The Journal of Family Practice

The US Preventive Services Task Force (USPSTF) published updated recommendations on screening for syphilis on September 27.¹ The Task Force continues to recommend screening for all adolescents and adults who are at increased risk for infection. (As part of previous recommendations, the USPSTF also advocates screening all pregnant women for syphilis early in their pregnancy to prevent congenital syphilis.²)

Who is at increased risk? Men who have sex with men (MSM), those with HIV or other sexually transmitted infections (STIs), those who use illicit drugs, and those with a history of incarceration, sex work, or military service are considered to be at increased risk for syphilis. Additionally, since state and local health departments collect and publish STI incidence data, it’s important to stay up to date on how common syphilis is in one’s community and tailor screening practices accordingly.

Men account for more than 80% of all primary and secondary syphilis infections, and MSM account for 53% of cases in men.³ The highest rates of syphilis are in men ages 25-29 years and 30-34 years (58.1 and 55.7 cases per 100,000, respectively).³

Why screening is important. Primary and secondary syphilis rates have increased steadily from an all-time low of 2.1 per 100,000 in 2000 to 12.7 per 100,000 in 2020.⁴ There were 171,074 cases reported in 2021.⁵

If not detected and treated, syphilis will progress from the primary and secondary stages to a latent form. About one-third of those with latent syphilis will develop tertiary syphilis, which can affect every organ system and cause multiple neurologic disorders.

How to screen. Syphilis screening typically involves a 2-step process. The first test that should be performed is a Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) test. This is followed by a treponemal antibody test if the initial test is positive. While the VDRL and RPR tests have high sensitivity, many other conditions can cause a false-positive result, necessitating confirmation with the more specific antibody test.

As far as frequency, the Task Force suggests screening annually for those at continued risk and more frequently (every 3 or 6 months) for those at highest risk.

Treatment for primary, secondary, and early latent syphilis (< 1 year’s duration) is a single intramuscular (IM) injection of benzathine penicillin, 2.4 million units. For late latent syphilis or syphilis of unknown duration, treatment is benzathine penicillin, 2.4 million units, administered in 3 weekly IM doses.

Treatment for those with penicillin allergies depends on the stage of syphilis and whether or not the patient is pregnant. Refer to the STD treatment guidelines for guidance.⁶

The CDC recommends presumptive treatment for anyone who has had sexual contact in the past 90 days with a person who’s been given a diagnosis of primary, secondary, or early latent syphilis.⁶

And finally, remember that all STIs are reportable to your local health department, which can assist with contract tracing and treatment follow-up.

The US Preventive Services Task Force (USPSTF) published updated recommendations on screening for syphilis on September 27.¹ The Task Force continues to recommend screening for all adolescents and adults who are at increased risk for infection. (As part of previous recommendations, the USPSTF also advocates screening all pregnant women for syphilis early in their pregnancy to prevent congenital syphilis.²)

Who is at increased risk? Men who have sex with men (MSM), those with HIV or other sexually transmitted infections (STIs), those who use illicit drugs, and those with a history of incarceration, sex work, or military service are considered to be at increased risk for syphilis. Additionally, since state and local health departments collect and publish STI incidence data, it’s important to stay up to date on how common syphilis is in one’s community and tailor screening practices accordingly.

Men account for more than 80% of all primary and secondary syphilis infections, and MSM account for 53% of cases in men.³ The highest rates of syphilis are in men ages 25-29 years and 30-34 years (58.1 and 55.7 cases per 100,000, respectively).³

Why screening is important. Primary and secondary syphilis rates have increased steadily from an all-time low of 2.1 per 100,000 in 2000 to 12.7 per 100,000 in 2020.⁴ There were 171,074 cases reported in 2021.⁵

If not detected and treated, syphilis will progress from the primary and secondary stages to a latent form. About one-third of those with latent syphilis will develop tertiary syphilis, which can affect every organ system and cause multiple neurologic disorders.

How to screen. Syphilis screening typically involves a 2-step process. The first test that should be performed is a Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) test. This is followed by a treponemal antibody test if the initial test is positive. While the VDRL and RPR tests have high sensitivity, many other conditions can cause a false-positive result, necessitating confirmation with the more specific antibody test.

As far as frequency, the Task Force suggests screening annually for those at continued risk and more frequently (every 3 or 6 months) for those at highest risk.

Treatment for primary, secondary, and early latent syphilis (< 1 year’s duration) is a single intramuscular (IM) injection of benzathine penicillin, 2.4 million units. For late latent syphilis or syphilis of unknown duration, treatment is benzathine penicillin, 2.4 million units, administered in 3 weekly IM doses.

Treatment for those with penicillin allergies depends on the stage of syphilis and whether or not the patient is pregnant. Refer to the STD treatment guidelines for guidance.⁶

The CDC recommends presumptive treatment for anyone who has had sexual contact in the past 90 days with a person who’s been given a diagnosis of primary, secondary, or early latent syphilis.⁶

And finally, remember that all STIs are reportable to your local health department, which can assist with contract tracing and treatment follow-up.

