Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Dupilumab is a fully humanized monoclonal antibody to the α subunit of the IL-4 receptor that inhibits the action of helper T cell (T_H2)–type cytokines IL-4 and IL-13. Dupilumab was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of moderate to severe atopic dermatitis (AD). We report 2 patients with AD who were treated with dupilumab and subsequently developed facial flushing after consuming alcohol.

Case Report

Patient 1
A 24-year-old woman presented to the dermatology clinic with a lifelong history of moderate to severe AD. She had a medical history of asthma and seasonal allergies, which were treated with fexofenadine and an inhaler, as needed. The patient had an affected body surface area of approximately 70% and had achieved only partial relief with topical corticosteroids and topical calcineurin inhibitors.

Because her disease was severe, the patient was started on dupilumab at FDA-approved dosing for AD: a 600-mg subcutaneous (SC) loading dose, followed by 300 mg SC every 2 weeks. She reported rapid skin clearance within 2 weeks of the start of treatment. Her course was complicated by mild head and neck dermatitis.

Seven months after starting treatment, the patient began to acutely experience erythema and warmth over the entire face that was triggered by drinking alcohol (Figure). Before starting dupilumab, she had consumed alcohol on multiple occasions without a flushing effect. This new finding was distinguishable from her facial dermatitis. Onset was within a few minutes after drinking alcohol; flushing self-resolved in 15 to 30 minutes. Although diffuse, erythema and warmth were concentrated around the jawline, eyebrows, and ears and occurred every time the patient drank alcohol. Moreover, she reported that consumption of hard (ie, distilled) liquor, specifically tequila, caused a more severe presentation. She denied other symptoms associated with dupilumab.

Comment

Two other single-patient case reports have discussed similar findings of alcohol-induced flushing associated with dupilumab.^1,2 Both of those patients—a 19-year-old woman and a 26-year-old woman—had not experienced flushing before beginning treatment with dupilumab for AD. Both experienced onset of facial flushing months after beginning dupilumab even though both had consumed alcohol before starting dupilumab, similar to the cases presented here. One patient had a history of asthma; the other had a history of seasonal and environmental allergies.

Possible Mechanism of Action
Acute alcohol ingestion causes dermal vasodilation of the skin (ie, flushing).³ A proposed mechanism is that flushing results from direct action on central vascular-control mechanisms. This theory results from observations that individuals with quadriplegia lack notable ethanol-induced vasodilation, suggesting that ethanol has a central neural site of action.Although some research has indicated that ethanol might induce these effects by altering the action of certain hormones (eg, angiotensin, vasopressin, and catecholamines), the precise mechanism by which ethanol alters vascular function in humans remains unexplained.³

Deficiencies in alcohol dehydrogenase (ADH), aldehyde dehydrogenase 2, and certain cytochrome P450 enzymes also might contribute to facial flushing. People of Asian, especially East Asian, descent often respond to an acute dose of ethanol with symptoms of facial flushing—predominantly the result of an elevated blood level of acetaldehyde caused by an inherited deficiency of aldehyde dehydrogenase 2,⁴ which is downstream from ADH in the metabolic pathway of alcohol. The major enzyme system responsible for metabolism of ethanol is ADH; however, the cytochrome P450–dependent ethanol-oxidizing system—including major CYP450 isoforms CYP3A, CYP2C19, CYP2C9, CYP1A2, and CYP2D6, as well as minor CYP450 isoforms, such as CYP2E1— also are involved, to a lesser extent.⁵

A Role for Dupilumab?
A recent pharmacokinetic study found that dupilumab appears to have little effect on the activity of the major CYP450 isoforms. However, the drug’s effect on ADH and minor CYP450 minor isoforms is unknown. Prior drug-drug interaction studies have shown that certain cytokines and cytokine modulators can markedly influence the expression, stability, and activity of specific CYP450 enzymes.⁶ For example, IL-6 causes a reduction in messenger RNA for CYP3A4 and, to a lesser extent, for other isoforms.⁷ Whether dupilumab influences enzymes involved in processing alcohol requires further study.

Conclusion

We describe 2 cases of dupilumab-induced facial flushing after alcohol consumption. The mechanism of this dupilumab-associated flushing is unknown and requires further research.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Practice Gap

It is well established that surgical complications and a poor scar outcome can have a remarkable impact on patient satisfaction.¹ A common complication following dermatologic surgery is suture spitting, in which a buried suture is extruded through the skin surface. When repairing a cutaneous defect following dermatologic surgery, absorbable or nonabsorbable sutures are placed under the skin surface to approximate wound edges, eliminate dead space, and reduce tension on the edges of the wound, improving the cosmetic outcomes.

Absorbable sutures constitute most buried sutures in cutaneous surgery and can be made of natural or synthetic fibers.² Absorbable sutures made from synthetic fibers are degraded by hydrolysis, in which water breaks down polymer chains of the suture filament. Natural absorbable sutures are composed of mammalian collagen; they are broken down by the enzymatic process of proteolysis.

Tensile strength is lost long before a suture is fully absorbed. Although synthetic fibers have, in general, higher tensile strength and generate less tissue inflammation, they take much longer to absorb.² During absorption, in some cases, a buried suture is pushed to the surface and extrudes along the wound edge or scar, which is known as spitting³ (Figure 1).

The Technique

Choice of suture material for buried sutures can influence the risk of spitting.

Factors Impacting Increased Spitting
The 3 most common absorbable sutures in dermatologic surgery include poliglecaprone 25, polyglactin 910, and polydioxanone; of them, polyglactin 910 has been found to have a higher rate of spitting than poliglecaprone 25 and polydioxanone.² However, because complete absorption of polydioxanone can take as long as 8 months, this suture might “spit” much later than polyglactin 910 or poliglecaprone 25, which typically are fully hydrolyzed by 3 and 4 months, respectively.² Placing sutures superficially in the dermis has been found to increase the rate of spitting.⁵ Throwing more knots per closure also has been found to increase the rate of spitting.⁵

How to Decrease Spitting
Careful choice of suture material and proper depth of suture placement might decrease the risk for spitting in dermatologic surgery. Furthermore, if polyglactin 910 or a long-lasting suture is to be used, sutures should be placed deeply.

What to Do If Sutures Spit
When a suture has begun to spit, the extruding foreign material needs to be removed and the surgical site assessed for infection or abscess. Exposed suture material typically can be removed with forceps without local anesthesia. In some cases, fine-tipped Bishop-Harmon tissue forceps or jewelers forceps might be required.

If the suture cannot be removed completely, it should be trimmed as short as possible. This can be accomplished by pulling on the exposed end of the suture, tenting the skin, and trimming it as close as possible to the surface. Once the foreign material is removed, assessment for signs of infection is paramount.

How to Manage Infection—Postoperative infection associated with a spitting suture can take the form of a periwound cellulitis or stitch abscess.³ A stitch abscess can reflect a sterile inflammatory response to the buried suture or a true infection⁴; the former is more common.³ In the event of an infected stitch abscess, provide warm compresses, obtain specimens for culture, and prescribe antibiotics after the spitting suture has been removed. Incision and drainage also might be required if notable fluctuance is present.

