspinatus muscle)
• resisted external rotation at the side of the body (the infraspinatus)
• resisted external rotation in abduction > 60° (the teres minor)
• resisted internal rotation (the subscapularis).

Specific tests for shoulder laxity and stability

It is important during the primary care follow-up examination to differentiate true instability and shoulder hyperlaxity, particularly in young, flexible patients (TABLE). Many of these patients present with painless hypermobility of the shoulder without true injury to the labrum or ligamentous structures. It might appear to the patient, or to family, that the shoulder is subluxating; however, the humeral head returns to a centered position on the glenoid in a hypermobile state—typically, without pain. Actual shoulder instability is defined as loss of the ability of the humeral head to re-center, accompanied by pain—pathology that is frequently associated with damage to the capsulolabral complex.

The load and shift test is used to assess anterior and posterior laxity. The patient is seated, and the forearm is allowed to rest on the thigh. Examination is performed using 1 hand to press anteriorly or posteriorly on the humeral head; the other hand is simultaneously positioned on the joint line to feel movement of the humeral head in relation to the glenoid (FIGURE 4).

The apprehension test is a common maneuver used to assess anterior shoulder instability. It is performed by positioning the affected arm to 90° external rotation and then elevating it to 90° abduction. Although this maneuver can be performed with the patient upright, it is beneficial to have them supine, to more easily control the arm (FIGURE 5). A positive test is noted when the patient reports a sensation of impending instability (apprehension), rather than pain alone.

Relocation test. When the apprehension test is positive, the supine position can be exploited to further perform the relocation test, in 2 stages (FIGURE 6):

• Apply a posteriorly directed force on the humeral head, which stabilizes the shoulder and typically alleviates symptoms.
• Release pressure quickly from the humeral head to assess recurrence of pain and apprehension as the humeral head snaps back against the anterior labrum.

Continue to: Combined, apprehension and relocation...

Combined, apprehension and relocation tests to identify anterior shoulder instability have been shown to significantly improve specificity while maintaining sensitivity.⁸

The posterior apprehension test is used to assess posterior instability. The patient is supine; the affected arm is placed in flexion, adduction, and internal rotation; and posterior pressure is applied (FIGURE 7). A positive test is noted when pain is reported at the posterior aspect of the shoulder. Clicking might be noted as the humeral head dislocates rearward.¹

Sulcus sign. Multidirectional instability is elicited using the sulcus sign. While the patient is seated upright, arms resting at their sides, a direct downward pull at elbow level will, when positive, reveal a depression (sulcus) at the lateral aspect of the affected shoulder as the humeral head translates inferiorly (FIGURE 8). A positive sulcus sign is documented in 3 grades, according to the amount of translation¹:

• Grade I: < 1 cm
• Grade II: 1-2 cm
• Grade III: > 2 cm.

Neurovascular status should be verified at every physical evaluation, with motor and sensory function tested in the axillary, musculocutaneous, median, radial, and ulnar nerve distributions. If nerve injury is suspected, electromyography and nerve-conduction testing is indicated.^9-13 Vascular compromise is much less common but equally important to assess.¹¹

Use of imaging

Post-reduction radiographs, including internal and external AP—and especially axillary—views are invaluable. Not only do they help to ensure reduction, but they also help to assess for fracture. A magnetic resonance imaging (MRI) arthrogram is the preferred imaging modality if a labral tear is suspected (FIGURE 9). Other concomitant shoulder injuries, such as subtle bone fracture, rotator cuff tear, and biceps pathology can also be reliably diagnosed with noncontrast MRI.

Continue to: Roadmap for treatment

The rate of recurrence after a first anterior shoulder dislocation is strongly associated with a person’s age and level of activity. Active patients younger than 20 years have a 92% to 96% recurrence rate¹⁴; patients 20 to 40 years, 25% to 48%; and patients older than 40 years, < 10%.¹⁵

Young, athletic patients who are treated nonoperatively are left at an unacceptably high risk of recurrence, leading to progressive damage to bony and soft-tissue structures.^16,17 Surgical labral repair after a first-time anterior dislocation produced improved outcomes in terms of recurrent dislocation (7.9%), compared to outcomes after nonsurgical treatment (52.9%),¹⁴ and has been associated with a lower incidence of future glenohumeral osteoarthritis.¹⁸ For those reasons, we recommend referral to an orthopedic surgeon for all patients younger than 20 years who sustain an anterior shoulder dislocation.

Patients older than 20 years who do not have concomitant shoulder injury, and who demonstrate full strength in abduction, external rotation, and internal rotation of the shoulder on clinical examination, have a low probability of associated rotator-cuff tear. They can be immobilized in a sling for 1 to 3 weeks, followed by a 6 to 12–week regimen of physical therapy.

Concomitant tear of the rotator cuff. Weakness on examination requires MRI or a magnetic resonance arthrogram for evaluation of associated rotator-cuff tear. A tear identified on MRI should be referred to an orthopedic surgeon because timely repair can be crucial to attaining best outcomes. Conservative treatment of traumatic full-­tendon rotator-cuff tear is associated with poor results, progression in the size of the tear, and advancement of muscle atrophy.^19,20 For patients younger than 40 years, arthroscopic rotator-cuff repair, with or without labral repair, produces excellent clinical outcomes, carries a low risk of complications, and results in a > 95% rate of return to a preoperative level of recreational and job activities.²¹

Patients who demonstrate weakness of the rotator-cuff muscles on examination, but who do not have a tear noted on MRI, should be evaluated by electromyography and nerve-conduction testing to assess nerve injury as an alternative cause of weakness.^10,11 If a neurologic deficit is found on nerve-conduction testing, the patient should be referred for neurologic evaluation.¹⁰

Continue to: Patients with negative findings...

Patients with negative findings on MRI and nerve-conduction studies should be offered physical therapy. Patients with recurrent anterior shoulder dislocation should be referred to an orthopedic surgeon for surgical repair. Frequently, improper or delayed treatment with chronic instability results in degenerative arthropathy of the joint²² (FIGURE 10).

Posterior and multidirectional instability can typically be treated conservatively; however, whereas posterior dislocation typically must be immobilized for 3 to 6 weeks post reduction, multidirectional instability does not require immobilization. Instead, physical therapy should start as soon as possible. In these cases, recurrent dislocation or subluxation that persists after conservative treatment should be referred for possible surgical intervention.⁵

Instability with associated fracture

Fracture concomitant with dislocation most commonly involves the humeral neck, humeral head, greater tuberosity, or the glenoid itself.² Clinical variables that predict a fracture associated with shoulder dislocation include²³:

• first episode of dislocation
• age ≥ 40 years
• fall from higher than 1 flight of stairs
• fight or assault
• motor vehicle crash.

A computed tomography scan with 3-dimensional reconstruction can help characterize associated fracture accurately—including location, size, and displacement—and can play an important role in treatment planning and prognosis in these complicated injuries. Displaced fracture should be referred to an orthopedic surgeon. Nondisplaced fracture of the humeral head or greater tuberosity (FIGURE 11) poses less risk of complications and can be treated conservatively with 6 weeks in an arm sling, followed by physical therapy.²⁴

Summing up

Management of shoulder dislocation must, first, be tailored to the individual and, second, account for several interactive factors—including age, direction of instability, functional demands, risk of recurrence, and associated injuries. In many patients, conservative treatment produces a favorable long-term outcome. Particularly in young, active patients with anterior shoulder instability, most surgeons consider open or arthroscopic reconstruction to be the treatment of choice.^2,18

Continue to: Pre-reduction and post-reduction...

Pre-reduction and post-reduction imaging should be carefully examined for the presence of concomitant injury, which might change the preferred treatment modality appreciably.

Last, communication among emergency department providers, the primary care provider, orthopedist, radiologist, and neurologist is crucial for determining an appropriate patient-centered approach to initial and long-term management.

CORRESPONDENCE
Nata Parnes, MD, Carthage Area Hospital, 3 Bridge Street, Carthage, NY; [email protected]

The architecture of the glenohumeral joint makes it the most common large joint to become dislocated, accounting for approximately 45% of all dislocations. Anterior dislocation constitutes more than 95% of glenohumeral joint dislocations; posterior dislocation, only 2% to 5%.^1,2

For the family physician, determining appropriate follow-up after emergent reduction depends on several distinct variables, which we review here; subsequent treatment might involve, as we outline, physical therapy, immobilization, surgical intervention, or a combination of several modalities. Treatment decisions can make the difference between successful rehabilitation and potential disability, particularly in typically young and active patients.

Numerous mechanisms of injury

Anterior shoulder dislocations typically occur with the affected shoulder in a position of abduction and external rotation; 90% of patients are 21 to 30 years of age, and men are affected 3 times more often than women.² Unsurprisingly, athletes are affected most frequently, with the common sports-related mechanism of injury being either sudden pressure exerted on the abducted and externally rotated arm or a fall onto an outstretched hand with the arm elevated. Repetitive microtrauma from such sports as swimming, baseball, and volleyball can also lead to instability.

Bankart lesion. This tear of the anterior or inferior section of the labrum is the most characteristic lesion noted in anterior dislocations, found in 73% of first-time dislocations and 100% of recurrent dislocations.^3,4

Hills-Sachs lesion is often associated with a Bankart lesion. The Hills-Sachs lesion is an impaction fracture of the posterolateral aspect of the humeral head resulting from its displacement over the anterior lip of the glenoid. Hill-Sachs lesions are seen in 71% of first-time and recurrent dislocations.³

Less common concomitant injuries during anterior shoulder dislocation include rupture of the rotator-cuff tendons (particularly in patients older than 40 years), glenoid and proximal humerus fractures, a tear of the superior labrum (known as a “SLAP lesion”), cartilage injury, and neurovascular injury.

Posterior instability typically occurs as a result of a strong muscle contraction, as seen in electrocution or seizure; however, it can be caused by athletic trauma, particularly in football.⁵ Repetitive forces exerted on the forward-flexed and internally rotated shoulder position during blocking puts football players at increased risk of posterior instability.⁵

Continue to: Multidirectional instability

Multidirectional instability is more frequently attributable to congenital hyperlaxity of the glenohumeral joint capsule, rather than to acute injury. However, athletes can also develop capsular laxity from repetitive microtrauma to the shoulder.⁵

Emergent reduction: Prompt action needed

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort. (Typically, but not always, this is done in the emergency department.) It is crucial to have effective muscle relaxation before any attempt at reduction, to minimize the risk of iatrogenic injury to bone, cartilage, tendons, and neurovascular structures.

Muscle relaxation can be facilitated with intravenous midazolam or other agents, as specified by institutional protocol. Intra-articular lidocaine injection or intravenous fentanyl is often utilized in conjunction with the sedating agent to reduce pain and further accommodate relaxation.