The US Preventive Services Task Force (USPSTF) published updated recommendations on screening for syphilis on September 27.¹ The Task Force continues to recommend screening for all adolescents and adults who are at increased risk for infection. (As part of previous recommendations, the USPSTF also advocates screening all pregnant women for syphilis early in their pregnancy to prevent congenital syphilis.²)

Who is at increased risk? Men who have sex with men (MSM), those with HIV or other sexually transmitted infections (STIs), those who use illicit drugs, and those with a history of incarceration, sex work, or military service are considered to be at increased risk for syphilis. Additionally, since state and local health departments collect and publish STI incidence data, it’s important to stay up to date on how common syphilis is in one’s community and tailor screening practices accordingly.

Men account for more than 80% of all primary and secondary syphilis infections, and MSM account for 53% of cases in men.³ The highest rates of syphilis are in men ages 25-29 years and 30-34 years (58.1 and 55.7 cases per 100,000, respectively).³

Why screening is important. Primary and secondary syphilis rates have increased steadily from an all-time low of 2.1 per 100,000 in 2000 to 12.7 per 100,000 in 2020.⁴ There were 171,074 cases reported in 2021.⁵

If not detected and treated, syphilis will progress from the primary and secondary stages to a latent form. About one-third of those with latent syphilis will develop tertiary syphilis, which can affect every organ system and cause multiple neurologic disorders.

How to screen. Syphilis screening typically involves a 2-step process. The first test that should be performed is a Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) test. This is followed by a treponemal antibody test if the initial test is positive. While the VDRL and RPR tests have high sensitivity, many other conditions can cause a false-positive result, necessitating confirmation with the more specific antibody test.

As far as frequency, the Task Force suggests screening annually for those at continued risk and more frequently (every 3 or 6 months) for those at highest risk.

Treatment for primary, secondary, and early latent syphilis (< 1 year’s duration) is a single intramuscular (IM) injection of benzathine penicillin, 2.4 million units. For late latent syphilis or syphilis of unknown duration, treatment is benzathine penicillin, 2.4 million units, administered in 3 weekly IM doses.

Treatment for those with penicillin allergies depends on the stage of syphilis and whether or not the patient is pregnant. Refer to the STD treatment guidelines for guidance.⁶

The CDC recommends presumptive treatment for anyone who has had sexual contact in the past 90 days with a person who’s been given a diagnosis of primary, secondary, or early latent syphilis.⁶

And finally, remember that all STIs are reportable to your local health department, which can assist with contract tracing and treatment follow-up.

Courtesy of Daniel Stulberg, MD

This patient had sustained multiple pressure injuries. The superior aspect of this image shows bullous change with intact dermis, which would classify that area of injury as a Stage 2 pressure injury.¹ An older injury in the coccygeal area was through the dermis (Stage 3), with some eschar seen at the base, making that area unstageable.¹ (There may have been deeper injury under the eschar.)

This patient was at heightened risk for pressure injury because of his paraplegia.² Fortunately, he had some preserved sensation. However, his rotator cuff surgery made it harder for him to smoothly transfer to and from the wheelchair, leading to sheer forces against his skin. Social determinates of health care pose an additional risk for pressure injuries. Without a properly fitted wheelchair and cushion, there is an increased risk of localized pressure over both bony prominences and parts of the body that come into contact with mechanical elements of the wheelchair.

Treatment for all pressure injuries includes relief of pressure on the affected area. In this patient’s case, he had to stay in bed (and out of the wheelchair) so that he could heal.

This patient was very knowledgeable about his condition and pressure injuries. He had already arranged for a wheelchair fitting and a visit with the wound care team. His Stage 2 injury had a bullous change instead of absent epithelium, so rather than an adherent hydrocolloid dressing (which would likely remove the loosened epithelium), he was provided with a nonadherent dressing to the area, then an absorbent foam overdressing.

An image of the patient’s deeper sacral injury was shared with the wound care team, which recommended filling the area with a silver rope dressing for its absorptive filler and antibacterial properties. The area was then covered with an absorbent foam. The patient planned to follow up with the Wound Care Clinic for reevaluation and ongoing treatment.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

Courtesy of Daniel Stulberg, MD

This patient had sustained multiple pressure injuries. The superior aspect of this image shows bullous change with intact dermis, which would classify that area of injury as a Stage 2 pressure injury.¹ An older injury in the coccygeal area was through the dermis (Stage 3), with some eschar seen at the base, making that area unstageable.¹ (There may have been deeper injury under the eschar.)

This patient was at heightened risk for pressure injury because of his paraplegia.² Fortunately, he had some preserved sensation. However, his rotator cuff surgery made it harder for him to smoothly transfer to and from the wheelchair, leading to sheer forces against his skin. Social determinates of health care pose an additional risk for pressure injuries. Without a properly fitted wheelchair and cushion, there is an increased risk of localized pressure over both bony prominences and parts of the body that come into contact with mechanical elements of the wheelchair.