It is crucial for dermatologic surgeons to identify and manage these complications. Figure 2 illustrates an algorithmic approach to managing spitting sutures.

Practical Implications

Spitting sutures are a common occurrence following dermatologic surgery that can lead to remarkable patient distress. Fortunately, in the absence of superimposed infection, spitting sutures have not been shown to worsen outcomes of healing and scarring.⁵ Nevertheless, it is important to identify and appropriately treat this common complication. The simple algorithm we provide (Figure 2) aids in cutaneous surgery by providing a straightforward approach to managing spitting sutures and their complications.

Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


Irritable bowel syndrome (IBS) is one of the most common disorders managed by primary care physicians and gastroenterologists.¹ Characterized by abdominal pain coinciding with altered stool form and/or frequency as defined by the Rome IV diagnostic criteria,² symptoms range from mild to debilitating and may remarkably impair quality of life and work productivity.¹

The cause of IBS is poorly understood. Proposed pathophysiologic factors include impaired mucosal function, microbial imbalance, visceral hypersensitivity, psychologic dysfunction, genetic factors, neurotransmitter imbalance, postinfectious gastroenteritis, inflammation, and food intolerance, any or all of which may lead to the development and maintenance of IBS symptoms.³ More recent observations of inflammation in the intestinal lining^4,5 and proinflammatory peripherally circulating cytokines⁶ challenge its traditional classification as a functional disorder.

The cause of this inflammation is of intense interest, with speculation that the bacterial microbiota, bile acids, association with postinfectious gastroenteritis and inflammatory bowel disease cases, and/or foods may contribute. Although approximately 50% of individuals with IBS report that foods aggravate their symptoms,⁷ studies investigating type I antibody–mediated immediate hypersensitivity have largely failed to demonstrate a substantial link, prompting many authorities to regard these associations as food “intolerances” rather than true allergies. Based on this body of literature, a large 2010 consensus report on all aspects of food allergies advises against food allergy testing for IBS.⁸

In contrast, by utilizing type IV food allergen skin patch testing, 2 proof-of-concept studies^9,10 investigated a different allergic mechanism in IBS, namely cell-mediated delayed-type hypersensitivity. Because many foods and food additives are known to cause allergic contact dermatitis,¹¹ it was hypothesized that these foods may elicit a similar delayed-type hypersensitivity response in the intestinal lining in previously sensitized individuals. By following a patch test–guided food avoidance diet, a large subpopulation of patients with IBS experienced partial or complete IBS symptom relief.^9,10 Our study further investigates a role for food-related delayed-type hypersensitivities in the pathogenesis of IBS.

Methods

Patient Selection
This study was conducted in a secondary care community-based setting. All patients were self-referred over an 18-month period ending in October 2019, had physician-diagnosed IBS, and/or met the Rome IV criteria for IBS and presented expressly for the food patch testing on a fee-for-service basis. Subtype of IBS was determined on presentation by the self-reported historically predominant symptom. Duration of IBS symptoms was self-reported and was rounded to the nearest year for purposes of data collection.

Exclusion criteria included pregnancy, known allergy to adhesive tape or any of the food allergens used in the study, severe skin rash, symptoms that had a known cause other than IBS, or active treatment with systemic immunosuppressive medications.

Patch Testing
Skin patch testing was initiated using an extensive panel of 117 type IV food allergens (eTable)¹¹ identified in the literature,¹² most of which utilized standard compounded formulations¹³ or were available from reputable patch test manufacturers (Brial Allergen GmbH; Chemotechnique Diagnostics). This panel was not approved by the US Food and Drug Administration. The freeze-dried vegetable formulations were taken from the 2018 report.⁹ Standard skin patch test procedure protocols¹² were used, affixing the patches to the upper aspect of the back.

Following patch test application on day 1, two follow-up visits occurred on day 3 and either day 4 or day 5. On day 3, patches were removed, and the initial results were read by a board-certified dermatologist according to a standard grading system.¹⁴ Interpretation of patch tests included no reaction, questionable reaction consisting of macular erythema, weak reaction consisting of erythema and slight edema, or strong reaction consisting of erythema and marked edema. On day 4 or day 5, the final patch test reading was performed, and patients were informed of their results. Patients were advised to avoid ingestion of all foods that elicited a questionable or positive patch test response for at least 3 months, and information about the foods and their avoidance also was distributed and reviewed.

Food Avoidance Questionnaire
Patients with questionable or positive patch tests at 72 or 96 hours were advised of their eligibility to participate in an institutional review board–approved food avoidance questionnaire study investigating the utility of patch test–guided food avoidance on IBS symptoms. The questionnaire assessed the following: (1) baseline average abdominal pain prior to patch test–guided avoidance diet (0=no symptoms; 10=very severe); (2) average abdominal pain since initiation of patch test–guided avoidance diet (0=no symptoms; 10=very severe); (3) degree of improvement in overall IBS symptoms by the end of the food avoidance period (0=no improvement; 10=great improvement); (4) compliance with the avoidance diet for the duration of the avoidance period (completely, partially, not at all, or not sure).

Questionnaires and informed consent were mailed to patients via the US Postal Service 3 months after completing the patch testing. The questionnaire and consent were to be completed and returned after dietary avoidance of the identified allergens for at least 3 months. Patients were not compensated for participation in the study.

Statistical Analysis
Statistical analysis of data collected from study questionnaires was performed with Microsoft Excel. Mean abdominal pain and mean global improvement scores were reported along with 1 SD of the mean. For comparison of mean abdominal pain and improvement in global IBS symptoms from baseline to after 3 months of identified allergen avoidance, a Mann-Whitney U test was performed, with P<.05 being considered statistically significant.

Results

Thirty-seven consecutive patients underwent the testing and were eligible for the study. Nineteen patients were included in the study by virtue of completing and returning their posttest food avoidance questionnaire and informed consent. Eighteen patients were White and 1 was Asian. Subcategories of IBS were diarrhea predominant (9 [47.4%]), constipation predominant (3 [15.8%]), mixed type (5 [26.3%]), and undetermined type (2 [10.5%]). Questionnaire answers were reported after a mean (SD) duration of patch test–directed food avoidance of 4.5 (3.0) months (Table 1).

Overall Improvement
Fifteen (78.9%) patients reported at least slight to great improvement in their global IBS symptoms, and 4 (21.1%) reported no improvement (Table 2), with a mean (SD) improvement score of 5.1 (3.3)(P<.00001).