Anterior reduction. Any one of several techniques can be used to perform emergent reduction of anterior shoulder dislocations, all of which have demonstrated success. The Milch technique is among the least traumatic for effective reduction.⁶ In this technique (FIGURE 1), the patient is supine; gentle but firm downward traction is applied to the humerus at the elbow of the affected arm while the arm is in abduction and external rotation. The provider can manipulate the humeral head at that point by placing a thumb in the patient’s axilla; the arm can also be further internally rotated and adducted until reduction is achieved.

Posterior reduction of a dislocation is performed while the patient is supine, with the body stabilized. Traction is applied on the adducted and internally rotated arm in conjunction with direct pressure on the posterior aspect of the humeral head (FIGURE 2).

Continue to: Follow-up actions

Follow-up actions. Before discharging the patient after reduction of a dislocation, it is essential to:

• perform post-reduction evaluation of shoulder stability at different levels of abduction
• perform a thorough neurovascular assessment
• obtain an anteroposterior (AP) radiograph to ensure proper positioning of the glenohumeral joint.

The reduced shoulder should be immobilized in a sling. The discharge plan should include pain management for several days and a follow-up appointment in 5 to 8 days with the primary care provider² (FIGURE 3).

Follow-up evaluation by the primary care provider

History. Prior to the initial examination at follow-up, obtain a comprehensive history that includes the nature of the injury and the direction of force that was placed on the shoulder. Determine whether the shoulder was reduced spontaneously or required manual reduction in the field or an emergency department. Note any associated injury sustained concurrently and the presence (or absence) of neck pain, numbness, tingling, or weakness in the affected arm.

Physical exam starts with thorough inspection of the affected shoulder, with comparison to the contralateral side, at rest and during shoulder motion. Palpation to reveal points of tenderness should include the anterior joint line, acromioclavicular joint, bicipital groove, subacromial space, acromion, and greater tuberosity.

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort.

Following inspection and palpation, assess active and passive range of motion in forward elevation, abduction, internal and external rotation at the side of the body, and internal and external rotation in shoulder abduction. Assessment might be limited by pain and apprehension, and should be performed within the patient’s comfortable range of motion.

Continue to: Once range of motion...

Once range of motion is determined, assess⁷:

• muscle power of the rotator cuff in abduction (for the supraspinatus muscle)
• resisted external rotation at the side of the body (the infraspinatus)
• resisted external rotation in abduction > 60° (the teres minor)
• resisted internal rotation (the subscapularis).

Specific tests for shoulder laxity and stability

It is important during the primary care follow-up examination to differentiate true instability and shoulder hyperlaxity, particularly in young, flexible patients (TABLE). Many of these patients present with painless hypermobility of the shoulder without true injury to the labrum or ligamentous structures. It might appear to the patient, or to family, that the shoulder is subluxating; however, the humeral head returns to a centered position on the glenoid in a hypermobile state—typically, without pain. Actual shoulder instability is defined as loss of the ability of the humeral head to re-center, accompanied by pain—pathology that is frequently associated with damage to the capsulolabral complex.

The load and shift test is used to assess anterior and posterior laxity. The patient is seated, and the forearm is allowed to rest on the thigh. Examination is performed using 1 hand to press anteriorly or posteriorly on the humeral head; the other hand is simultaneously positioned on the joint line to feel movement of the humeral head in relation to the glenoid (FIGURE 4).

The apprehension test is a common maneuver used to assess anterior shoulder instability. It is performed by positioning the affected arm to 90° external rotation and then elevating it to 90° abduction. Although this maneuver can be performed with the patient upright, it is beneficial to have them supine, to more easily control the arm (FIGURE 5). A positive test is noted when the patient reports a sensation of impending instability (apprehension), rather than pain alone.

Relocation test. When the apprehension test is positive, the supine position can be exploited to further perform the relocation test, in 2 stages (FIGURE 6):

• Apply a posteriorly directed force on the humeral head, which stabilizes the shoulder and typically alleviates symptoms.
• Release pressure quickly from the humeral head to assess recurrence of pain and apprehension as the humeral head snaps back against the anterior labrum.

Continue to: Combined, apprehension and relocation...

Combined, apprehension and relocation tests to identify anterior shoulder instability have been shown to significantly improve specificity while maintaining sensitivity.⁸

The posterior apprehension test is used to assess posterior instability. The patient is supine; the affected arm is placed in flexion, adduction, and internal rotation; and posterior pressure is applied (FIGURE 7). A positive test is noted when pain is reported at the posterior aspect of the shoulder. Clicking might be noted as the humeral head dislocates rearward.¹

Sulcus sign. Multidirectional instability is elicited using the sulcus sign. While the patient is seated upright, arms resting at their sides, a direct downward pull at elbow level will, when positive, reveal a depression (sulcus) at the lateral aspect of the affected shoulder as the humeral head translates inferiorly (FIGURE 8). A positive sulcus sign is documented in 3 grades, according to the amount of translation¹:

• Grade I: < 1 cm
• Grade II: 1-2 cm
• Grade III: > 2 cm.

Neurovascular status should be verified at every physical evaluation, with motor and sensory function tested in the axillary, musculocutaneous, median, radial, and ulnar nerve distributions. If nerve injury is suspected, electromyography and nerve-conduction testing is indicated.^9-13 Vascular compromise is much less common but equally important to assess.¹¹

Use of imaging

Post-reduction radiographs, including internal and external AP—and especially axillary—views are invaluable. Not only do they help to ensure reduction, but they also help to assess for fracture. A magnetic resonance imaging (MRI) arthrogram is the preferred imaging modality if a labral tear is suspected (FIGURE 9). Other concomitant shoulder injuries, such as subtle bone fracture, rotator cuff tear, and biceps pathology can also be reliably diagnosed with noncontrast MRI.

Continue to: Roadmap for treatment

The rate of recurrence after a first anterior shoulder dislocation is strongly associated with a person’s age and level of activity. Active patients younger than 20 years have a 92% to 96% recurrence rate¹⁴; patients 20 to 40 years, 25% to 48%; and patients older than 40 years, < 10%.¹⁵

Young, athletic patients who are treated nonoperatively are left at an unacceptably high risk of recurrence, leading to progressive damage to bony and soft-tissue structures.^16,17 Surgical labral repair after a first-time anterior dislocation produced improved outcomes in terms of recurrent dislocation (7.9%), compared to outcomes after nonsurgical treatment (52.9%),¹⁴ and has been associated with a lower incidence of future glenohumeral osteoarthritis.¹⁸ For those reasons, we recommend referral to an orthopedic surgeon for all patients younger than 20 years who sustain an anterior shoulder dislocation.

Patients older than 20 years who do not have concomitant shoulder injury, and who demonstrate full strength in abduction, external rotation, and internal rotation of the shoulder on clinical examination, have a low probability of associated rotator-cuff tear. They can be immobilized in a sling for 1 to 3 weeks, followed by a 6 to 12–week regimen of physical therapy.

Concomitant tear of the rotator cuff. Weakness on examination requires MRI or a magnetic resonance arthrogram for evaluation of associated rotator-cuff tear. A tear identified on MRI should be referred to an orthopedic surgeon because timely repair can be crucial to attaining best outcomes. Conservative treatment of traumatic full-­tendon rotator-cuff tear is associated with poor results, progression in the size of the tear, and advancement of muscle atrophy.^19,20 For patients younger than 40 years, arthroscopic rotator-cuff repair, with or without labral repair, produces excellent clinical outcomes, carries a low risk of complications, and results in a > 95% rate of return to a preoperative level of recreational and job activities.²¹

Patients who demonstrate weakness of the rotator-cuff muscles on examination, but who do not have a tear noted on MRI, should be evaluated by electromyography and nerve-conduction testing to assess nerve injury as an alternative cause of weakness.^10,11 If a neurologic deficit is found on nerve-conduction testing, the patient should be referred for neurologic evaluation.¹⁰

Continue to: Patients with negative findings...

Patients with negative findings on MRI and nerve-conduction studies should be offered physical therapy. Patients with recurrent anterior shoulder dislocation should be referred to an orthopedic surgeon for surgical repair. Frequently, improper or delayed treatment with chronic instability results in degenerative arthropathy of the joint²² (FIGURE 10).

Posterior and multidirectional instability can typically be treated conservatively; however, whereas posterior dislocation typically must be immobilized for 3 to 6 weeks post reduction, multidirectional instability does not require immobilization. Instead, physical therapy should start as soon as possible. In these cases, recurrent dislocation or subluxation that persists after conservative treatment should be referred for possible surgical intervention.⁵

Instability with associated fracture

Fracture concomitant with dislocation most commonly involves the humeral neck, humeral head, greater tuberosity, or the glenoid itself.² Clinical variables that predict a fracture associated with shoulder dislocation include²³:

• first episode of dislocation
• age ≥ 40 years
• fall from higher than 1 flight of stairs
• fight or assault
• motor vehicle crash.

A computed tomography scan with 3-dimensional reconstruction can help characterize associated fracture accurately—including location, size, and displacement—and can play an important role in treatment planning and prognosis in these complicated injuries. Displaced fracture should be referred to an orthopedic surgeon. Nondisplaced fracture of the humeral head or greater tuberosity (FIGURE 11) poses less risk of complications and can be treated conservatively with 6 weeks in an arm sling, followed by physical therapy.²⁴

Summing up

Management of shoulder dislocation must, first, be tailored to the individual and, second, account for several interactive factors—including age, direction of instability, functional demands, risk of recurrence, and associated injuries. In many patients, conservative treatment produces a favorable long-term outcome. Particularly in young, active patients with anterior shoulder instability, most surgeons consider open or arthroscopic reconstruction to be the treatment of choice.^2,18

Continue to: Pre-reduction and post-reduction...

Pre-reduction and post-reduction imaging should be carefully examined for the presence of concomitant injury, which might change the preferred treatment modality appreciably.

Last, communication among emergency department providers, the primary care provider, orthopedist, radiologist, and neurologist is crucial for determining an appropriate patient-centered approach to initial and long-term management.

CORRESPONDENCE
Nata Parnes, MD, Carthage Area Hospital, 3 Bridge Street, Carthage, NY; [email protected]

The architecture of the glenohumeral joint makes it the most common large joint to become dislocated, accounting for approximately 45% of all dislocations. Anterior dislocation constitutes more than 95% of glenohumeral joint dislocations; posterior dislocation, only 2% to 5%.^1,2

For the family physician, determining appropriate follow-up after emergent reduction depends on several distinct variables, which we review here; subsequent treatment might involve, as we outline, physical therapy, immobilization, surgical intervention, or a combination of several modalities. Treatment decisions can make the difference between successful rehabilitation and potential disability, particularly in typically young and active patients.