Treatment for all pressure injuries includes relief of pressure on the affected area. In this patient’s case, he had to stay in bed (and out of the wheelchair) so that he could heal.

This patient was very knowledgeable about his condition and pressure injuries. He had already arranged for a wheelchair fitting and a visit with the wound care team. His Stage 2 injury had a bullous change instead of absent epithelium, so rather than an adherent hydrocolloid dressing (which would likely remove the loosened epithelium), he was provided with a nonadherent dressing to the area, then an absorbent foam overdressing.

An image of the patient’s deeper sacral injury was shared with the wound care team, which recommended filling the area with a silver rope dressing for its absorptive filler and antibacterial properties. The area was then covered with an absorbent foam. The patient planned to follow up with the Wound Care Clinic for reevaluation and ongoing treatment.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

Courtesy of Daniel Stulberg, MD

This patient had sustained multiple pressure injuries. The superior aspect of this image shows bullous change with intact dermis, which would classify that area of injury as a Stage 2 pressure injury.¹ An older injury in the coccygeal area was through the dermis (Stage 3), with some eschar seen at the base, making that area unstageable.¹ (There may have been deeper injury under the eschar.)

This patient was at heightened risk for pressure injury because of his paraplegia.² Fortunately, he had some preserved sensation. However, his rotator cuff surgery made it harder for him to smoothly transfer to and from the wheelchair, leading to sheer forces against his skin. Social determinates of health care pose an additional risk for pressure injuries. Without a properly fitted wheelchair and cushion, there is an increased risk of localized pressure over both bony prominences and parts of the body that come into contact with mechanical elements of the wheelchair.

Treatment for all pressure injuries includes relief of pressure on the affected area. In this patient’s case, he had to stay in bed (and out of the wheelchair) so that he could heal.

This patient was very knowledgeable about his condition and pressure injuries. He had already arranged for a wheelchair fitting and a visit with the wound care team. His Stage 2 injury had a bullous change instead of absent epithelium, so rather than an adherent hydrocolloid dressing (which would likely remove the loosened epithelium), he was provided with a nonadherent dressing to the area, then an absorbent foam overdressing.

An image of the patient’s deeper sacral injury was shared with the wound care team, which recommended filling the area with a silver rope dressing for its absorptive filler and antibacterial properties. The area was then covered with an absorbent foam. The patient planned to follow up with the Wound Care Clinic for reevaluation and ongoing treatment.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

Courtesy of Daniel Stulberg, MD

These lesions, called Bohn nodules, manifest on the buccal or lingual portion of the maxillary alveolar ridge and, less frequently, on the mandibular alveolar ridge. Because Bohn nodules are white and have a firm consistency, they are often confused with teeth. They can be differentiated by location, as teeth usually erupt from the distal aspect of the alveolar ridge.

Bohn nodules are epithelial cysts that are filled with keratin, which gives them their white color. They are caused by portions of epithelium that get trapped under surrounding epithelial cells. Bohn nodules usually resolve when the overlying epithelium ruptures and releases the keratinaceous material (usually by the time the child is 3 months of age).¹

These nodules can be confused with neonatal or supernumerary teeth. Neonatal teeth can be abnormally small and pointed; they are true deciduous teeth that have erupted early. If they are removed, the child will not replace them until the time of their adult tooth eruption. Additionally, there are supernumerary teeth, which are extra teeth that are often abnormally shaped and loosely adherent. These abnormal teeth warrant extraction to avoid trauma to the tongue or aspiration.²

In this case, the family was advised regarding the benign nature of the nodules and the expectation that they would spontaneously resolve.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

Courtesy of Daniel Stulberg, MD

These lesions, called Bohn nodules, manifest on the buccal or lingual portion of the maxillary alveolar ridge and, less frequently, on the mandibular alveolar ridge. Because Bohn nodules are white and have a firm consistency, they are often confused with teeth. They can be differentiated by location, as teeth usually erupt from the distal aspect of the alveolar ridge.

Bohn nodules are epithelial cysts that are filled with keratin, which gives them their white color. They are caused by portions of epithelium that get trapped under surrounding epithelial cells. Bohn nodules usually resolve when the overlying epithelium ruptures and releases the keratinaceous material (usually by the time the child is 3 months of age).¹

These nodules can be confused with neonatal or supernumerary teeth. Neonatal teeth can be abnormally small and pointed; they are true deciduous teeth that have erupted early. If they are removed, the child will not replace them until the time of their adult tooth eruption. Additionally, there are supernumerary teeth, which are extra teeth that are often abnormally shaped and loosely adherent. These abnormal teeth warrant extraction to avoid trauma to the tongue or aspiration.²

In this case, the family was advised regarding the benign nature of the nodules and the expectation that they would spontaneously resolve.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

Courtesy of Daniel Stulberg, MD

These lesions, called Bohn nodules, manifest on the buccal or lingual portion of the maxillary alveolar ridge and, less frequently, on the mandibular alveolar ridge. Because Bohn nodules are white and have a firm consistency, they are often confused with teeth. They can be differentiated by location, as teeth usually erupt from the distal aspect of the alveolar ridge.