Comment

Despite intense research interest and a growing number of new medications for IBS approved by the US Food and Drug Administration, there remains a large void in the search for cost-effective and efficacious approaches for IBS evaluation and treatment. In addition to major disturbances in quality of life,^14,15 the cost to society in direct medical expenses and indirect costs associated with loss of productivity and work absenteeism is considerable; estimates range from $21 billion or more annually.¹⁶

Food Hypersensitivities Triggering IBS
This study further evaluated a role for skin patch testing to identify delayed-type (type IV) food hypersensitivities that trigger IBS symptoms and differed from the prior investigations^9,10 in that the symptoms used to define IBS were updated from the Rome III¹⁷ to the newer Rome IV² criteria. The data presented here show moderate to great improvement in global IBS symptoms in 58% (11/19) of patients, which is in line with a 2018 report of 40 study participants for whom follow-up at 3 or more months was available,⁹ providing additional support for a role for type IV food allergies in causing the same gastrointestinal tract symptoms that define IBS. The distinction between food-related studies, including this one, that implicate food allergies^9,10 and prior studies that did not support a role for food allergies in IBS pathogenesis⁸ can be accounted for by the type of allergy investigated. Conclusions that IBS flares after food ingestion were attributable to intolerance rather than true allergy were based on results investigating only the humoral arm and failed to consider the cell-mediated arm of the immune system. As such, foods that appear to trigger IBS symptoms on an allergic basis in our study are recognized in the literature¹² as type IV allergens that elicit cell-mediated immunologic responses rather than more widely recognized type I allergens, such as peanuts and shellfish, that elicit immediate-type hypersensitivity responses. Although any type IV food allergen(s) could be responsible, a pattern emerged in this study and the study published in 2018.⁹ Namely, some foods stood out as more frequently inducing patch test reactions, with the 3 most common being carmine, cinnamon bark oil, and sodium bisulfite (eTable). The sample size is relatively small, but the results raise the question of whether these foods are the most likely to trigger IBS symptoms in the general population. If so, is it the result of a higher innate sensitizing potential and/or a higher frequency of exposure in commonly eaten foods? Larger randomized clinical trials are needed.

Immune Response and IBS
There is mounting evidence that the immune system may play a role in the pathophysiology of IBS.¹⁸ Both lymphocyte infiltration of the myenteric plexus and an increase in intestinal mucosal T lymphocytes have been observed, and it is generally accepted that the mucosal immune system seems to be activated, at least in a subset of patients with IBS.¹⁹ Irritable bowel syndrome associations with quiescent inflammatory bowel disease or postinfectious gastroenteritis provide 2 potential causes for the inflammation, but most IBS patients have had neither.²⁰ The mucosal lining of the intestine and immune system have vast exposure to intraluminal allergens in transit, and it is hypothesized that the same delayed-type hypersensitivity response elicited in the skin by patch testing is elicited in the intestine, resulting in the inflammation that triggers IBS symptoms.¹⁰ The results here add to the growing body of evidence that ingestion of type IV food allergens by previously sensitized individuals could, in fact, be the primary source of the inflammation observed in a large subpopulation of individuals who carry a diagnosis of IBS.

Food Allergens in Patch Testing
Many of the food allergens used in this study are commonly found in various nonfood products that may contact the skin. For example, many flavorings are used as fragrances, and many preservatives, binders, thickeners, emulsifiers, and stabilizers serve the same role in moisturizers, cosmetics, and topical medications. Likewise, nickel sulfate hexahydrate, ubiquitous in foods that arise from the earth, often is found in metal in jewelry, clothing components, and cell phones. All are potential sensitizers. Thus, the question may arise whether the causal relationship between the food allergens identified by patch testing and IBS symptoms might be more of a systemic effect akin to systemic contact dermatitis as sometimes follows ingestion of an allergen to which an individual has been topically sensitized, rather than the proposed localized immunologic response in the intestinal lining. We were unaware of patient history of allergic contact dermatitis to any of the patch test allergens in this study, but the dermatologist author here (M.S.) has unpublished experience with 2 other patients with IBS who have benefited from low-nickel diets after having had positive patch tests to nickel sulfate hexahydrate and who, in retrospect, did report a history of earring dermatitis. Future investigations using pre– and post–food challenge histologic assessments of the intestinal mucosa in patients who benefit from patch test–guided food avoidance diets should help to better define the mechanism.

Because IBS has not been traditionally associated with structural or biochemical abnormalities detectable with current routine diagnostic tools, it has long been viewed as a functional disorder. The findings published more recently,^9,10 in addition to this study’s results, would negate this functional classification in the subset of patients with IBS symptoms who experience sustained relief of their symptoms by patch test–directed food avoidance. The underlying delayed-type hypersensitivity pathogenesis of the IBS-like symptoms in these individuals would mandate an organic classification, aptly named allergic contact enteritis.¹⁰

Follow-up Data
The mean (SD) follow-up duration for this study and the 2018 report⁹ was 4.5 (3.0) months and 7.6 (3.9) months, respectively. The placebo effect is a concern for disorders such as IBS in which primarily subjective outcome measures are available,²¹ and in a retrospective analysis of 25 randomized, placebo-controlled IBS clinical trials, Spiller²² concluded the optimum length of such trials to be more than 3 months, which these studies exceed. Although not blinded or placebo controlled, the length of follow-up in the 2018 report⁹ and here enhances the validity of the results.

Limitation
The retrospective manner in which the self-assessments were reported in this study introduces the potential for recall bias, a variable that could affect results. The presence and direction of bias by any given individual cannot be known, making it difficult to determine any effect it may have had. Further investigation should include daily assessments and refine the primary study end points to include both abdominal pain and the defecation considerations that define IBS.

Conclusion

Food patch testing has the potential to offer a safe, cost-effective approach to the evaluation and management of IBS symptoms. Randomized clinical trials are needed to further investigate the validity of the proof-of-concept results to date. For patients who benefit from a patch test–guided avoidance diet, invasive and costly endoscopic, radiologic, and laboratory testing and pharmacologic management could be averted. Symptomatic relief could be attained simply by avoiding the implicated foods, essentially doing more by doing less. 


Aerobic exercise may help reduce blood pressure in patients whose hypertension responds poorly to medications, a new study suggests.

A randomized controlled clinical trial showed that patients with resistant hypertension assigned to a moderate-intensity aerobic exercise training program had lower blood pressure compared with patients who received usual care.

“Resistant hypertension persists as a big clinical challenge because the available treatment options to lower blood pressure in this clinical population, namely drugs and renal denervation, show limited success,” Fernando Ribeiro, PhD, University of Aveiro, Portugal, told this news organization. “Aerobic exercise was safe and associated with a significant and clinically relevant reduction in 24-hour, daytime ambulatory, and office blood pressure.”

The findings were published online August 4 in JAMA Cardiology.

The researchers enrolled 53 patients aged 40-75 years with a diagnosis of resistant hypertension in this prospective, single-blinded trial. Nearly half (24) were women.

Resistant hypertension was defined as having a “mean systolic BP of 130 mm Hg or greater on 24-hour ambulatory BP monitoring and/or 135 mm Hg or greater during daytime hours while taking maximally tolerated doses of at least 3 antihypertensive agents, including a diuretic, or to have a controlled BP while taking 4 or more antihypertensive agents.”

From March 2017 to December 2019 at two sites in Portugal, 26 patients were randomly assigned to a 12-week aerobic exercise training program involving three 40-minute supervised sessions per week in addition to usual care. Another 27 patients in the control group were allocated to receive usual care only.