Numerous mechanisms of injury

Anterior shoulder dislocations typically occur with the affected shoulder in a position of abduction and external rotation; 90% of patients are 21 to 30 years of age, and men are affected 3 times more often than women.² Unsurprisingly, athletes are affected most frequently, with the common sports-related mechanism of injury being either sudden pressure exerted on the abducted and externally rotated arm or a fall onto an outstretched hand with the arm elevated. Repetitive microtrauma from such sports as swimming, baseball, and volleyball can also lead to instability.

Bankart lesion. This tear of the anterior or inferior section of the labrum is the most characteristic lesion noted in anterior dislocations, found in 73% of first-time dislocations and 100% of recurrent dislocations.^3,4

Hills-Sachs lesion is often associated with a Bankart lesion. The Hills-Sachs lesion is an impaction fracture of the posterolateral aspect of the humeral head resulting from its displacement over the anterior lip of the glenoid. Hill-Sachs lesions are seen in 71% of first-time and recurrent dislocations.³

Less common concomitant injuries during anterior shoulder dislocation include rupture of the rotator-cuff tendons (particularly in patients older than 40 years), glenoid and proximal humerus fractures, a tear of the superior labrum (known as a “SLAP lesion”), cartilage injury, and neurovascular injury.

Posterior instability typically occurs as a result of a strong muscle contraction, as seen in electrocution or seizure; however, it can be caused by athletic trauma, particularly in football.⁵ Repetitive forces exerted on the forward-flexed and internally rotated shoulder position during blocking puts football players at increased risk of posterior instability.⁵

Continue to: Multidirectional instability

Multidirectional instability is more frequently attributable to congenital hyperlaxity of the glenohumeral joint capsule, rather than to acute injury. However, athletes can also develop capsular laxity from repetitive microtrauma to the shoulder.⁵

Emergent reduction: Prompt action needed

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort. (Typically, but not always, this is done in the emergency department.) It is crucial to have effective muscle relaxation before any attempt at reduction, to minimize the risk of iatrogenic injury to bone, cartilage, tendons, and neurovascular structures.

Muscle relaxation can be facilitated with intravenous midazolam or other agents, as specified by institutional protocol. Intra-articular lidocaine injection or intravenous fentanyl is often utilized in conjunction with the sedating agent to reduce pain and further accommodate relaxation.

Anterior reduction. Any one of several techniques can be used to perform emergent reduction of anterior shoulder dislocations, all of which have demonstrated success. The Milch technique is among the least traumatic for effective reduction.⁶ In this technique (FIGURE 1), the patient is supine; gentle but firm downward traction is applied to the humerus at the elbow of the affected arm while the arm is in abduction and external rotation. The provider can manipulate the humeral head at that point by placing a thumb in the patient’s axilla; the arm can also be further internally rotated and adducted until reduction is achieved.

Posterior reduction of a dislocation is performed while the patient is supine, with the body stabilized. Traction is applied on the adducted and internally rotated arm in conjunction with direct pressure on the posterior aspect of the humeral head (FIGURE 2).

Continue to: Follow-up actions

Follow-up actions. Before discharging the patient after reduction of a dislocation, it is essential to:

• perform post-reduction evaluation of shoulder stability at different levels of abduction
• perform a thorough neurovascular assessment
• obtain an anteroposterior (AP) radiograph to ensure proper positioning of the glenohumeral joint.

The reduced shoulder should be immobilized in a sling. The discharge plan should include pain management for several days and a follow-up appointment in 5 to 8 days with the primary care provider² (FIGURE 3).

Follow-up evaluation by the primary care provider

History. Prior to the initial examination at follow-up, obtain a comprehensive history that includes the nature of the injury and the direction of force that was placed on the shoulder. Determine whether the shoulder was reduced spontaneously or required manual reduction in the field or an emergency department. Note any associated injury sustained concurrently and the presence (or absence) of neck pain, numbness, tingling, or weakness in the affected arm.

Physical exam starts with thorough inspection of the affected shoulder, with comparison to the contralateral side, at rest and during shoulder motion. Palpation to reveal points of tenderness should include the anterior joint line, acromioclavicular joint, bicipital groove, subacromial space, acromion, and greater tuberosity.

Acute dislocation of the shoulder should be reduced as soon as possible to minimize neurovascular injury and patient discomfort.

Following inspection and palpation, assess active and passive range of motion in forward elevation, abduction, internal and external rotation at the side of the body, and internal and external rotation in shoulder abduction. Assessment might be limited by pain and apprehension, and should be performed within the patient’s comfortable range of motion.

Continue to: Once range of motion...

Once range of motion is determined, assess⁷:

• muscle power of the rotator cuff in abduction (for the supraspinatus muscle)
• resisted external rotation at the side of the body (the infraspinatus)
• resisted external rotation in abduction > 60° (the teres minor)
• resisted internal rotation (the subscapularis).

Specific tests for shoulder laxity and stability

It is important during the primary care follow-up examination to differentiate true instability and shoulder hyperlaxity, particularly in young, flexible patients (TABLE). Many of these patients present with painless hypermobility of the shoulder without true injury to the labrum or ligamentous structures. It might appear to the patient, or to family, that the shoulder is subluxating; however, the humeral head returns to a centered position on the glenoid in a hypermobile state—typically, without pain. Actual shoulder instability is defined as loss of the ability of the humeral head to re-center, accompanied by pain—pathology that is frequently associated with damage to the capsulolabral complex.

The load and shift test is used to assess anterior and posterior laxity. The patient is seated, and the forearm is allowed to rest on the thigh. Examination is performed using 1 hand to press anteriorly or posteriorly on the humeral head; the other hand is simultaneously positioned on the joint line to feel movement of the humeral head in relation to the glenoid (FIGURE 4).

The apprehension test is a common maneuver used to assess anterior shoulder instability. It is performed by positioning the affected arm to 90° external rotation and then elevating it to 90° abduction. Although this maneuver can be performed with the patient upright, it is beneficial to have them supine, to more easily control the arm (FIGURE 5). A positive test is noted when the patient reports a sensation of impending instability (apprehension), rather than pain alone.

Relocation test. When the apprehension test is positive, the supine position can be exploited to further perform the relocation test, in 2 stages (FIGURE 6):

• Apply a posteriorly directed force on the humeral head, which stabilizes the shoulder and typically alleviates symptoms.
• Release pressure quickly from the humeral head to assess recurrence of pain and apprehension as the humeral head snaps back against the anterior labrum.

Continue to: Combined, apprehension and relocation...

Combined, apprehension and relocation tests to identify anterior shoulder instability have been shown to significantly improve specificity while maintaining sensitivity.⁸

The posterior apprehension test is used to assess posterior instability. The patient is supine; the affected arm is placed in flexion, adduction, and internal rotation; and posterior pressure is applied (FIGURE 7). A positive test is noted when pain is reported at the posterior aspect of the shoulder. Clicking might be noted as the humeral head dislocates rearward.¹

Sulcus sign. Multidirectional instability is elicited using the sulcus sign. While the patient is seated upright, arms resting at their sides, a direct downward pull at elbow level will, when positive, reveal a depression (sulcus) at the lateral aspect of the affected shoulder as the humeral head translates inferiorly (FIGURE 8). A positive sulcus sign is documented in 3 grades, according to the amount of translation¹:

• Grade I: < 1 cm
• Grade II: 1-2 cm
• Grade III: > 2 cm.

Neurovascular status should be verified at every physical evaluation, with motor and sensory function tested in the axillary, musculocutaneous, median, radial, and ulnar nerve distributions. If nerve injury is suspected, electromyography and nerve-conduction testing is indicated.^9-13 Vascular compromise is much less common but equally important to assess.¹¹

Use of imaging

Post-reduction radiographs, including internal and external AP—and especially axillary—views are invaluable. Not only do they help to ensure reduction, but they also help to assess for fracture. A magnetic resonance imaging (MRI) arthrogram is the preferred imaging modality if a labral tear is suspected (FIGURE 9). Other concomitant shoulder injuries, such as subtle bone fracture, rotator cuff tear, and biceps pathology can also be reliably diagnosed with noncontrast MRI.

Continue to: Roadmap for treatment

The rate of recurrence after a first anterior shoulder dislocation is strongly associated with a person’s age and level of activity. Active patients younger than 20 years have a 92% to 96% recurrence rate¹⁴; patients 20 to 40 years, 25% to 48%; and patients older than 40 years, < 10%.¹⁵

Young, athletic patients who are treated nonoperatively are left at an unacceptably high risk of recurrence, leading to progressive damage to bony and soft-tissue structures.^16,17 Surgical labral repair after a first-time anterior dislocation produced improved outcomes in terms of recurrent dislocation (7.9%), compared to outcomes after nonsurgical treatment (52.9%),¹⁴ and has been associated with a lower incidence of future glenohumeral osteoarthritis.¹⁸ For those reasons, we recommend referral to an orthopedic surgeon for all patients younger than 20 years who sustain an anterior shoulder dislocation.

Patients older than 20 years who do not have concomitant shoulder injury, and who demonstrate full strength in abduction, external rotation, and internal rotation of the shoulder on clinical examination, have a low probability of associated rotator-cuff tear. They can be immobilized in a sling for 1 to 3 weeks, followed by a 6 to 12–week regimen of physical therapy.

Concomitant tear of the rotator cuff. Weakness on examination requires MRI or a magnetic resonance arthrogram for evaluation of associated rotator-cuff tear. A tear identified on MRI should be referred to an orthopedic surgeon because timely repair can be crucial to attaining best outcomes. Conservative treatment of traumatic full-­tendon rotator-cuff tear is associated with poor results, progression in the size of the tear, and advancement of muscle atrophy.^19,20 For patients younger than 40 years, arthroscopic rotator-cuff repair, with or without labral repair, produces excellent clinical outcomes, carries a low risk of complications, and results in a > 95% rate of return to a preoperative level of recreational and job activities.²¹

Patients who demonstrate weakness of the rotator-cuff muscles on examination, but who do not have a tear noted on MRI, should be evaluated by electromyography and nerve-conduction testing to assess nerve injury as an alternative cause of weakness.^10,11 If a neurologic deficit is found on nerve-conduction testing, the patient should be referred for neurologic evaluation.¹⁰

Continue to: Patients with negative findings...

Patients with negative findings on MRI and nerve-conduction studies should be offered physical therapy. Patients with recurrent anterior shoulder dislocation should be referred to an orthopedic surgeon for surgical repair. Frequently, improper or delayed treatment with chronic instability results in degenerative arthropathy of the joint²² (FIGURE 10).