Bohn nodules are epithelial cysts that are filled with keratin, which gives them their white color. They are caused by portions of epithelium that get trapped under surrounding epithelial cells. Bohn nodules usually resolve when the overlying epithelium ruptures and releases the keratinaceous material (usually by the time the child is 3 months of age).¹

These nodules can be confused with neonatal or supernumerary teeth. Neonatal teeth can be abnormally small and pointed; they are true deciduous teeth that have erupted early. If they are removed, the child will not replace them until the time of their adult tooth eruption. Additionally, there are supernumerary teeth, which are extra teeth that are often abnormally shaped and loosely adherent. These abnormal teeth warrant extraction to avoid trauma to the tongue or aspiration.²

In this case, the family was advised regarding the benign nature of the nodules and the expectation that they would spontaneously resolve.

‌

Images and text courtesy of Daniel Stulberg, MD, FAAFP, Professor and Chair, Department of Family and Community Medicine, Western Michigan University Homer Stryker, MD School of Medicine Kalamazoo.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

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

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

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

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

A 65-YEAR-OLD WOMAN was brought into the emergency department by her daughter for spontaneous bruising, fatigue, and weakness of several weeks’ duration. She denied taking any medications or illicit drugs and had not experienced any falls or trauma. On a daily basis, she smoked 5 to 7 cigarettes and drank 6 or 7 beers, as had been her custom for several years. The patient lived alone and was grieving the death of her beloved dog, who had died a month earlier. She reported that since the death of her dog, her diet, which hadn’t been especially good to begin with, had deteriorated; it now consisted of beer and crackers.

On admission, she was mildly tachycardic (105 beats/min) with a blood pressure of 125/66 mm Hg. Physical examination revealed a frail-appearing woman who was in no acute distress but was unable to stand without assistance. She had diffuse ecchymoses and perifollicular, purpuric, hyperkeratotic papules and plaques on both of her legs (FIGURES 1A and 1B). In addition, she had faint perifollicular purpuric macules on her upper back. An oral examination revealed poor dentition.

A punch biopsy was performed on her leg, and it revealed noninflammatory dermal hemorrhage without evidence of vasculitis or vasculopathy.

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

Based on the patient’s appearance and her dietary history, we suspected scurvy, so a serum vitamin C level was ordered. The results took several days to return. In the meantime, additional lab work revealed hyponatremia (sodium, 129 mmol/L; normal range, 135-145 mmol/L), hypokalemia (potassium, 3 mmol/L; normal range, 3.5-5.2 mmol/L), hypophosphatemia (phosphorus, 2.3 mg/dL; normal range, 2.8-4.5 mg/dL); low serum vitamin D (6 ng/mL; normal range, 20-40 ng/mL); and macrocytic anemia (hemoglobin, 7.4 g/dL; normal range, 11-18 g/dL) with a mean corpuscular volume of 101.1 fL (normal range, 80-100 fL). Her iron panel showed normal serum iron and total iron binding capacity with a normal ferritin level (294 ng/mL; normal range, 30-300 ng/mL). A peripheral blood smear test uncovered mild anisocytosis and polychromasia, with no schistocytes. A fecal immunochemical test was negative.

Several days after admission, the results of the patient’s vitamin C test came back. Her levels were undetectable (< 5 µmol/L; normal range, 11-23 µmol/L), confirming that the patient had scurvy.

A health hazard to marinersthat is still around today

Scurvy is a condition that arises from a deficiency of vitamin C, or ascorbic acid. The first known case of scurvy was in 1550 BC.¹ Hippocrates termed the condition “ileos ematitis” and stated that “the mouth feels bad; the gums are detached from the teeth; blood runs from the nostrils … ulcerations on the legs … skin is thin.”¹ Scurvy was a major health hazard of mariners between the 15thand 18th centuries.² Today, the deficiency is uncommon in industrialized countries because there are many sources of vitamin C available through diet and vitamin supplements.³ In the United States, the prevalence of vitamin C deficiency is approximately 7%.⁴

Patients with scurvy may initially experience malaise and irritability. Dermatologic findings include hyperkeratotic lesions, gingival swelling, petechiae, and corkscrew hairs.

An essential nutrient in humans, vitamin C is required as a cofactor in the synthesis of mature collagen.³ Collagen is found in skin, bone, and endothelium. Inadequate collagen levels can result in poor dermal support of vessels and tissue fragility, leading to hemorrhage, which can occur in nearly any organ system.