24-hour ambulatory systolic blood pressure was reduced by 7.1 mm Hg (95% confidence interval, -12.8 to -1.4; P = .02) in patients in the exercise group compared with the control group. In the exercise group, there were additional reductions of:

• -5.1 mm Hg of 24-hour ambulatory diastolic blood pressure (95% CI, -7.9 to -2.3; P = .001)
• -8.4 mm Hg of daytime systolic blood pressure (95% CI, -14.3 to -2.5, P = .006)
• -5.7 mm Hg of daytime diastolic blood pressure (95% CI, -9.0 to -2.4; P = .001)
• -10.0 mm Hg of office systolic blood pressure (95% CI, -17.6 to -2.5; P = .01)

Additionally, a significant improvement in cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5-6.6; P < .001) was observed in the exercise group compared with the control group.

Although prior research has suggested that exercise may lower blood pressure, this study is particularly useful because it “outlines very specifically what types of exercise you can recommend,” said Daniel Lackland, DrPH, Medical University of South Carolina, Charleston.

Although important, exercise is “one part of the overall management of high blood pressure. If people are being prescribed medication, they should continue taking it and work on lifestyle changes like reducing salt intake and drinking in moderation,” added Dr. Lackland, who was not involved in the research.

Also commenting on the findings, Wanpen Vongpatanasin, MD, UT Southwestern Medical Center, Dallas, pointed out that there are many potential benefits from exercise training. “It might improve endothelial function, decrease vascular stiffness and nervous system reactivity to stress, and improve quality of life for patients,” she said.

The study has several limitations, including a small sample size and a patient population that mostly has “relatively mild hypertension,” Dr. Vongpatanasin said, adding, “We don’t know whether these findings will apply to patients with more severe hypertension.”

It would also have been helpful if investigators monitored patient adherence to prescribed medications through urine or blood samples rather than a questionnaire, and to measure nighttime blood pressure, which is a more important predictor of cardiovascular outcomes, said Dr. Vongpatanasin, who was not associated with the research.

Moving forward, it will be important to “investigate why some patients are nonresponders to the exercise intervention and why some are super-responders,” study author Dr. Ribeiro said.

Dr. Ribeiro, Dr. Lackland, and Dr. Vongpatanasin have disclosed no relevant financial relationships. This study was funded by the European Union through the European Regional Development Fund Operational Competitiveness Factors Program (COMPETE) and by the Portuguese government through the Foundation for Science and Technology. The funders had no role in the study.

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

Aerobic exercise may help reduce blood pressure in patients whose hypertension responds poorly to medications, a new study suggests.

A randomized controlled clinical trial showed that patients with resistant hypertension assigned to a moderate-intensity aerobic exercise training program had lower blood pressure compared with patients who received usual care.

“Resistant hypertension persists as a big clinical challenge because the available treatment options to lower blood pressure in this clinical population, namely drugs and renal denervation, show limited success,” Fernando Ribeiro, PhD, University of Aveiro, Portugal, told this news organization. “Aerobic exercise was safe and associated with a significant and clinically relevant reduction in 24-hour, daytime ambulatory, and office blood pressure.”

The findings were published online August 4 in JAMA Cardiology.

The researchers enrolled 53 patients aged 40-75 years with a diagnosis of resistant hypertension in this prospective, single-blinded trial. Nearly half (24) were women.

Resistant hypertension was defined as having a “mean systolic BP of 130 mm Hg or greater on 24-hour ambulatory BP monitoring and/or 135 mm Hg or greater during daytime hours while taking maximally tolerated doses of at least 3 antihypertensive agents, including a diuretic, or to have a controlled BP while taking 4 or more antihypertensive agents.”

From March 2017 to December 2019 at two sites in Portugal, 26 patients were randomly assigned to a 12-week aerobic exercise training program involving three 40-minute supervised sessions per week in addition to usual care. Another 27 patients in the control group were allocated to receive usual care only.

24-hour ambulatory systolic blood pressure was reduced by 7.1 mm Hg (95% confidence interval, -12.8 to -1.4; P = .02) in patients in the exercise group compared with the control group. In the exercise group, there were additional reductions of:

• -5.1 mm Hg of 24-hour ambulatory diastolic blood pressure (95% CI, -7.9 to -2.3; P = .001)
• -8.4 mm Hg of daytime systolic blood pressure (95% CI, -14.3 to -2.5, P = .006)
• -5.7 mm Hg of daytime diastolic blood pressure (95% CI, -9.0 to -2.4; P = .001)
• -10.0 mm Hg of office systolic blood pressure (95% CI, -17.6 to -2.5; P = .01)

Additionally, a significant improvement in cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5-6.6; P < .001) was observed in the exercise group compared with the control group.

Although prior research has suggested that exercise may lower blood pressure, this study is particularly useful because it “outlines very specifically what types of exercise you can recommend,” said Daniel Lackland, DrPH, Medical University of South Carolina, Charleston.

Although important, exercise is “one part of the overall management of high blood pressure. If people are being prescribed medication, they should continue taking it and work on lifestyle changes like reducing salt intake and drinking in moderation,” added Dr. Lackland, who was not involved in the research.

Also commenting on the findings, Wanpen Vongpatanasin, MD, UT Southwestern Medical Center, Dallas, pointed out that there are many potential benefits from exercise training. “It might improve endothelial function, decrease vascular stiffness and nervous system reactivity to stress, and improve quality of life for patients,” she said.

The study has several limitations, including a small sample size and a patient population that mostly has “relatively mild hypertension,” Dr. Vongpatanasin said, adding, “We don’t know whether these findings will apply to patients with more severe hypertension.”

It would also have been helpful if investigators monitored patient adherence to prescribed medications through urine or blood samples rather than a questionnaire, and to measure nighttime blood pressure, which is a more important predictor of cardiovascular outcomes, said Dr. Vongpatanasin, who was not associated with the research.

Moving forward, it will be important to “investigate why some patients are nonresponders to the exercise intervention and why some are super-responders,” study author Dr. Ribeiro said.

Dr. Ribeiro, Dr. Lackland, and Dr. Vongpatanasin have disclosed no relevant financial relationships. This study was funded by the European Union through the European Regional Development Fund Operational Competitiveness Factors Program (COMPETE) and by the Portuguese government through the Foundation for Science and Technology. The funders had no role in the study.

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

Aerobic exercise may help reduce blood pressure in patients whose hypertension responds poorly to medications, a new study suggests.

A randomized controlled clinical trial showed that patients with resistant hypertension assigned to a moderate-intensity aerobic exercise training program had lower blood pressure compared with patients who received usual care.

“Resistant hypertension persists as a big clinical challenge because the available treatment options to lower blood pressure in this clinical population, namely drugs and renal denervation, show limited success,” Fernando Ribeiro, PhD, University of Aveiro, Portugal, told this news organization. “Aerobic exercise was safe and associated with a significant and clinically relevant reduction in 24-hour, daytime ambulatory, and office blood pressure.”

The findings were published online August 4 in JAMA Cardiology.

The researchers enrolled 53 patients aged 40-75 years with a diagnosis of resistant hypertension in this prospective, single-blinded trial. Nearly half (24) were women.

Resistant hypertension was defined as having a “mean systolic BP of 130 mm Hg or greater on 24-hour ambulatory BP monitoring and/or 135 mm Hg or greater during daytime hours while taking maximally tolerated doses of at least 3 antihypertensive agents, including a diuretic, or to have a controlled BP while taking 4 or more antihypertensive agents.”