Posterior and multidirectional instability can typically be treated conservatively; however, whereas posterior dislocation typically must be immobilized for 3 to 6 weeks post reduction, multidirectional instability does not require immobilization. Instead, physical therapy should start as soon as possible. In these cases, recurrent dislocation or subluxation that persists after conservative treatment should be referred for possible surgical intervention.⁵

Instability with associated fracture

Fracture concomitant with dislocation most commonly involves the humeral neck, humeral head, greater tuberosity, or the glenoid itself.² Clinical variables that predict a fracture associated with shoulder dislocation include²³:

• first episode of dislocation
• age ≥ 40 years
• fall from higher than 1 flight of stairs
• fight or assault
• motor vehicle crash.

A computed tomography scan with 3-dimensional reconstruction can help characterize associated fracture accurately—including location, size, and displacement—and can play an important role in treatment planning and prognosis in these complicated injuries. Displaced fracture should be referred to an orthopedic surgeon. Nondisplaced fracture of the humeral head or greater tuberosity (FIGURE 11) poses less risk of complications and can be treated conservatively with 6 weeks in an arm sling, followed by physical therapy.²⁴

Summing up

Management of shoulder dislocation must, first, be tailored to the individual and, second, account for several interactive factors—including age, direction of instability, functional demands, risk of recurrence, and associated injuries. In many patients, conservative treatment produces a favorable long-term outcome. Particularly in young, active patients with anterior shoulder instability, most surgeons consider open or arthroscopic reconstruction to be the treatment of choice.^2,18

Continue to: Pre-reduction and post-reduction...

Pre-reduction and post-reduction imaging should be carefully examined for the presence of concomitant injury, which might change the preferred treatment modality appreciably.

Last, communication among emergency department providers, the primary care provider, orthopedist, radiologist, and neurologist is crucial for determining an appropriate patient-centered approach to initial and long-term management.

CORRESPONDENCE
Nata Parnes, MD, Carthage Area Hospital, 3 Bridge Street, Carthage, NY; [email protected]

During the 2020-2021 influenza season, fewer cases of influenza were reported than in any previous year since 1997, when data were first recorded.¹FIGURE 1² shows the dramatic decline in the number of influenza-positive clinical samples reported to the Centers for Disease Control and Prevention (CDC) during the 2020-2021 influenza season compared with the 2019-2020 season. There was only one pediatric death attributed to influenza in 2020-2021, compared with a mean of 177 per year in the previous 3 seasons.

Deaths attributed to pneumonia and influenza were recorded over a recent 5-year period, with COVID-19 added in early mid-2020 (FIGURE 2).¹ Total cumulative deaths for 2020-2021 were extremely high, mostly due to COVID-19. Of the relatively few influenza cases last season, 37.5% were caused by influenza A and 62.5% by influenza B. The extremely low incidence of influenza precludes determining influenza vaccine effectiveness for last season.¹

In addition, other common respiratory pathogens—parainfluenza, adenoviruses, rhinoviruses, enteroviruses, and common coronaviruses—circulated last winter at historic lows.³ All of these historic lows can be attributed to the measures taken to mitigate the effect of the COVID-19 pandemic, including masks, social distancing, closure of certain venues that normally attract large crowds, and the closure of schools with a resulting increase in schooling at home. With the anticipated relaxation of these measures in 2021-2022, we can expect more influenza and other respiratory ailments due to common pathogens.

Updates to influenza vaccine recommendations

At its June 2021 meeting, the Advisory Committee on Immunization Practices (ACIP) approved the influenza vaccine recommendations for the 2021-2022 season.⁴ The central recommendation is unchanged: Everyone ≥ 6 months of age should receive a vaccine unless they have a contraindication. Updates to the previous recommendations include the content of the 2021 vaccines, the specific vaccines that will be available for different age groups, the timing of vaccine administration, advice on co-administration with COVID-19 vaccines, and the list of contraindications and precautions based on vaccine type.⁴

Viral composition of US vaccines for the 2021-22 season

The antigens that will be included in the 2021-2022 influenza vaccines are listed in TABLE 1.⁴ The B strains are the same as last year; the A strains have been updated. The H3N2 strain is the same in all vaccines, but the H1N1 strain differs based on whether the vaccine is egg based or non-egg based. The advantage of non-egg-based vaccines is that the production process does not take as long and can be delayed in an attempt to better reflect the influenza stains in worldwide circulation.

The influenza vaccines expected to be available for the 2021-22 season

TABLE 2⁴ lists the influenza vaccines approved for use in the United States and the ages for which they are approved.⁴ All products for 2021-2022 will be quadrivalent, containing 2 type-A and 2 type-B antigens. The only change in age indications is that cell culture–based inactivated influenza vaccine (ccIIV4) (Flucelvax Quadrivalent) is now approved for use starting at age 2 years; previously it was approved starting at age 4 years.⁴

Timing of vaccination

The onsets and peaks of influenza disease occur at different times each year and can also vary by geographic location. An analysis of 36 influenza seasons starting in 1982 showed that peak activity occurred most frequently in February (15 seasons), followed by December (7 seasons), and January and March (6 seasons each).⁵ Only once did peak activity occur in October and once in November. This information, along with observational studies showing the waning of influenza vaccine effectiveness after 5 to 6 months, especially in the elderly, informed the ACIP decision to modify their recommendation on the timing of vaccination. The recommendation now states that vaccine should be administered by the end of October and that July and August would have been too early, especially for older adults.

Continue to: Children ages 6 months...

Children ages 6 months through 8 years who have not been vaccinated previously require 2 doses separated by at least 4 weeks, and the first dose should be administered early enough to allow for the second by the end of October.⁴ Children who require only 1 dose can also receive the vaccine as soon as it is available, as there is less evidence that vaccine effectiveness wanes in children.

Earlier administration is also recommended for pregnant women in their third trimester. Delaying vaccination in this group could result in postpartum administration of the vaccine, thereby depriving infants of protection against influenza illness during their first 6 months after birth.⁴

Co-administration of influenza and COVID-19 vaccines

Current guidance from the CDC states that COVID-19 vaccines can be co-administered with other vaccines including influenza vaccines.⁶ However, there are no data by which to judge the efficacy of each vaccine in coadministration or the potential for increased adverse reactions. ACIP advises caution on 2 points: (1) physicians should watch for updated guidance as more information becomes available, and (2) there is the potential for increased reactogenicity after co-administration, especially with the more reactogenic influenza vaccines: adjuvanted inactivated influenza vaccine (aIIV4) and high-dose inactivated influenza vaccine (HD-IIV4). Moreover, these vaccines and the co-administered COVID-19 vaccine should be injected into different limbs.

Contraindications and precautions

Serious allergic reactions to influenza vaccines are rare—about 1.3 incidents per million doses administered.⁷ However, a previous severe allergic reaction to a particular vaccine or to any component of the vaccine is a contraindication for use of that vaccine. In addition, a history of severe allergic reaction to any influenza vaccine is a contraindication for all egg-based vaccines.

There are 2 precautions for all influenza vaccines: a concurrent moderate or severe acute illness (with or without fever), and a history of Guillain-Barré syndrome within 6 weeks of receiving any influenza vaccine. An additional precaution for ccIIV4 and recombinant influenza vaccine (RIV4) is a history of severe allergic reaction after administration of any other influenza vaccine. Administration of RIV4 or ccIIV4 to someone with such a history should occur in a medical setting and be supervised by someone who can recognize and treat a severe reaction.

Continue to: Live attenuated influenza vaccine...

Live attenuated influenza vaccine (LAIV) continues to have a considerably longer list of contraindications, which can be found in the published recommendations for 2021-2022.⁸

Final advice

The upcoming influenza season has the potential to be clinically challenging with the possibility of co-existing high rates of both COVID-19 and influenza. Recommend both influenza and COVID-19 vaccination to patients. Also, be sure to encourage and practice other preventive measures such as masking in crowds, frequent hand washing, isolation when sick, respiratory hygiene, and (for physicians) selected prescribing of influenza antiviral medications and meticulous office-based infection control practices.⁹

During the 2020-2021 influenza season, fewer cases of influenza were reported than in any previous year since 1997, when data were first recorded.¹FIGURE 1² shows the dramatic decline in the number of influenza-positive clinical samples reported to the Centers for Disease Control and Prevention (CDC) during the 2020-2021 influenza season compared with the 2019-2020 season. There was only one pediatric death attributed to influenza in 2020-2021, compared with a mean of 177 per year in the previous 3 seasons.

Deaths attributed to pneumonia and influenza were recorded over a recent 5-year period, with COVID-19 added in early mid-2020 (FIGURE 2).¹ Total cumulative deaths for 2020-2021 were extremely high, mostly due to COVID-19. Of the relatively few influenza cases last season, 37.5% were caused by influenza A and 62.5% by influenza B. The extremely low incidence of influenza precludes determining influenza vaccine effectiveness for last season.¹

In addition, other common respiratory pathogens—parainfluenza, adenoviruses, rhinoviruses, enteroviruses, and common coronaviruses—circulated last winter at historic lows.³ All of these historic lows can be attributed to the measures taken to mitigate the effect of the COVID-19 pandemic, including masks, social distancing, closure of certain venues that normally attract large crowds, and the closure of schools with a resulting increase in schooling at home. With the anticipated relaxation of these measures in 2021-2022, we can expect more influenza and other respiratory ailments due to common pathogens.

Updates to influenza vaccine recommendations

At its June 2021 meeting, the Advisory Committee on Immunization Practices (ACIP) approved the influenza vaccine recommendations for the 2021-2022 season.⁴ The central recommendation is unchanged: Everyone ≥ 6 months of age should receive a vaccine unless they have a contraindication. Updates to the previous recommendations include the content of the 2021 vaccines, the specific vaccines that will be available for different age groups, the timing of vaccine administration, advice on co-administration with COVID-19 vaccines, and the list of contraindications and precautions based on vaccine type.⁴

Viral composition of US vaccines for the 2021-22 season

The antigens that will be included in the 2021-2022 influenza vaccines are listed in TABLE 1.⁴ The B strains are the same as last year; the A strains have been updated. The H3N2 strain is the same in all vaccines, but the H1N1 strain differs based on whether the vaccine is egg based or non-egg based. The advantage of non-egg-based vaccines is that the production process does not take as long and can be delayed in an attempt to better reflect the influenza stains in worldwide circulation.