Vitamin C deficiency occurs when serum concentration falls below 11.4 µmol/L, at which point noticeable manifestations of scurvy can begin.^1,4 Alcohol use, tobacco use, poverty, male sex, and poor nutrition are risk factors.^1,4

Continue to: Scurvy manifests after 8 to 12 weeks

Scurvy manifests after 8 to 12 weeks of inadequate vitamin C intake.¹ Patients may initially experience malaise and irritability. Anemia is common. Dermatologic findings include hyperkeratotic lesions, ecchymoses, poor wound healing, gingival swelling with loss of teeth, petechiae, and corkscrew hairs. Perifollicular hemorrhage is a characteristic finding of scurvy, generally seen on the lower extremities, where the capillaries are under higher hydrostatic pressure.³ Patients may also have musculoskeletal involvement with osteopenia or hemarthroses, which may be seen on imaging.^3,5 Cardiorespiratory, gastrointestinal, ophthalmologic, and neurologic findings have also been reported.³

Differential is broad; zero in on patient’s history

The differential diagnosis for hemorrhagic skin lesions is extensive and includes scurvy, coagulopathies, trauma, vasculitis, and vasculopathies.

The presence of perifollicular hemorrhage with corkscrew hairs and a dietary history of inadequate vitamin C intake can differentiate scurvy from other conditions. Serum testing revealing low plasma vitamin C will support the diagnosis, but this is an insensitive test, as values increase with recent intake. Leukocyte ascorbic acid concentrations are more representative of total body stores, but impractical for routine use.⁶ Skin biopsy is not necessary but may help to rule out other conditions.

Ascorbic acid will facilitate a speedy recovery

Treatment of scurvy includes vitamin C replacement. Response is rapid, with improvement to lethargy within several days and disappearance of other manifestations within several weeks.³ Recommendations on supplementation doses and forms vary, but adults require 300 to 1000 mg/d of ascorbic acid for at least 1 week or until clinical symptoms resolve and stores are repleted.^3,5,7

During our patient’s hospital stay, she remained stable and improved clinically with vitamin supplementation (ascorbic acid 1 g/d for 3 days, 500 mg/d after that) and physical therapy. She was counseled on a healthy diet, which would include citrus fruits, tomatoes, and leafy vegetables. The patient was also advised to refrain from drinking alcohol and was given information on an alcohol abstinence program.

At her 1-month follow-up, her condition had improved with near resolution of the skin lesions. She reported that she had given up cigarettes and alcohol. She said she’d also begun eating more citrus fruits and leafy vegetables.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

EVIDENCE SUMMARY

Early Dx didn’t improve smoking cessation rates or treatment outcomes

A 2016 evidence report and systematic review for the US Preventive Services Task Force (USPSTF) identified no studies directly comparing the effectiveness of COPD screening on patient outcomes, so the authors looked first at studies on the outcomes of screening, followed by studies exploring the effects of early treatment.¹

The authors identified 5 fair-quality RCTs (N = 1694) addressing the effect of screening asymptomatic patients for COPD with spirometry on the outcome of smoking cessation. One trial (n = 561) found better 12-month smoking cessation rates in patients who underwent spirometry screening and were given their “lung age” (13.6% vs 6.4% not given a lung age; P < .005; number needed to treat [NNT] = 14). However, a similar study (n = 542) published a year later found no significant difference in quit rates with or without “lung age” discussions (10.9% vs 13%, respectively; P not significant). In the other 3 studies, screening produced no significant effect on smoking cessation rates.¹

As for possible early treatment benefits, the review authors identified only 1 RCT (n = 1175) that included any patients with mild COPD (defined as COPD with a forced expiratory volume in 1 second [FEV₁] ≥ 80% of predicted normal value). It assessed treatment with inhaled corticosteroids (ICS) in patients with mild COPD who continued to smoke. The trial did not record symptoms (if any) at intake. ICS therapy reduced the frequency of COPD exacerbations (relative risk = 0.63; 95% CI, 0.47-0.85), although patients with milder COPD benefitted little in absolute terms (by 0.02 exacerbations/year).¹ The review authors further noted that data were insufficient to make definitive statements about the effect of ICS on dyspnea or health-related quality of life.

But later diagnosis is associated with poorer outcomes

Two recent, large retrospective observational cohort studies, however, have examined the impact of an early vs late COPD diagnosis in patients with dyspnea or other symptoms of COPD.^2,3 A later diagnosis was associated with worse outcomes.

In the first study, researchers in Sweden identified patients older than 40 years who had received a new diagnosis of COPD between 2000 and 2014.² They examined electronic health record data for 6 different “indicators” of COPD during the 5 years prior to date of diagnosis: pneumonia, other respiratory disease, oral steroids, antibiotics for respiratory infection, prescribed drugs for respiratory symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (if they had ≤ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3870), late diagnosis (n = 8827) was associated with

• a higher annual rate of exacerbations within the first 2 years after diagnosis (2.67 vs 1.41; hazard ratio [HR] = 1.89; 95% CI, 1.83-1.96; P < .0001; number of early diagnoses needed to prevent 1 exacerbation in 1 year = 79),
• shorter time to first exacerbation (HR = 1.61; 95% CI, 1.54-1.69; P < .0001), and
• higher direct health care costs (by €1500 per year; no P value given).