From March 2017 to December 2019 at two sites in Portugal, 26 patients were randomly assigned to a 12-week aerobic exercise training program involving three 40-minute supervised sessions per week in addition to usual care. Another 27 patients in the control group were allocated to receive usual care only.

24-hour ambulatory systolic blood pressure was reduced by 7.1 mm Hg (95% confidence interval, -12.8 to -1.4; P = .02) in patients in the exercise group compared with the control group. In the exercise group, there were additional reductions of:

• -5.1 mm Hg of 24-hour ambulatory diastolic blood pressure (95% CI, -7.9 to -2.3; P = .001)
• -8.4 mm Hg of daytime systolic blood pressure (95% CI, -14.3 to -2.5, P = .006)
• -5.7 mm Hg of daytime diastolic blood pressure (95% CI, -9.0 to -2.4; P = .001)
• -10.0 mm Hg of office systolic blood pressure (95% CI, -17.6 to -2.5; P = .01)

Additionally, a significant improvement in cardiorespiratory fitness (5.05 mL/kg per minute of oxygen consumption; 95% CI, 3.5-6.6; P < .001) was observed in the exercise group compared with the control group.

Although prior research has suggested that exercise may lower blood pressure, this study is particularly useful because it “outlines very specifically what types of exercise you can recommend,” said Daniel Lackland, DrPH, Medical University of South Carolina, Charleston.

Although important, exercise is “one part of the overall management of high blood pressure. If people are being prescribed medication, they should continue taking it and work on lifestyle changes like reducing salt intake and drinking in moderation,” added Dr. Lackland, who was not involved in the research.

Also commenting on the findings, Wanpen Vongpatanasin, MD, UT Southwestern Medical Center, Dallas, pointed out that there are many potential benefits from exercise training. “It might improve endothelial function, decrease vascular stiffness and nervous system reactivity to stress, and improve quality of life for patients,” she said.

The study has several limitations, including a small sample size and a patient population that mostly has “relatively mild hypertension,” Dr. Vongpatanasin said, adding, “We don’t know whether these findings will apply to patients with more severe hypertension.”

It would also have been helpful if investigators monitored patient adherence to prescribed medications through urine or blood samples rather than a questionnaire, and to measure nighttime blood pressure, which is a more important predictor of cardiovascular outcomes, said Dr. Vongpatanasin, who was not associated with the research.

Moving forward, it will be important to “investigate why some patients are nonresponders to the exercise intervention and why some are super-responders,” study author Dr. Ribeiro said.

Dr. Ribeiro, Dr. Lackland, and Dr. Vongpatanasin have disclosed no relevant financial relationships. This study was funded by the European Union through the European Regional Development Fund Operational Competitiveness Factors Program (COMPETE) and by the Portuguese government through the Foundation for Science and Technology. The funders had no role in the study.

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

The Centers for Disease Control and Prevention has recommended that everyone get a COVID-19 vaccine, even if they’ve had the virus before. Yet many skeptics have held off getting the shots, believing that immunity generated by their previous infection will protect them if they should encounter the virus again. 

A new study published in the CDC’s Morbidity and Mortality Weekly Report pokes holes in this notion. It shows people who have recovered from COVID-19 but haven’t been vaccinated have more than double the risk of testing positive for the virus again, compared with someone who was vaccinated after an initial infection.

The study looked at 738 Kentucky residents who had an initial bout of COVID-19 in 2020. About 250 of them tested positive for COVID-19 a second time between May and July of 2021, when the Delta variant became dominant in the United States. 

The study matched each person who’d been reinfected with two people of the same sex and roughly the same age who had caught their initial COVID infection within the same week. The researchers then cross-matched those cases with data from Kentucky’s Immunization Registry.

They found that those who were unvaccinated had more than double the risk of being reinfected during the Delta wave. Partial vaccination appeared to have no significant impact on the risk of reinfection.

Among those who were reinfected, 20% were fully vaccinated, while 34% of those who did not get reinfected were fully vaccinated.

The study is observational, meaning it can’t show cause and effect; and the researchers had no information on the severity of the infections. Alyson Cavanaugh, PhD, a member of the CDC’s Epidemic Intelligence Service who led the study, said it is possible that some of the people who tested positive a second time had asymptomatic infections that were picked up through routine screening.

Still, the study backs up previous research and suggests that vaccination offers important additional protection.

“Our laboratory studies have shown that there’s an added benefit of vaccine for people who’ve had previous COVID-19. This is a real-world, epidemiologic study that found that among people who’d previously already had COVID-19, those who were vaccinated had lower odds of being reinfected,” Dr. Cavanaugh said.

“If you have had COVID-19 before, please still get vaccinated,” said CDC Director Rochelle Walensky, MD, in a written media statement. “This study shows you are twice as likely to get infected again if you are unvaccinated. Getting the vaccine is the best way to protect yourself and others around you, especially as the more contagious Delta variant spreads around the country.”

In a White House COVID-19 Response Team briefing in May, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease, explained why vaccines create stronger immunity than infection. He highlighted new research showing that two doses of an mRNA vaccine produce levels of neutralizing antibodies that are up to 10 times higher than the levels found in the blood of people who’ve recovered from COVID-19. Vaccines also enhance B cells and T cells in people who’ve recovered from COVID-19, which broadens the spectrum of protection and helps to fend off variants.

The study has some important limitations, which the authors acknowledged. The first is that second infections weren’t confirmed with genetic sequencing, so the researchers couldn’t definitively tell if a person tested positive a second time because they caught a new virus, or if they were somehow still shedding virus from their first infection. Given that the tests were at least 5 months apart, though, the researchers think reinfection is the most likely explanation.

Another bias in the study could have something to do with vaccination. Vaccinated people may have been less likely to be tested for COVID-19 after their vaccines, so the association or reinfection with a lack of vaccination may be overestimated. 

Also, people who were vaccinated at federal sites or in another state were not logged in the state’s immunization registry, which may have skewed the data.

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

The Centers for Disease Control and Prevention has recommended that everyone get a COVID-19 vaccine, even if they’ve had the virus before. Yet many skeptics have held off getting the shots, believing that immunity generated by their previous infection will protect them if they should encounter the virus again. 

A new study published in the CDC’s Morbidity and Mortality Weekly Report pokes holes in this notion. It shows people who have recovered from COVID-19 but haven’t been vaccinated have more than double the risk of testing positive for the virus again, compared with someone who was vaccinated after an initial infection.

The study looked at 738 Kentucky residents who had an initial bout of COVID-19 in 2020. About 250 of them tested positive for COVID-19 a second time between May and July of 2021, when the Delta variant became dominant in the United States. 

The study matched each person who’d been reinfected with two people of the same sex and roughly the same age who had caught their initial COVID infection within the same week. The researchers then cross-matched those cases with data from Kentucky’s Immunization Registry.

They found that those who were unvaccinated had more than double the risk of being reinfected during the Delta wave. Partial vaccination appeared to have no significant impact on the risk of reinfection.

Among those who were reinfected, 20% were fully vaccinated, while 34% of those who did not get reinfected were fully vaccinated.