The influenza vaccines expected to be available for the 2021-22 season

TABLE 2⁴ lists the influenza vaccines approved for use in the United States and the ages for which they are approved.⁴ All products for 2021-2022 will be quadrivalent, containing 2 type-A and 2 type-B antigens. The only change in age indications is that cell culture–based inactivated influenza vaccine (ccIIV4) (Flucelvax Quadrivalent) is now approved for use starting at age 2 years; previously it was approved starting at age 4 years.⁴

Timing of vaccination

The onsets and peaks of influenza disease occur at different times each year and can also vary by geographic location. An analysis of 36 influenza seasons starting in 1982 showed that peak activity occurred most frequently in February (15 seasons), followed by December (7 seasons), and January and March (6 seasons each).⁵ Only once did peak activity occur in October and once in November. This information, along with observational studies showing the waning of influenza vaccine effectiveness after 5 to 6 months, especially in the elderly, informed the ACIP decision to modify their recommendation on the timing of vaccination. The recommendation now states that vaccine should be administered by the end of October and that July and August would have been too early, especially for older adults.

Continue to: Children ages 6 months...

Children ages 6 months through 8 years who have not been vaccinated previously require 2 doses separated by at least 4 weeks, and the first dose should be administered early enough to allow for the second by the end of October.⁴ Children who require only 1 dose can also receive the vaccine as soon as it is available, as there is less evidence that vaccine effectiveness wanes in children.

Earlier administration is also recommended for pregnant women in their third trimester. Delaying vaccination in this group could result in postpartum administration of the vaccine, thereby depriving infants of protection against influenza illness during their first 6 months after birth.⁴

Co-administration of influenza and COVID-19 vaccines

Current guidance from the CDC states that COVID-19 vaccines can be co-administered with other vaccines including influenza vaccines.⁶ However, there are no data by which to judge the efficacy of each vaccine in coadministration or the potential for increased adverse reactions. ACIP advises caution on 2 points: (1) physicians should watch for updated guidance as more information becomes available, and (2) there is the potential for increased reactogenicity after co-administration, especially with the more reactogenic influenza vaccines: adjuvanted inactivated influenza vaccine (aIIV4) and high-dose inactivated influenza vaccine (HD-IIV4). Moreover, these vaccines and the co-administered COVID-19 vaccine should be injected into different limbs.

Contraindications and precautions

Serious allergic reactions to influenza vaccines are rare—about 1.3 incidents per million doses administered.⁷ However, a previous severe allergic reaction to a particular vaccine or to any component of the vaccine is a contraindication for use of that vaccine. In addition, a history of severe allergic reaction to any influenza vaccine is a contraindication for all egg-based vaccines.

There are 2 precautions for all influenza vaccines: a concurrent moderate or severe acute illness (with or without fever), and a history of Guillain-Barré syndrome within 6 weeks of receiving any influenza vaccine. An additional precaution for ccIIV4 and recombinant influenza vaccine (RIV4) is a history of severe allergic reaction after administration of any other influenza vaccine. Administration of RIV4 or ccIIV4 to someone with such a history should occur in a medical setting and be supervised by someone who can recognize and treat a severe reaction.

Continue to: Live attenuated influenza vaccine...

Live attenuated influenza vaccine (LAIV) continues to have a considerably longer list of contraindications, which can be found in the published recommendations for 2021-2022.⁸

Final advice

The upcoming influenza season has the potential to be clinically challenging with the possibility of co-existing high rates of both COVID-19 and influenza. Recommend both influenza and COVID-19 vaccination to patients. Also, be sure to encourage and practice other preventive measures such as masking in crowds, frequent hand washing, isolation when sick, respiratory hygiene, and (for physicians) selected prescribing of influenza antiviral medications and meticulous office-based infection control practices.⁹

During the 2020-2021 influenza season, fewer cases of influenza were reported than in any previous year since 1997, when data were first recorded.¹FIGURE 1² shows the dramatic decline in the number of influenza-positive clinical samples reported to the Centers for Disease Control and Prevention (CDC) during the 2020-2021 influenza season compared with the 2019-2020 season. There was only one pediatric death attributed to influenza in 2020-2021, compared with a mean of 177 per year in the previous 3 seasons.

Deaths attributed to pneumonia and influenza were recorded over a recent 5-year period, with COVID-19 added in early mid-2020 (FIGURE 2).¹ Total cumulative deaths for 2020-2021 were extremely high, mostly due to COVID-19. Of the relatively few influenza cases last season, 37.5% were caused by influenza A and 62.5% by influenza B. The extremely low incidence of influenza precludes determining influenza vaccine effectiveness for last season.¹

In addition, other common respiratory pathogens—parainfluenza, adenoviruses, rhinoviruses, enteroviruses, and common coronaviruses—circulated last winter at historic lows.³ All of these historic lows can be attributed to the measures taken to mitigate the effect of the COVID-19 pandemic, including masks, social distancing, closure of certain venues that normally attract large crowds, and the closure of schools with a resulting increase in schooling at home. With the anticipated relaxation of these measures in 2021-2022, we can expect more influenza and other respiratory ailments due to common pathogens.

Updates to influenza vaccine recommendations

At its June 2021 meeting, the Advisory Committee on Immunization Practices (ACIP) approved the influenza vaccine recommendations for the 2021-2022 season.⁴ The central recommendation is unchanged: Everyone ≥ 6 months of age should receive a vaccine unless they have a contraindication. Updates to the previous recommendations include the content of the 2021 vaccines, the specific vaccines that will be available for different age groups, the timing of vaccine administration, advice on co-administration with COVID-19 vaccines, and the list of contraindications and precautions based on vaccine type.⁴

Viral composition of US vaccines for the 2021-22 season

The antigens that will be included in the 2021-2022 influenza vaccines are listed in TABLE 1.⁴ The B strains are the same as last year; the A strains have been updated. The H3N2 strain is the same in all vaccines, but the H1N1 strain differs based on whether the vaccine is egg based or non-egg based. The advantage of non-egg-based vaccines is that the production process does not take as long and can be delayed in an attempt to better reflect the influenza stains in worldwide circulation.

The influenza vaccines expected to be available for the 2021-22 season

TABLE 2⁴ lists the influenza vaccines approved for use in the United States and the ages for which they are approved.⁴ All products for 2021-2022 will be quadrivalent, containing 2 type-A and 2 type-B antigens. The only change in age indications is that cell culture–based inactivated influenza vaccine (ccIIV4) (Flucelvax Quadrivalent) is now approved for use starting at age 2 years; previously it was approved starting at age 4 years.⁴

Timing of vaccination

The onsets and peaks of influenza disease occur at different times each year and can also vary by geographic location. An analysis of 36 influenza seasons starting in 1982 showed that peak activity occurred most frequently in February (15 seasons), followed by December (7 seasons), and January and March (6 seasons each).⁵ Only once did peak activity occur in October and once in November. This information, along with observational studies showing the waning of influenza vaccine effectiveness after 5 to 6 months, especially in the elderly, informed the ACIP decision to modify their recommendation on the timing of vaccination. The recommendation now states that vaccine should be administered by the end of October and that July and August would have been too early, especially for older adults.

Continue to: Children ages 6 months...

Children ages 6 months through 8 years who have not been vaccinated previously require 2 doses separated by at least 4 weeks, and the first dose should be administered early enough to allow for the second by the end of October.⁴ Children who require only 1 dose can also receive the vaccine as soon as it is available, as there is less evidence that vaccine effectiveness wanes in children.

Earlier administration is also recommended for pregnant women in their third trimester. Delaying vaccination in this group could result in postpartum administration of the vaccine, thereby depriving infants of protection against influenza illness during their first 6 months after birth.⁴

Co-administration of influenza and COVID-19 vaccines

Current guidance from the CDC states that COVID-19 vaccines can be co-administered with other vaccines including influenza vaccines.⁶ However, there are no data by which to judge the efficacy of each vaccine in coadministration or the potential for increased adverse reactions. ACIP advises caution on 2 points: (1) physicians should watch for updated guidance as more information becomes available, and (2) there is the potential for increased reactogenicity after co-administration, especially with the more reactogenic influenza vaccines: adjuvanted inactivated influenza vaccine (aIIV4) and high-dose inactivated influenza vaccine (HD-IIV4). Moreover, these vaccines and the co-administered COVID-19 vaccine should be injected into different limbs.

Contraindications and precautions

Serious allergic reactions to influenza vaccines are rare—about 1.3 incidents per million doses administered.⁷ However, a previous severe allergic reaction to a particular vaccine or to any component of the vaccine is a contraindication for use of that vaccine. In addition, a history of severe allergic reaction to any influenza vaccine is a contraindication for all egg-based vaccines.

There are 2 precautions for all influenza vaccines: a concurrent moderate or severe acute illness (with or without fever), and a history of Guillain-Barré syndrome within 6 weeks of receiving any influenza vaccine. An additional precaution for ccIIV4 and recombinant influenza vaccine (RIV4) is a history of severe allergic reaction after administration of any other influenza vaccine. Administration of RIV4 or ccIIV4 to someone with such a history should occur in a medical setting and be supervised by someone who can recognize and treat a severe reaction.

Continue to: Live attenuated influenza vaccine...

Live attenuated influenza vaccine (LAIV) continues to have a considerably longer list of contraindications, which can be found in the published recommendations for 2021-2022.⁸

Final advice

The upcoming influenza season has the potential to be clinically challenging with the possibility of co-existing high rates of both COVID-19 and influenza. Recommend both influenza and COVID-19 vaccination to patients. Also, be sure to encourage and practice other preventive measures such as masking in crowds, frequent hand washing, isolation when sick, respiratory hygiene, and (for physicians) selected prescribing of influenza antiviral medications and meticulous office-based infection control practices.⁹

Our approach to caring for the growing number of community-dwelling US adults ages ≥ 65 years has shifted. Although we continue to manage disease and disability, there is an increasing emphasis on the promotion of healthy aging by optimizing health care needs and quality of life (QOL).

The American Geriatric Society (AGS) uses the term “healthy aging” to reflect a dedication to improving the health, independence, and QOL of older people.¹ The World Health Organization (WHO) defines healthy aging as “the process of developing and maintaining the functional ability that enables well-being in older age.”² Functional ability encompasses capabilities that align with a person’s values, including meeting basic needs; learning, growing, and making independent decisions; being mobile; building and maintaining healthy relationships; and contributing to society.² Similarly, the US Department of Health and Human Services has adopted a multidimensional approach to support people in creating “a productive and meaningful life” as they grow older.³

Numerous theoretical models have emerged from research on aging as a multidimensional construct, as evidenced by a 2016 citation analysis that identified 1755 articles written between 1902 and 2015 relating to “successful aging.”⁴ The analysis revealed 609 definitions operationalized by researchers’ measurement tools (mostly focused on physical function and other health metrics) and 1146 descriptions created by older adults, many emphasizing psychosocial strategies and cultural factors as key to successful aging.⁴

One approach that is likely to be useful for family physicians is the Age-Friendly Health System. This is an initiative of The John A. Hartford Foundation and the Institute for Healthcare Improvement that uses a multidisciplinary approach to create environments that foster inclusivity and address the needs of older people.⁵ Following this guidance, primary care providers use evidence-informed strategies that promote safety and address what matters most to older adults and their family caregivers.