Mortality was not different between the groups (HR = 1.04; 95% CI, 0.98-1.11; P = .18).

The second investigation was a similarly designed retrospective observational cohort study using a large UK database.³ Researchers enrolled patients who were at least 40 years old and received a new diagnosis of COPD between 2011 and 2014.

Continue to: Researchers examined electronic...

Researchers examined electronic health record data in the 5 years prior to diagnosis for 7 possible indicators of early COPD: pneumonia, respiratory disease other than pneumonia, chest radiograph, prescription of oral steroids, prescription of antibiotics for lung infection, prescription to manage respiratory disease symptoms, and lung function measurement. Researchers categorized patients as early diagnosis (≥ 2 indicators prior to diagnosis) or late diagnosis (≥ 3 indicators prior to diagnosis). Compared with early diagnosis (n = 3375), late diagnosis (n = 6783) was associated with a higher annual rate of exacerbations over 3-year follow-up (1.09 vs 0.57; adjusted HR = 1.68; 95% CI, 1.59-1.79; P < .0001; or 1 additional exacerbation in 192 patients in 1 year), shorter mean time to first exacerbation (HR = 1.46; 95% CI: 1.38-1.55; P < .0001), and a higher risk of hospitalization within 3 years (rate ratio = 1.18; 95% CI, 1.08-1.28; P = .0001). The researchers did not evaluate for mortality.

Even smoking cessation rates were not improved by an early COPD diagnosis.

Importantly, patients in the late COPD diagnosis group in both trials had higher rates of other severe illnesses that cause dyspnea, including cardiovascular disease and other pulmonary diseases. As a result, dyspnea of other etiologies may have contributed to both the later diagnoses and the poorer clinical outcomes of the late-­diagnosis group. Both studies had a high risk of lead-time bias.

Recommendations from others

In 2016, the USPSTF gave a “D” rating (moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits) to screening asymptomatic adults without respiratory symptoms for COPD.⁴ Likewise, the 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report did not recommend routine screening with spirometry but did advocate trying to make an accurate diagnosis using spirometry in patients with risk factors for COPD and chronic, progressive symptoms.⁵

Editor’s takeaway

Reasonably good evidence failed to find a benefit from an early COPD diagnosis. Even smoking cessation rates were not improved. Without better disease-modifying treatments, spirometry—the gold standard for confirming a COPD diagnosis—should not be used for screening asymptomatic patients.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

ILLUSTRATIVE CASE

A 43-year-old woman presents to the clinic with diffuse, intermittent abdominal discomfort, bloating, and diarrhea that has slowly but steadily worsened over the past few years to now-daily symptoms. She states her overall health is otherwise good. Her review of systems is pertinent only for 8 lbs of unintentional weight loss over the past year and increased fatigue. She takes no supplements or routine over-the-counter or prescription medications, except for low-dose combination oral contraceptives, and is unaware of any family history of gastrointestinal (GI) diseases. She does not drink or smoke. She is up to date with immunizations and with cervical and breast cancer screening. Her body mass index is 23, her vital signs are within normal limits, and her physical exam is normal except for mild, diffuse abdominal tenderness without any masses, organomegaly, or peritoneal signs.

Her diagnostic work-up includes a complete metabolic panel, magnesium level, complete blood count, thyroid-stimulating hormone measurement, cytomegalovirus IgG and IgM serology, and stool studies for fecal leukocytes, ova and parasites, and fecal fat, in addition to a kidney, ureter, and bladder noncontrast computed tomography scan. All diagnostic testing is negative except for slightly elevated fecal fat, thereby decreasing the likelihood of infection, thyroid disorder, electrolyte abnormalities, or malignancy as a source of her symptoms.

She says that based on her online searches, her symptoms seem consistent with CD—with which you concur. However, she is fearful of an endoscopic procedure and asks if there is any other way to diagnose CD.

CD is an immune-mediated disorder in genetically susceptible people that is triggered by dietary gluten, causing damage to the small intestine.^1-6 The estimated worldwide prevalence of CD is approximately 1%, with greater prevalence in females.^1-6 A strong genetic predisposition also has been noted: prevalence among first-degree relatives is 10% to 44%.^2,3,6 Although CD can be diagnosed at any age, in the United States the mean age at diagnosis is in the fifth decade of life.⁶

The incidence of CD is on the rise due to true increases in disease incidence and prevalence, increased detection through better diagnostic tools, and increased screening of at-risk populations (eg, first-degree relatives, those with specific human leukocyte antigen variant genotypes, and those with certain chromosomal disorders, such as Down syndrome and Turner syndrome).^2-6 However, despite the increasing prevalence of CD, most patients remain undiagnosed.¹

The consistently strong predictive value of tTG-IgA serum testing may enable celiac disease diagnosis at a much lower cost and reduced risk vs traditional invasive procedures.