The study is observational, meaning it can’t show cause and effect; and the researchers had no information on the severity of the infections. Alyson Cavanaugh, PhD, a member of the CDC’s Epidemic Intelligence Service who led the study, said it is possible that some of the people who tested positive a second time had asymptomatic infections that were picked up through routine screening.

Still, the study backs up previous research and suggests that vaccination offers important additional protection.

“Our laboratory studies have shown that there’s an added benefit of vaccine for people who’ve had previous COVID-19. This is a real-world, epidemiologic study that found that among people who’d previously already had COVID-19, those who were vaccinated had lower odds of being reinfected,” Dr. Cavanaugh said.

“If you have had COVID-19 before, please still get vaccinated,” said CDC Director Rochelle Walensky, MD, in a written media statement. “This study shows you are twice as likely to get infected again if you are unvaccinated. Getting the vaccine is the best way to protect yourself and others around you, especially as the more contagious Delta variant spreads around the country.”

In a White House COVID-19 Response Team briefing in May, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease, explained why vaccines create stronger immunity than infection. He highlighted new research showing that two doses of an mRNA vaccine produce levels of neutralizing antibodies that are up to 10 times higher than the levels found in the blood of people who’ve recovered from COVID-19. Vaccines also enhance B cells and T cells in people who’ve recovered from COVID-19, which broadens the spectrum of protection and helps to fend off variants.

The study has some important limitations, which the authors acknowledged. The first is that second infections weren’t confirmed with genetic sequencing, so the researchers couldn’t definitively tell if a person tested positive a second time because they caught a new virus, or if they were somehow still shedding virus from their first infection. Given that the tests were at least 5 months apart, though, the researchers think reinfection is the most likely explanation.

Another bias in the study could have something to do with vaccination. Vaccinated people may have been less likely to be tested for COVID-19 after their vaccines, so the association or reinfection with a lack of vaccination may be overestimated. 

Also, people who were vaccinated at federal sites or in another state were not logged in the state’s immunization registry, which may have skewed the data.

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

The Centers for Disease Control and Prevention has recommended that everyone get a COVID-19 vaccine, even if they’ve had the virus before. Yet many skeptics have held off getting the shots, believing that immunity generated by their previous infection will protect them if they should encounter the virus again. 

A new study published in the CDC’s Morbidity and Mortality Weekly Report pokes holes in this notion. It shows people who have recovered from COVID-19 but haven’t been vaccinated have more than double the risk of testing positive for the virus again, compared with someone who was vaccinated after an initial infection.

The study looked at 738 Kentucky residents who had an initial bout of COVID-19 in 2020. About 250 of them tested positive for COVID-19 a second time between May and July of 2021, when the Delta variant became dominant in the United States. 

The study matched each person who’d been reinfected with two people of the same sex and roughly the same age who had caught their initial COVID infection within the same week. The researchers then cross-matched those cases with data from Kentucky’s Immunization Registry.

They found that those who were unvaccinated had more than double the risk of being reinfected during the Delta wave. Partial vaccination appeared to have no significant impact on the risk of reinfection.

Among those who were reinfected, 20% were fully vaccinated, while 34% of those who did not get reinfected were fully vaccinated.

The study is observational, meaning it can’t show cause and effect; and the researchers had no information on the severity of the infections. Alyson Cavanaugh, PhD, a member of the CDC’s Epidemic Intelligence Service who led the study, said it is possible that some of the people who tested positive a second time had asymptomatic infections that were picked up through routine screening.

Still, the study backs up previous research and suggests that vaccination offers important additional protection.

“Our laboratory studies have shown that there’s an added benefit of vaccine for people who’ve had previous COVID-19. This is a real-world, epidemiologic study that found that among people who’d previously already had COVID-19, those who were vaccinated had lower odds of being reinfected,” Dr. Cavanaugh said.

“If you have had COVID-19 before, please still get vaccinated,” said CDC Director Rochelle Walensky, MD, in a written media statement. “This study shows you are twice as likely to get infected again if you are unvaccinated. Getting the vaccine is the best way to protect yourself and others around you, especially as the more contagious Delta variant spreads around the country.”

In a White House COVID-19 Response Team briefing in May, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Disease, explained why vaccines create stronger immunity than infection. He highlighted new research showing that two doses of an mRNA vaccine produce levels of neutralizing antibodies that are up to 10 times higher than the levels found in the blood of people who’ve recovered from COVID-19. Vaccines also enhance B cells and T cells in people who’ve recovered from COVID-19, which broadens the spectrum of protection and helps to fend off variants.

The study has some important limitations, which the authors acknowledged. The first is that second infections weren’t confirmed with genetic sequencing, so the researchers couldn’t definitively tell if a person tested positive a second time because they caught a new virus, or if they were somehow still shedding virus from their first infection. Given that the tests were at least 5 months apart, though, the researchers think reinfection is the most likely explanation.

Another bias in the study could have something to do with vaccination. Vaccinated people may have been less likely to be tested for COVID-19 after their vaccines, so the association or reinfection with a lack of vaccination may be overestimated. 

Also, people who were vaccinated at federal sites or in another state were not logged in the state’s immunization registry, which may have skewed the data.

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

COVID-19 is still in the early stages of understanding, although it is known to be complicated by individual patient comorbidities. The management and treatment of COVID-19 continues to quickly evolve as more is discovered regarding the virus. Multiple treatments have been preliminarily tested and used under a Food and Drug Administration emergency use authorization (EUA) determination. The long-term success of these therapies, however, is yet to be determined. Additionally, if a patient has a second clinical presentation for COVID-19, it is not known whether this represents latency with subsequent reactivation from the previous infection or a second de novo infection. The uncertainty calls into question the duration of immunity, if any, following a primary infection.

COVID-19 management becomes more complicated when patients have complex medical conditions, such as myasthenia gravis (MG). This autoimmune neuromuscular disorder can present with varying weakness, and many patients are on immunomodulator medications. The weakness can worsen into a myasthenic crisis (MC), resulting in profound weakness of the respiratory muscles. Therefore, patients with MG are at increased risk for COVID-19 and may have a more complicated course when infected.

Our patient with MG presented for severe COVID-19 symptoms twice and later developed MC. He received 2 treatment modalities available under an EUA (remdesivir and convalescent plasma) for COVID-19, resulting in symptom resolution and a negative polymerize chain reaction (PCR) test result for the virus. However, after receiving his typical maintenance therapy of IV immunoglobulin (IVIG) for his MG, he again developed symptoms consistent with COVID-19 and tested positive. After recovering from the second episode of COVID-19, the patient went into MC requiring plasmapheresis.

Case Presentation

A 56-year-old male, US Army veteran presented to Carl R. Darnall Army Medical Center emergency department (ED) 6 days after testing positive for COVID-19, with worsening sputum, cough, congestion, dyspnea, and fever. Due to his MG, the patient had a home oxygen monitor and reported that his oxygenation saturation dropped below 90% with minimal exertion. His medical history was significant for MG, status postthymectomy and radiation treatment, left hemidiaphragm paralysis secondary to phrenic nerve injury, and corticosteroid-induced insulin-dependent diabetes mellitus. His current home medications included pyridostigmine 60 mg 3 times a day, mycophenolate (MMF) 1500 mg twice daily, IV immunoglobulin (IVIG) every 3 weeks, insulin aspart up to 16 U per meal, insulin glargine 30 U twice a day, dulaglutide 0.75 mg every week, and metformin 1000 mg twice daily.