Medicare annual wellness visits provide an opportunity to assess current health status as well as discuss behavior-change and risk-reduction strategies with patients.

The Age-Friendly Health System, as well as AGS and WHO, recognize that there are multiple aspects to well-being as one grows older. By using focused, evidence-based screening, assessments, and interventions, family physicians can best support aging patients in living their most fulfilling lives.

Here we present a review of evidence-based strategies that promote safety and address what matters most to older adults and their family caregivers using a 4-pronged framework, in the style of the Age-Friendly Health System model. However, the literature on healthy aging includes important messages about patient context and lifelong health behaviors, which we capture in an expanded set of thematic guidance. As such, we encourage family physicians to approach healthy aging as follows: (1) monitor health (screening and prevention), (2) promote mobility (physical function), (3) manage mentation (emotional health and cognitive function), and (4) encourage maintenance of social connections (social networks and QOL).

Monitoring health

Leverage Medicare annual wellness visits. A systematic approach is needed to prevent frailty and functional decline, and thus increase the QOL of older adults. To do this, it is important to focus on health promotion and disease prevention, while addressing existing ailments. One method is to leverage the Medicare annual wellness visit (AWV), which provides an opportunity to assess current health status as well as discuss behavior-change and risk-reduction strategies with patients.

Continue to: Although AWVs...

Although AWVs are an opportunity to improve patient outcomes, we are not taking full advantage of them.⁶ While AWVs have gained traction since their introduction in 2011, usage rates among ethnoracial minority groups has lagged behind.⁶ A 2018 cohort study examined reasons for disparate utilization rates among individuals ages ≥ 66 years (N = 14,687).⁷ Researchers found that differences in utilization between ethnoracial groups were explained by socioeconomic factors. Lower education and lower income, as well as rural living, were associated with lower rates of AWV completion.⁷ In addition, having a usual, nonemergent place to obtain medical care served as a powerful predictor of AWV utilization for all groups.⁷

Strategies to increase AWV completion rates among all eligible adults include increasing staff awareness of health literacy challenges and ensuring communication strategies are inclusive by providing printed materials in multiple languages, Braille, or larger typefaces; using accessible vocabulary that does not include medical jargon; and making medical interpreters accessible. In addition, training clinicians about unconscious bias and cultural humility can help foster empathy and awareness of differences in health beliefs and behaviors within diverse patient populations.

A 2019 scoping review of 11 studies (N > 60 million) focused on outcomes from Medicare AWVs for patients ages ≥ 65 years.⁸ This included uptake of preventive services, such as vaccinations or cancer screenings; advice, education, or referrals offered during the AWV; medication use; and hospitalization rates. Overall findings showed that older adults who received a Medicare AWV were more likely to receive referrals for preventive screenings and follow-through on these recommendations compared with those who did not undergo an AWV.⁸

The approach to caring for individuals later in life has shifted from management of disease and disability to promotion of healthy aging by optimizing health care needs and QOL.

Completion rates for vaccines, while remaining low overall, were higher among those who completed an AWV. Additionally, these studies showed improved completion of screenings for breast cancer, bone density, and colon cancer. Several studies in the scoping review supported the use of AWVs as an effective means by which to offer health education and advice related to health promotion and risk reduction, such as diet and lifestyle modifications.⁸ Little evidence exists on long-term outcomes related to AWV completion.⁸

Utilize shared decision-making to determine whether preventive screening makes sense for your patient. Although cancer remains the second leading cause of death among Americans ages ≥ 65 years,⁹ clear screening guidelines for this age group remain elusive.¹⁰ Physicians and patients often are reluctant to stop cancer screening despite lower life expectancy and fewer potential benefits of diagnosis in this population.⁹ Some recent studies reinforce the heterogeneity of the older adult population and further underscore the importance of individual-level decision-making.^11-14 It is important to let older adult patients and their caregivers know about the potential risks of screening tests, especially the possibility that incidental findings may lead to unwarranted additional care or monitoring.⁹

Continue to: Avoid these screening conversation missteps

Avoid these screening conversation missteps. A 2017 qualitative study asked 40 community-dwelling older adults (mean age = 76 years) about their preferences for discussing screening cessation with their physicians.¹³ Three themes emerged.First, they were open to stopping their screenings, especially when suggested by a trusted physician. Second, health status and physical function made sense as decision points, but life expectancy did not. Finally, lengthy discussions with expanded details about risks and benefits were not appreciated, especially if coupled with comments on the limited benefits for those nearing the end of life. When discussing life expectancy, patients preferred phrasing that focused on how the screening was unnecessary because it would not help them live longer.¹³

Ensure that your message is understood—and culturally relevant. Recent studies on lower health literacy among older adults^15,16 and ethnic and racial minorities^17-21—as revealed in the 2003 National Assessment of Adult Literacy²²—might offer clues to patient receptivity to discussions about preventive screening and other health decisions.

One study found a significant correlation between higher self-rated health literacy and higher engagement in health behaviors such as mammography screening, moderate physical activity, and tobacco avoidance.¹⁶ Perceptions of personal control over health status, as well as perceived social standing, also correlated with health literacy score levels.¹⁶ Another study concluded that lower health literacy combined with lower self-­efficacy, cultural beliefs about health topics (eg, diet and exercise), and distrust in the health care system contributed to lower rates of preventive care utilization among ethnocultural minority older adults in Canada, the United Kingdom, the United States, and Australia.¹⁸

Ensuring that easy-to-understand information is equitably shared with older adults of all races and ethnicities is critical. A 2018 study showed that distrust of the health system and cultural issues contributed to the lower incidence of colorectal cancer screenings in Hispanic and Asian American patients ages 50 to 75 years.²¹ Patients whose physicians engaged in “health literate practices” (eg, offering clear explanations of diagnostic plans and asking patients to describe what they understood) were more likely to obtain recommended breast and colorectal cancer screenings.²⁰ In particular, researchers found that non-Hispanic Blacks were nearly twice as likely to follow through on colorectal cancer screening if their physicians engaged in health literate practices.²⁰ In addition, receiving clear instructions from physicians increased the odds of completing breast cancer screening among Hispanic and non-­Hispanic White women.²⁰

Overall, screening information and recommendations should be standardized for all patients. This is particularly important in light of research that found that older non-Hispanic Black patients were less likely than their non-Hispanic White counterparts to receive information from their physicians about colorectal cancer screening.²⁰

Continue to: Mobility

Mobility

Encourage physical activity. Frequent exercise and other forms of physical activity are associated with healthy aging, as shown in a 2017 systematic review and meta-analysis of 23 studies (N = 174,114).²³ Despite considerable heterogeneity between studies in how researchers defined healthy aging and physical activity, they found that adults who incorporate regular movement and exercise into daily life are likely to continue to benefit from it into older age.²³ In addition, a 2016 secondary analysis of data from the InCHIANTI longitudinal aging study concluded that adults ages ≥ 65 years (N = 1149) who had maintained higher physical activity levels throughout adulthood had less physical function decline and reduced rates of mobility disability and premature death compared with those who reported being less active.²⁴

Preserve gait speed (and bolster health) with these activities. Walking speed, or gait, measured on a level surface has been used as a predictor for various aspects of well-being in older age, such as daily function, mobility, independence, falls, mortality, and hospitalization risk.²⁵ Reduced gait speed is also one of the key indicators of functional impairment in older adults.

A 2015 systematic review sought to determine which type of exercise intervention (resistance, coordination, or multimodal training) would be most effective in preserving gait speed in healthy older adults (N = 2495; mean age = 74.2 years).²⁵ While the 42 included studies were deemed to be fairly low quality, the review revealed (with large effect size [0.84]) that a number of exercise modalities might stave off loss of gait speed in older adults. Patients in the resistance training group had the greatest improvement in gait speed (0.11 m/s), followed by those in the coordination training group (0.09 m/s) and the multimodal training group (0.05 m/s).²⁵

Individuals who had maintained higher physical activity levels throughout adulthood had less physical functional decline and reduced rates of mobility disability and premature death.

Finally, muscle mass and strength offer a measure of physical performance and functionality. A 2020 systematic review of 83 studies (N = 108,428) showed that low muscle mass and strength, reduced handgrip strength, and lower physical performance were predictive of reduced capacities in activities of daily living and instrumental activities of daily living.²⁶ It is important to counsel adults to remain active throughout their lives and to include resistance training to maintain muscle mass and strength to preserve their motor function, mobility, independence, and QOL.

Use 1 of these scales to identify frailty. Frailty is a distinct clinical syndrome, in which an individual has low reserves and is highly vulnerable to internal and external stressors. It affects many community-­dwelling older adults. Within the literature, there has been ongoing discussion regarding the definition of frailty²⁷ (TABLE 1^28-31).

Continue to: The Fried Frailty Index...

The Fried Frailty Index defines frailty as a purely physical condition; patients need to exhibit 3 of 5 components (ie, weight loss, exhaustion, weakness, slowness, and low physical activity) to be deemed frail.³¹ The Edmonton Frail Scale is commonly used in geriatric assessments and counts impairments across several domains including physical activity, mood, cognition, and incontinence.^30,32,33 Physicians need to complete a training course prior to its use. Finally, the definition of frailty used by Rockwood et al^{28, 29} was used to develop the Clinical Frailty Scale, which relies on broader criteria that include social and psychological elements in addition to physical elements.The Clinical Frailty Scale uses clinician judgment to evaluate patient-specific domains (eg, comorbidities, functionality, and cognition) and to generate a score ranging from 1 (very fit) to 9 (terminally ill).²⁹ This scale is accessible and easy to implement. As a result, use of this scale has increased during the COVID-19 pandemic. All definitions include a pre-frail state, indicating the dynamic nature of frailty over time.