The diagnosis of CD in adults is typically made with elevated serum tTG-IgA and endomysial IgA antibodies (EMAs) on initial screening, followed by a duodenal biopsy via EGD for confirmatory testing and/or elucidation of differential diagnoses.^7,8 In 2020, guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition advised that the diagnosis of CD in children can be made without the need for biopsy.⁹ They stated that serum tTG-IgA antibodies ≥ 10 times the ULN, in conjunction with a positive serum EMA, effectively make the diagnosis without endoscopy. Although the gold standard of EGD with biopsy for diagnosing CD has its own inherent risks and can be expensive, a “no-biopsy” approach has yet to be adopted into guidelines for diagnosing CD in adults.^7,8

STUDY SUMMARY

tTG-IgA titers were highly predictive of CD in 3 distinct cohorts

This 2021 hybrid prospective/retrospective study with 3 distinct cohorts aimed to assess the utility of serum tTG-IgA titers compared to traditional EGD with duodenal biopsy for the diagnosis of CD in adult participants (defined as ≥ 16 years of age). A serum tTG-IgA titer ≥ 10 times the ULN was set as the minimal cutoff value, and standardized duodenal biopsy sampling and evaluation for histologic mucosal changes consistent with Marsh 3 lesions was used as the diagnostic reference standard.

Continue to: Cohort 1 was a...

Cohort 1 was a prospective analysis of adults (N = 740) considered to have a high suspicion for CD, recruited from a single CD subspecialty clinic in the United Kingdom. Patients with a previous diagnosis of CD, those adhering to a gluten-free diet, and those with IgA deficiency were excluded. Study patients had tTG-IgA titers drawn and, within 6 weeks, underwent endoscopy with ≥ 1 biopsy from the duodenal bulb and/or the second part of the duodenum. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 98.7% (95% CI, 97%-99.4%).

Cohort 2 was a retrospective analysis of adult patients (N = 532) considered to have low suspicion for CD. These patients were referred for endoscopy for generalized GI complaints in the same hospital as Cohort 1, but not the subspecialty clinic. Exclusion criteria and timing of IgA titers and endoscopy were identical to those of Cohort 1. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 100%.

Cohort 3 (which included patients in 8 countries) was a retrospective analysis of the performance of multiple assays to enhance the validity of this approach in a wide range of settings. Adult patients (N = 145) with tTG-IgA serology positive for celiac who then underwent endoscopy with 4 to 6 duodenal biopsy samples were included in this analysis. Eleven distinct laboratories performed the tTG-IgA assay. The PPV of tTG-IgA titers ≥ 10 times the ULN in patients with biopsy-proven CD was 95.2% (95% CI, 84.6%-98.6%).

In total, this study included 1417 adult patients; 431 (30%) had tTG-IgA titers ≥ 10 times the ULN. Of those patients, 424 (98%) had histopathologic findings on duodenal biopsy consistent with CD.

Of note, there was no standardization as to the assays used for the tTG-IgA titers: Cohort 1 used 2 different manufacturers’ assays, Cohort 2 used 1 assay, and Cohort 3 used 5 assays. Regardless, the “≥ 10 times the ULN” calculation was based on each manufacturer’s published assay ranges. The lack of assay standardization did create variance in false-positive rates, however: Across all 3 cohorts, the false-positive rate for trusting the “≥ 10 times the ULN” threshold as the sole marker for CD in adults increased from 1% (Cohorts 1 and 2) to 5% (all 3 cohorts).

Continue to: WHAT'S NEW

Less invasive, less costly diagnosis of celiac disease in adults

In adults with symptoms suggestive of CD, the diagnosis can be made with a high level of certainty if a serum tTG-IgA titer is ≥ 10 times the ULN. Through informed, shared decision making in the presence of such a finding, patients may accept a serologic diagnosis and forgo an invasive EGD with biopsy and its inherent costs and risks. Indeed, if the majority of patients with CD are undiagnosed or underdiagnosed, and there exists a minimally invasive blood test that is highly cost effective in the absence of “red flags,” the overall benefit of this path could be substantial.

CAVEATS

“No biopsy” does not mean no risk/benefit discussion

While the PPVs are quite high, the negative predictive value varied greatly: 13%, 98%, and 10% for Cohorts 1, 2, and 3, respectively. Therefore, although serum tTG-IgA titers ≥ 10 times the ULN are useful for diagnosis, a negative result (serum tTG-IgA titers < 10 times the ULN) should not be used to rule out CD, and other testing should be pursued.