On initial examination, the patient’s heart rate (HR) was 111 beats/min, respiratory rate (RR), 22 breaths/min, blood pressure (BP), 138/88 mm Hg, temperature, 100.9 ^oF, and his initial pulse oximetry, 91% on room air. On physical examination, the patient was tachypneic, though without other signs of respiratory distress. Lung auscultation revealed no adventitial lung sounds. His cardiac examination was notable only for tachycardia. His neurologic examination demonstrated intact cranial nerves, with 5 out of 5 (scale 1 to 5) strength throughout the upper and lower extremities, sensation was intact to light touch, and he had normal cerebellar function. The rest of the examination was normal.

Initial laboratory investigation was notable for a white blood cell count of 14.15x10³ cells/mcL with 84% neutrophils, and 6% lymphocytes. Additional tests revealed a C-reactive protein (CRP) level, 17.97 mg/dL (reference range, 0-0.5 mg/dL), ferritin level, 647 ng/mL (reference range, 22-274 ng/mL), d-dimer, 0.64 mcg/mL (reference range, 0-0.47mcg/mL), and a repeated positive COVID-19 PCR test. A portable chest X-ray showed bibasilar opacities (Figure 1).

Discussion

Reinfection with the COVID-19 has been continuously debated with alternative explanations suggested for a positive test after a previous negative PCR test in the setting of symptom resolution.^1,2 Proposed causes include dynamic PCR results due to prolonged viral shedding and inaccurate or poorly sensitive tests. The repeat positive cases in these scenarios, however, occurred in asymptomatic patients.^1,2 COVID-19 shedding averages 20 to 22 days after symptom onset but has been seen up to 36 days after symptom resolution.^2,3 This would suggest that fluctuating results during the immediate postsymptom period may be due to variations in viral shedding load and or sampling error—especially in asymptomatic patients. On the other hand, patients who experience return of symptoms days to weeks after previous convalescence leave clinicians wondering whether this represents clinical latency with reactivation or COVID-19 reinfection. A separate case of initial COVID-19 in a patient that had subsequent clinical recovery with a negative PCR developed recurrent respiratory symptoms and had a positive PCR test only 10 days later, further highlighting the reinfection vs reactivation issue of COVID-19.² Further understanding of this issue may have implications on the extent of natural immunity following primary infection; potential vaccine dosage schedules; and global public health policies.

Although reactivation may be plausible given his immunomodulatory therapy, our patient’s second COVID-19 symptoms started 40 days after the initial symptoms, and 26 days after the initial course resolution; previous cases of return of severe symptoms occurred between 3 and 6 days.¹ Given our patient’s time course between resolution and return of symptoms, if latency is the mechanism at play, this case demonstrates an exceptionally longer latency period than the ones that have been reported. Additionally, if latency is an issue in COVID-19, using remdesivir as a treatment further complicates the understanding of this disease.

Remdesivir, a nucleoside analogue antiviral, was shown to benefit recovery in patients with severe symptoms in the Adaptive COVID-19 Treatment Trial-1 study.⁴ Our patient had originally been placed on a 10-day course; however, on treatment day 8, his symptoms resolved and the remdesivir was discontinued. This is a similar finding to half the patients in the 10-day arm of the study by McCreary and colleagues.⁵ Although our patient was asymptomatic 4 weeks after the start of remdesivir, consistent with the majority of patients in the McCreary 10-day study arm, further comparison of the presented patient is limited due to study length and follow-up considerations.⁵ No previous data exist on reactivation, reinfection, or long-term mortality after being treated with remdesivir for COVID-19 infection.

IVIG is being studied in the treatment of COVID-19 and bears consideration as it relates to our patient. There is no evidence that IVIG used in the treatment of autoimmune diseases increases the risk of infection compared with that of other medications used in the treatment of such diseases. Furthermore, the current guidance from the MG expert panel does not suggest that IVIG increases the risk of contracting COVID-19 aside from the risks of exposure to hospital infrastructure.⁶ Yet the guidance does not discuss the use of IVIG for MG in patients who are already symptomatic from COVID-19 or for patients recovering from the clinical disease or does it discuss a possible compounding risk of thromboembolic events associated with IVIG and COVID-19.^6,7 Our patient received his maintenance IVIG during his first admission without any worsening of symptoms or increased oxygen requirements. The day following our patient’s next scheduled IVIG infusion—while asymptomatic—he again developed respiratory symptoms; this could suggest that IVIG did not contribute to his second clinical course nor protect against.

CP is a treatment modality that has been used and studied in previous infectious outbreaks such as the first severe acute respiratory syndrome, and the H1N1 influenza virus.⁸ Current data on CP for COVID-19 are limited, but early descriptive studies have shown a benefit in improvement of symptoms 5 days sooner in those requiring supplemental oxygen, but no benefit for those requiring mechanical ventilation.⁹ Like patients that benefitted in these studies, our patient received CP early, 6 days after first testing positive and onset of symptoms. This patient’s reinfection or return of symptoms draws into question the hindrance or even prevention of long-term immunity from administration of CP.

COVID-19 presents many challenges when managing this patient’s coexisting MG, especially as the patient was already being treated with immunosuppressing therapies. The guidance does recommend continuation of standard MG therapies during hospitalizations, including immunosuppression medications such as MMF.⁶ Immunosuppression is associated with worsened severity of COVID-19 symptoms, although no relation exists to degree of immunosuppression and severity.^7,10 To the best of our knowledge there has been no case report of reinfection or reactivation of COVID-19 associated with immunosuppressive agents used in the treatment of MG.

Our patient also was taking pyridostigmine for the treatment of his MG. There is no evidence this medication increases the risk of infection; but the cholinergic activity can increase bronchial secretions, which could theoretically worsen the COVID-19 respiratory symptoms.^6,11 During both ICU admissions, our patient continued pyridostigmine use, observing complete return to baseline after discharge. Given the possible association with worsened respiratory outcomes after the second ICU admission, the balance between managing MG symptoms and COVID-19 symptoms needs further examination.

The patient was in MC during his third presentation to the ED. Although respiratory symptoms may be difficult to differentiate from COVID-19, the additional neurologic symptoms seen in this patient allowed for quick determination of the need for MC treatment. There are many potential etiologies contributing to the development of the MC presented here, and it was likely due to multifactorial precipitants. A common cause of MC is viral upper respiratory infections, further challenging the care of these patients during this pandemic.¹² Many medications have been cited as causing a MC, 2 of which our patient received during admission for COVID-19: azithromycin and levoquin.¹² Although the patient did not receive hydroxychloroquine, which was still being considered as an appropriate COVID-19 treatment at the time, it also is a drug known for precipitating MC and its use scrutinized in patients with MG.¹²

A key aspect to diagnosing and guiding therapies in myasthenic crisis in addition to the clinical symptoms of acute weakness is respiratory assessment through the nonaerosolizing NIF test.¹² Our patient’s NIF measured < 30 cmH₂O when in MC, while the reference range is < 75 cmH₂O, and for mechanical ventilation is recommended at 20 cmH₂O. Although the patient was maintaining O₂ saturation > 95%, his NIF value was concerning, and preparations were made in case of precipitous decline. Compounding the NIF assessment in this patient is his history of left phrenic nerve palsy. Without a documented baseline NIF, results were limited in determining his diaphragm strength.¹³ Treatment for MC includes IVIG or plasmapheresis, since this patient had failed his maintenance therapy IVIG, plasmapheresis was coordinated for definitive therapy.