It is important to identify pre-frail and frail older adults using 1 of these screening tools. Interventions to reverse frailty that can be initiated in the primary care setting include identifying treatable medical conditions, assessing medication appropriateness, providing nutritional advice, and developing an exercise plan.³⁴

Conduct a nutritional assessment; consider this diet. Studies show that nutritional status can predict physical function and frailty risk in older adults. A 2017 systematic review of 19 studies (N = 22,270) of frail adults ages ≥ 65 years found associations related to specific dietary constructs (ie, micronutrients, macronutrients, antioxidants, overall diet quality, and timing of consumption).³⁵ Plant-based diets with higher levels of micronutrients, such as vitamins C and E and beta-carotene, or diets with more protein or macronutrients, regardless of source foods, all resulted in inverse associations with frailty syndrome.³⁵

A 2017 study showed that physical exercise and maintaining good nutritional status may be effective for preventing frailty in ­community-dwelling pre-frail older individuals.³⁶ A 2019 study showed that a combination of muscle strength training and protein supplementation was the most effective intervention to delay or reverse frailty and was easiest to implement in primary care.³⁷ A 2020 meta-analysis of 31 studies (N = 4794) addressing frailty among primary care patients > 60 years showed that interventions using predominantly resistance-based exercise and nutrition supplementation improved frailty status over the control.³⁸ Researchers also found that a comprehensive geriatric assessment or exercise—alone or in combination with nutrition education—reduced physical frailty.

Mentation

Screen and treat cognitive impairments. Cognitive function and autonomy in ­decision-making are important factors in healthy aging. Aspects of mental health (eg, depression and anxiety), sensory impairment (eg, visual and auditory impairment), and mentation issues (eg, delirium, dementia, and related conditions), as well as diet, physical exercise, and mobility, can all impede cognitive functionality. The long-term effects of depression, anxiety,³⁹ sensory deficits,⁴⁰ mobility,⁴¹ diet,⁴² and, ultimately, aging may impact Alzheimer disease (AD). The risk of an AD diagnosis increases with age.³⁹

Continue to: A 2018 prospective cohort study...

A 2018 prospective cohort study using data from the National Alzheimer’s Coordinating Center followed individuals (N = 12,053) who were cognitively asymptomatic at their initial visits to determine who developed clinical signs of AD.³⁹ Survival analysis showed several psychosocial factors—anxiety, sleep disturbances, and depressive episodes of any type (occurring within the past 2 years, clinician verified, lifetime report)—were significantly associated with an eventual AD diagnosis and increased the risk of AD.³⁹ More research is needed to verify the impact of early intervention for these conditions on neurodegenerative disease; however, screening and treating psychosocial factors such as anxiety and depression should be maintained.

For patients ages ≥ 65 years, it is recommended that eye examinations occur every 1 to 2 years.

Researchers evaluated the impact of a dual sensory impairment (DSI) on dementia risk using data from 2051 participants in the Ginkgo Evaluation of Memory Study.⁴⁰ Hearing and visual impairments (defined as DSI when these conditions coexist) or visual impairment alone were significantly associated with increased risk of dementia in older adults. The researchers reported that DSI was significantly associated with a higher risk of all-cause dementia (hazard ratio [HR] = 1.86; 95% CI, 1.25-2.76) and AD (HR = 2.12; 95% CI, 1.34-3.36).⁴⁰ Visual impairment alone was associated with an increased risk of all-cause dementia (HR = 1.32; 95% CI, 1.02-1.71).⁴⁰ These results suggest that screening of DSI or visual impairment earlier in the patient’s lifespan may identify those at high risk of dementia in older adulthood.

The American Academy of Ophthalmology recommends patients with healthy eyes be screened once during their 20s and twice in their 30s; a full examination is recommended by age 40. For patients ages ≥ 65 years, it is recommended that eye examinations occur every 1 to 2 years.⁴³

Diet and mobility play a big role in cognition. Diet⁴³ and exercise^41,42,44 are believed to have an impact on mentation, and recent studies show memory and global cognition could be malleable later in life. A 2015 meta-analysis of 490 treatment arms of 24 randomized controlled studies showed improvement in global cognition with consumption of a Mediterranean diet plus olive oil (effect size [ES] standardized mean difference [SMD] = 0.22; 95% CI, 0.16-0.27) and tai chi exercises (ES SMD = 0.18; 95% CI, 0.06-0.29).⁴² The analysis also found improved memory among participants who consumed the Mediterranean diet/olive oil combination (ES SMD = 0.22; 95% CI, 0.12-0.32) and soy isoflavone supplements (ES SMD = 0.11; 95% CI, 0.04-0.17). Although the ESs are small, they are significant and offer promising evidence that individual choices related to nutrition or exercise may influence cognition and memory.

A 2018 systematic review found that all domains of cognition showed improvement with 45 to 60 minutes of moderate-to-vigorous physical exercise.⁴⁴ Attention, executive function, memory, and working memory showed significant increases, whereas global cognition improvements were not statistically significant.⁴⁴ A 2016 meta-analysis of 26 studies (N = 26,355) found a positive association between an objective mobility measure (gait, lower-extremity function, and balance) and cognitive function (global, executive function, memory, and processing speed) in older adults.⁴¹ These results highlight that diet, mobility, and physical exercise impact cognitive functioning.

Continue to: Maintaining social connections

Maintaining social connections

Social isolation and loneliness—compounded by a pandemic. The US Department of Health and Human Services notes that “community connections” are among the key factors required for healthy aging.³ Similarly, the WHO definition of healthy aging considers whether individuals can build and sustain relationships with other people and find ways to engender their personal values through these connections.²

Prioritizing interventions that identify and connect isolated older adults to social support may increase survivability.

As people age, their social connections often decrease due to the death of friends and family, shifts in living arrangements, loss of mobility or eyesight (and thus self-­transport), and the onset or increased acuity of illness or chronic conditions.⁴⁵ This has been exacerbated by the COVID-19 pandemic, which has spurred shelter-in-place and stay-at-home orders along with recommendations for physical distancing (also known as social distancing), especially for older adults who are at higher risk.⁴⁶ Smith et al⁴⁷ calls this the COVID-19 Social Connectivity Paradox, in which older adults limit their interactions with others to protect their physical health and reduce their risk of contracting the virus, but as a result they may undermine their psychosocial health by placing themselves at risk of social isolation and loneliness.⁴⁷

The double threat. Social isolation and loneliness have been shown to negatively impact physical health and well-being, resulting in an increased risk of early death^48-50; higher likelihood of specific diagnoses, including dementia and cardiovascular conditions^48,50; and more frequent use of health care services.⁵⁰ These concepts, while related, represent different mechanisms for negative health outcomes. Social isolation is an objective condition when one has a lack of opportunities for interaction with other people; loneliness refers to the emotional disconnect one feels when separated from others. Few studies have compared outcomes between these concepts, but in those that have, social isolation appears to be more strongly associated with early death.^48-50

A 2013 observational study using data from the English Longitudinal Study on Aging found that both social isolation and loneliness were associated with increased mortality among men and women ages ≥ 52 years (N = 6500).⁴⁸ However, when studied independently, loneliness was not found to be a significant risk factor. In contrast, social isolation significantly impacted mortality risk, even after adjusting for demographic factors and baseline health status.⁴⁸ These findings are supported by a 2018 cohort study of individuals (N = 479,054) with a history of an acute cardiovascular event that concluded social isolation was a predictor of mortality, whereas loneliness was not.⁵⁰

A large 2015 meta-analysis (70 studies, N = 3,407,134) of mortality causes among community-dwelling older adults (average age, 66) confirmed that both objective measures of isolation, as well as subjective measures (such as feelings of loneliness or living alone), have a significant predictive effect in longer-term studies. Each measure shows an approximately 30% increase in the likelihood of death after an average of 7 years.⁴⁹

Continue to: Health care remains a connection point

The report offered information about potential avenues for intervention by primary care professionals beyond screening, such as participating in research studies that investigate screening tools and multisystem interventions; social prescribing (linking patients to embedded social work services or ­community-based organizations); referring patients to support groups; initiating ­cognitive-based therapy or other behavioral health interventions; or recommending mindfulness practices.⁵¹ However, most of the cited intervention studies were not specific to primary care settings and contained poor-quality evidence related to efficacy.

Isolation creates a greater reliance on health services due to a lack of a social support system, while a feeling of emotional disconnection (loneliness) seems to be a barrier to accessing care. A 2017 cohort study linking data from the Health and Retirement Study and Medicare claims revealed that social isolation predicts higher annual health expenditures (> $1600 per beneficiary) driven by hospitalization and skilled nursing facility usage, along with greater mortality, whereas individuals who are lonely result in reduced costs (a reduction of $770 annually) due to lower usage of inpatient and outpatient services.⁵² Prioritizing interventions that identify and connect isolated older adults to social support, therefore, may increase survivability by ensuring they have access to resources and health care interventions when needed.

Assessing and treating vision and hearing impairments and mental health issues may guard against losses in cognition.

In addition, these findings underscore the importance of looking at quality—not just quantity—of older adults’ social connections. A number of validated screening tools exist for social isolation and loneliness (TABLE 2^53-59); however, concerns exist about assessing risk using a unidimensional tool for a complex concern,⁴⁷ as well as identifying a problem without having evidence-based interventions to offer as solutions.^47,51 Until future studies resolve these concerns, leveraging the physician-patient relationship to broach these difficult subjects may help normalize the issues and create safe spaces to identify individuals who are at risk.

QOL is key to healthy aging. As Kusumastuti et al⁴ state, “successful ageing lies in the eyes of the beholder.” A 2019 systematic review of 48 qualitative studies revealed that community-dwelling older adults ages ≥ 50 years in 11 countries (N > 4175) perceive well-being by considering QOL within 9 domains: health perception, autonomy, role and activity, relationships, emotional comfort, attitude and adaptation, spirituality, financial security, and home and neighborhood.⁶⁰ Researchers found that as engagement in any one of these domains declines, older adults may shift their definition of health toward their remaining abilities.⁶⁰ This offers an explanation as to why patients might rate their health status much higher than their physicians do: older adults tend to have a more holistic concept of health.

Continue to: Take a multidimensional approach to healthy aging

Take a multidimensional approach to healthy aging

Although we have separately examined each of the 4 components of managing healthy aging in a community-dwelling adult, applying a multidimensional approach is most effective. Increasing use of the Medicare AWV provides an opportunity to assess patient health status, determine care preferences, and improve follow-through on preventive screening. It is also important to encourage older adults to engage in regular physical activity—especially muscle-strengthening exercises—and to discuss nutrition and caloric intake to prevent frailty and functional decline.

Assessing and treating vision and hearing impairments and mental health issues, including anxiety and depression, may guard against losses in cognition. When speaking with older adult patients about their social connections, consider asking not only about frequency of contact and access to resources such as food and transportation, but also about whether they are finding ways to bring their own values into those relationships to bolster their QOL. This guidance also may be useful for primary care practices and health care networks when planning future quality-improvement initiatives.

Additional research is needed to support the evidence base for aligning older adult preferences in health care interventions, such as preventive screenings. Also, clinical decision-making requires more clarity about the efficacy of specific diet and exercise interventions for older adults; the impact of early intervention for depression, anxiety, and sleep disorders on neurodegenerative disease; whether loneliness predicts mortality; and how health care delivery systems can be effective at building social connectivity.