Additionally (although rare), patients with CD who have IgA deficiency may obtain false-negative results using the tTG-IgA ≥ 10 times the ULN diagnostic criterion.^7,8

Also, both Cohorts 1 and 2 took place in general or subspecialty GI clinics (Cohort 3’s site types were not specified). However, the objective interpretation of tTG-IgA serology means it could be considered as an additional diagnostic tool for primary care physicians, as well.

If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued.

Finally, if a primary care physician and their patient decide to go the “no-biopsy” route, it should be with a full discussion of the possible risks and benefits of not pursuing EGD. If there are any potential “red flag” symptoms suggesting the possibility of a more concerning differential diagnosis, EGD evaluation should still be pursued. Such symptoms might include (but not be limited to) chronic dyspepsia, dysphagia, weight loss, and unexplained anemia.⁷

Continue to: CHALLENGES TO IMPLEMENTATION

Diagnostic guidelines still favor EGD with biopsy for adults

The 2013 American College of Gastroenterology guidelines support the use of EGD and duodenal biopsy to diagnose CD in both low- and high-risk patients, regardless of serologic findings.⁷ In a 2019 Clinical Practice Update, the American Gastrointestinal Association (AGA) stated that when tTG-IgA titers are ≥ 10 times the ULN and EMAs are positive, the PPV is “virtually 100%” for CD. Yet they still state that in this scenario “EGD and duodenal biopsies may then be performed for purposes of differential diagnosis.”⁸ Furthermore, the AGA does not discuss informed and shared decision making with patients for the option of a “no-biopsy” diagnosis.⁸

Additionally, there may be challenges in finding commercial laboratories that report reference ranges with a clear ULN. Although costs for the serum tTG-IgA assay vary, they are less expensive than endoscopy with biopsy and histopathologic examination, and therefore may present less of a financial barrier.

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology

Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.⁸

mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.

mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:

• They are nonreplicating.
• They do not integrate into the host genome.
• They are highly effective.
• They can produce antibody and cellular immunity.
• They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.

Continue to: Vaccines against SARS-CoV-2

Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–­approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen ­COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).⁹

Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.^10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)

The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.

The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.^13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.

Efficacy of COVID-19 vaccines

The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.¹⁰ This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-­confirmed COVID-19 at 3-month follow-up.¹⁰ Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.

Continue to: Data from trials...

Although mRNA vaccines seem novel, they have been in development for more than 30 years.

Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.^15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.¹⁷

Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.¹⁸ During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.¹⁹

In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.¹⁶ A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.²⁰ The efficacy of the vaccines is summarized in TABLE 1.^21-24

Even in patients who have natural infection, several studies have shown that ­COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.^9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.

Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully ­vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.^27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.²⁹

Continue to: Vaccine adverse effects

Vaccine adverse effects: Common, rare, myths

Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 1^21-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.^a

Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.^30,31

Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.^30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.

A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.³³ Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.³⁴ In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.³⁴

Even in patients who have natural infection, vaccination increases the level and durability of immune response to infection and reinfection and improves outcomes.

A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.³⁵ Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.

Continue to: There is emerging evidence...

There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.³⁶ That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.

TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.³⁶ The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.³⁶) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations³⁶ (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).

Myths surrounding vaccination

Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).³⁷ There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.³⁸

Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.³⁹ No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.^40,41

Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.⁸

Continue to: Boosters and vaccine mix-and-match

As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.⁴² There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.⁴² Five patients were hospitalized; none died.⁴² A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.

Vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.

Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.⁴³ Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.^19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.

Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.⁴⁹

Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity⁵⁰ (TABLE 2⁵¹).

Vaccination in special populations

Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”

Continue to: Pregnant patients

Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.⁵² CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.⁵³

A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from ­COVID-19 vaccination.⁵⁴ Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.

Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.⁵⁵

Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.⁵⁶ In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.⁵⁷

Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:

• the absence of comorbidities often seen in adults
• evidence that pediatric patients might have reduced expression of ACE-2
• a more active T-cell response in infected children, due to an active thymus.⁵⁶

Continue to: Although the number of children affected...

A large US study demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.

Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.⁵⁸ The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.⁵⁸ Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.^59,60

Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.⁶¹ Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.⁶² Antibody response to vaccination was also less robust in this group.

There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.⁶³ Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.^b

Predictions (or, why is a COVID-19 vaccine important?)

What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.⁶⁴ First, only relative immunity is produced after infection with a seasonal coronavirus.⁶⁴ Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.⁶⁵ Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.

Boosters provide additional reduction in the risk of death and hospitalization, which led to a recommendation that all patients ≥ 5 years of age receive a booster.

The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.⁶⁶ During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.

Continue to: At approximately that time...

At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.⁵⁷ In view of warning signs from wastewater surveillance, priorities for vaccination should be to:

• increase uptake in the hesitant
• get boosters to the eligible
• prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.

As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.

^awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html

^b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.

CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]

Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.¹ Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.^2-4

In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”

SARS-CoV-2 virology

As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.^5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.⁷

After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.⁵ The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.

Basic mRNA vaccine immunology