Initiating health education, screening, and prevention throughout the patient’s lifespan can promote healthy aging outcomes later in life.

For now, it is essential to recognize that initiating health education, screening, and prevention throughout the patient’s lifespan can promote healthy aging outcomes. As family physicians, it is important to capitalize on longitudinal relationships with patients and begin educating younger patients using this multidimensional framework to promote living “a productive and meaningful life”at any age.³

CORRESPONDENCE

Lynn M. Wilson, DO, 707 Hamilton Street, 8th floor, Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA 18101; [email protected]

Our approach to caring for the growing number of community-dwelling US adults ages ≥ 65 years has shifted. Although we continue to manage disease and disability, there is an increasing emphasis on the promotion of healthy aging by optimizing health care needs and quality of life (QOL).

The American Geriatric Society (AGS) uses the term “healthy aging” to reflect a dedication to improving the health, independence, and QOL of older people.¹ The World Health Organization (WHO) defines healthy aging as “the process of developing and maintaining the functional ability that enables well-being in older age.”² Functional ability encompasses capabilities that align with a person’s values, including meeting basic needs; learning, growing, and making independent decisions; being mobile; building and maintaining healthy relationships; and contributing to society.² Similarly, the US Department of Health and Human Services has adopted a multidimensional approach to support people in creating “a productive and meaningful life” as they grow older.³

Numerous theoretical models have emerged from research on aging as a multidimensional construct, as evidenced by a 2016 citation analysis that identified 1755 articles written between 1902 and 2015 relating to “successful aging.”⁴ The analysis revealed 609 definitions operationalized by researchers’ measurement tools (mostly focused on physical function and other health metrics) and 1146 descriptions created by older adults, many emphasizing psychosocial strategies and cultural factors as key to successful aging.⁴

One approach that is likely to be useful for family physicians is the Age-Friendly Health System. This is an initiative of The John A. Hartford Foundation and the Institute for Healthcare Improvement that uses a multidisciplinary approach to create environments that foster inclusivity and address the needs of older people.⁵ Following this guidance, primary care providers use evidence-informed strategies that promote safety and address what matters most to older adults and their family caregivers.

Medicare annual wellness visits provide an opportunity to assess current health status as well as discuss behavior-change and risk-reduction strategies with patients.

The Age-Friendly Health System, as well as AGS and WHO, recognize that there are multiple aspects to well-being as one grows older. By using focused, evidence-based screening, assessments, and interventions, family physicians can best support aging patients in living their most fulfilling lives.

Here we present a review of evidence-based strategies that promote safety and address what matters most to older adults and their family caregivers using a 4-pronged framework, in the style of the Age-Friendly Health System model. However, the literature on healthy aging includes important messages about patient context and lifelong health behaviors, which we capture in an expanded set of thematic guidance. As such, we encourage family physicians to approach healthy aging as follows: (1) monitor health (screening and prevention), (2) promote mobility (physical function), (3) manage mentation (emotional health and cognitive function), and (4) encourage maintenance of social connections (social networks and QOL).

Monitoring health

Leverage Medicare annual wellness visits. A systematic approach is needed to prevent frailty and functional decline, and thus increase the QOL of older adults. To do this, it is important to focus on health promotion and disease prevention, while addressing existing ailments. One method is to leverage the Medicare annual wellness visit (AWV), which provides an opportunity to assess current health status as well as discuss behavior-change and risk-reduction strategies with patients.

Continue to: Although AWVs...

Although AWVs are an opportunity to improve patient outcomes, we are not taking full advantage of them.⁶ While AWVs have gained traction since their introduction in 2011, usage rates among ethnoracial minority groups has lagged behind.⁶ A 2018 cohort study examined reasons for disparate utilization rates among individuals ages ≥ 66 years (N = 14,687).⁷ Researchers found that differences in utilization between ethnoracial groups were explained by socioeconomic factors. Lower education and lower income, as well as rural living, were associated with lower rates of AWV completion.⁷ In addition, having a usual, nonemergent place to obtain medical care served as a powerful predictor of AWV utilization for all groups.⁷

Strategies to increase AWV completion rates among all eligible adults include increasing staff awareness of health literacy challenges and ensuring communication strategies are inclusive by providing printed materials in multiple languages, Braille, or larger typefaces; using accessible vocabulary that does not include medical jargon; and making medical interpreters accessible. In addition, training clinicians about unconscious bias and cultural humility can help foster empathy and awareness of differences in health beliefs and behaviors within diverse patient populations.

A 2019 scoping review of 11 studies (N > 60 million) focused on outcomes from Medicare AWVs for patients ages ≥ 65 years.⁸ This included uptake of preventive services, such as vaccinations or cancer screenings; advice, education, or referrals offered during the AWV; medication use; and hospitalization rates. Overall findings showed that older adults who received a Medicare AWV were more likely to receive referrals for preventive screenings and follow-through on these recommendations compared with those who did not undergo an AWV.⁸

The approach to caring for individuals later in life has shifted from management of disease and disability to promotion of healthy aging by optimizing health care needs and QOL.

Completion rates for vaccines, while remaining low overall, were higher among those who completed an AWV. Additionally, these studies showed improved completion of screenings for breast cancer, bone density, and colon cancer. Several studies in the scoping review supported the use of AWVs as an effective means by which to offer health education and advice related to health promotion and risk reduction, such as diet and lifestyle modifications.⁸ Little evidence exists on long-term outcomes related to AWV completion.⁸

Utilize shared decision-making to determine whether preventive screening makes sense for your patient. Although cancer remains the second leading cause of death among Americans ages ≥ 65 years,⁹ clear screening guidelines for this age group remain elusive.¹⁰ Physicians and patients often are reluctant to stop cancer screening despite lower life expectancy and fewer potential benefits of diagnosis in this population.⁹ Some recent studies reinforce the heterogeneity of the older adult population and further underscore the importance of individual-level decision-making.^11-14 It is important to let older adult patients and their caregivers know about the potential risks of screening tests, especially the possibility that incidental findings may lead to unwarranted additional care or monitoring.⁹

Continue to: Avoid these screening conversation missteps

Avoid these screening conversation missteps. A 2017 qualitative study asked 40 community-dwelling older adults (mean age = 76 years) about their preferences for discussing screening cessation with their physicians.¹³ Three themes emerged.First, they were open to stopping their screenings, especially when suggested by a trusted physician. Second, health status and physical function made sense as decision points, but life expectancy did not. Finally, lengthy discussions with expanded details about risks and benefits were not appreciated, especially if coupled with comments on the limited benefits for those nearing the end of life. When discussing life expectancy, patients preferred phrasing that focused on how the screening was unnecessary because it would not help them live longer.¹³

Ensure that your message is understood—and culturally relevant. Recent studies on lower health literacy among older adults^15,16 and ethnic and racial minorities^17-21—as revealed in the 2003 National Assessment of Adult Literacy²²—might offer clues to patient receptivity to discussions about preventive screening and other health decisions.

One study found a significant correlation between higher self-rated health literacy and higher engagement in health behaviors such as mammography screening, moderate physical activity, and tobacco avoidance.¹⁶ Perceptions of personal control over health status, as well as perceived social standing, also correlated with health literacy score levels.¹⁶ Another study concluded that lower health literacy combined with lower self-­efficacy, cultural beliefs about health topics (eg, diet and exercise), and distrust in the health care system contributed to lower rates of preventive care utilization among ethnocultural minority older adults in Canada, the United Kingdom, the United States, and Australia.¹⁸

Ensuring that easy-to-understand information is equitably shared with older adults of all races and ethnicities is critical. A 2018 study showed that distrust of the health system and cultural issues contributed to the lower incidence of colorectal cancer screenings in Hispanic and Asian American patients ages 50 to 75 years.²¹ Patients whose physicians engaged in “health literate practices” (eg, offering clear explanations of diagnostic plans and asking patients to describe what they understood) were more likely to obtain recommended breast and colorectal cancer screenings.²⁰ In particular, researchers found that non-Hispanic Blacks were nearly twice as likely to follow through on colorectal cancer screening if their physicians engaged in health literate practices.²⁰ In addition, receiving clear instructions from physicians increased the odds of completing breast cancer screening among Hispanic and non-­Hispanic White women.²⁰

Overall, screening information and recommendations should be standardized for all patients. This is particularly important in light of research that found that older non-Hispanic Black patients were less likely than their non-Hispanic White counterparts to receive information from their physicians about colorectal cancer screening.²⁰

Continue to: Mobility

Mobility

Encourage physical activity. Frequent exercise and other forms of physical activity are associated with healthy aging, as shown in a 2017 systematic review and meta-analysis of 23 studies (N = 174,114).²³ Despite considerable heterogeneity between studies in how researchers defined healthy aging and physical activity, they found that adults who incorporate regular movement and exercise into daily life are likely to continue to benefit from it into older age.²³ In addition, a 2016 secondary analysis of data from the InCHIANTI longitudinal aging study concluded that adults ages ≥ 65 years (N = 1149) who had maintained higher physical activity levels throughout adulthood had less physical function decline and reduced rates of mobility disability and premature death compared with those who reported being less active.²⁴

Preserve gait speed (and bolster health) with these activities. Walking speed, or gait, measured on a level surface has been used as a predictor for various aspects of well-being in older age, such as daily function, mobility, independence, falls, mortality, and hospitalization risk.²⁵ Reduced gait speed is also one of the key indicators of functional impairment in older adults.

A 2015 systematic review sought to determine which type of exercise intervention (resistance, coordination, or multimodal training) would be most effective in preserving gait speed in healthy older adults (N = 2495; mean age = 74.2 years).²⁵ While the 42 included studies were deemed to be fairly low quality, the review revealed (with large effect size [0.84]) that a number of exercise modalities might stave off loss of gait speed in older adults. Patients in the resistance training group had the greatest improvement in gait speed (0.11 m/s), followed by those in the coordination training group (0.09 m/s) and the multimodal training group (0.05 m/s).²⁵

Individuals who had maintained higher physical activity levels throughout adulthood had less physical functional decline and reduced rates of mobility disability and premature death.

Finally, muscle mass and strength offer a measure of physical performance and functionality. A 2020 systematic review of 83 studies (N = 108,428) showed that low muscle mass and strength, reduced handgrip strength, and lower physical performance were predictive of reduced capacities in activities of daily living and instrumental activities of daily living.²⁶ It is important to counsel adults to remain active throughout their lives and to include resistance training to maintain muscle mass and strength to preserve their motor function, mobility, independence, and QOL.