Conclusions

Federal facilities have seen an increase in the amount of respiratory complaints over the past months. Although COVID-19 is a concerning diagnosis, it is crucial to consider comorbidities in the diagnostic workup of each, even with a previous recent diagnosis of COVID-19. As treatment recommendations for COVID-19 continue to fluctuate coupled with the limitations and difficulties associated with MG patients, so too treatment and evaluation must be carefully considered at each presentation.

COVID-19 is still in the early stages of understanding, although it is known to be complicated by individual patient comorbidities. The management and treatment of COVID-19 continues to quickly evolve as more is discovered regarding the virus. Multiple treatments have been preliminarily tested and used under a Food and Drug Administration emergency use authorization (EUA) determination. The long-term success of these therapies, however, is yet to be determined. Additionally, if a patient has a second clinical presentation for COVID-19, it is not known whether this represents latency with subsequent reactivation from the previous infection or a second de novo infection. The uncertainty calls into question the duration of immunity, if any, following a primary infection.

COVID-19 management becomes more complicated when patients have complex medical conditions, such as myasthenia gravis (MG). This autoimmune neuromuscular disorder can present with varying weakness, and many patients are on immunomodulator medications. The weakness can worsen into a myasthenic crisis (MC), resulting in profound weakness of the respiratory muscles. Therefore, patients with MG are at increased risk for COVID-19 and may have a more complicated course when infected.

Our patient with MG presented for severe COVID-19 symptoms twice and later developed MC. He received 2 treatment modalities available under an EUA (remdesivir and convalescent plasma) for COVID-19, resulting in symptom resolution and a negative polymerize chain reaction (PCR) test result for the virus. However, after receiving his typical maintenance therapy of IV immunoglobulin (IVIG) for his MG, he again developed symptoms consistent with COVID-19 and tested positive. After recovering from the second episode of COVID-19, the patient went into MC requiring plasmapheresis.

Case Presentation

A 56-year-old male, US Army veteran presented to Carl R. Darnall Army Medical Center emergency department (ED) 6 days after testing positive for COVID-19, with worsening sputum, cough, congestion, dyspnea, and fever. Due to his MG, the patient had a home oxygen monitor and reported that his oxygenation saturation dropped below 90% with minimal exertion. His medical history was significant for MG, status postthymectomy and radiation treatment, left hemidiaphragm paralysis secondary to phrenic nerve injury, and corticosteroid-induced insulin-dependent diabetes mellitus. His current home medications included pyridostigmine 60 mg 3 times a day, mycophenolate (MMF) 1500 mg twice daily, IV immunoglobulin (IVIG) every 3 weeks, insulin aspart up to 16 U per meal, insulin glargine 30 U twice a day, dulaglutide 0.75 mg every week, and metformin 1000 mg twice daily.

On initial examination, the patient’s heart rate (HR) was 111 beats/min, respiratory rate (RR), 22 breaths/min, blood pressure (BP), 138/88 mm Hg, temperature, 100.9 ^oF, and his initial pulse oximetry, 91% on room air. On physical examination, the patient was tachypneic, though without other signs of respiratory distress. Lung auscultation revealed no adventitial lung sounds. His cardiac examination was notable only for tachycardia. His neurologic examination demonstrated intact cranial nerves, with 5 out of 5 (scale 1 to 5) strength throughout the upper and lower extremities, sensation was intact to light touch, and he had normal cerebellar function. The rest of the examination was normal.

Initial laboratory investigation was notable for a white blood cell count of 14.15x10³ cells/mcL with 84% neutrophils, and 6% lymphocytes. Additional tests revealed a C-reactive protein (CRP) level, 17.97 mg/dL (reference range, 0-0.5 mg/dL), ferritin level, 647 ng/mL (reference range, 22-274 ng/mL), d-dimer, 0.64 mcg/mL (reference range, 0-0.47mcg/mL), and a repeated positive COVID-19 PCR test. A portable chest X-ray showed bibasilar opacities (Figure 1).

Discussion

Reinfection with the COVID-19 has been continuously debated with alternative explanations suggested for a positive test after a previous negative PCR test in the setting of symptom resolution.^1,2 Proposed causes include dynamic PCR results due to prolonged viral shedding and inaccurate or poorly sensitive tests. The repeat positive cases in these scenarios, however, occurred in asymptomatic patients.^1,2 COVID-19 shedding averages 20 to 22 days after symptom onset but has been seen up to 36 days after symptom resolution.^2,3 This would suggest that fluctuating results during the immediate postsymptom period may be due to variations in viral shedding load and or sampling error—especially in asymptomatic patients. On the other hand, patients who experience return of symptoms days to weeks after previous convalescence leave clinicians wondering whether this represents clinical latency with reactivation or COVID-19 reinfection. A separate case of initial COVID-19 in a patient that had subsequent clinical recovery with a negative PCR developed recurrent respiratory symptoms and had a positive PCR test only 10 days later, further highlighting the reinfection vs reactivation issue of COVID-19.² Further understanding of this issue may have implications on the extent of natural immunity following primary infection; potential vaccine dosage schedules; and global public health policies.

Although reactivation may be plausible given his immunomodulatory therapy, our patient’s second COVID-19 symptoms started 40 days after the initial symptoms, and 26 days after the initial course resolution; previous cases of return of severe symptoms occurred between 3 and 6 days.¹ Given our patient’s time course between resolution and return of symptoms, if latency is the mechanism at play, this case demonstrates an exceptionally longer latency period than the ones that have been reported. Additionally, if latency is an issue in COVID-19, using remdesivir as a treatment further complicates the understanding of this disease.

Remdesivir, a nucleoside analogue antiviral, was shown to benefit recovery in patients with severe symptoms in the Adaptive COVID-19 Treatment Trial-1 study.⁴ Our patient had originally been placed on a 10-day course; however, on treatment day 8, his symptoms resolved and the remdesivir was discontinued. This is a similar finding to half the patients in the 10-day arm of the study by McCreary and colleagues.⁵ Although our patient was asymptomatic 4 weeks after the start of remdesivir, consistent with the majority of patients in the McCreary 10-day study arm, further comparison of the presented patient is limited due to study length and follow-up considerations.⁵ No previous data exist on reactivation, reinfection, or long-term mortality after being treated with remdesivir for COVID-19 infection.

IVIG is being studied in the treatment of COVID-19 and bears consideration as it relates to our patient. There is no evidence that IVIG used in the treatment of autoimmune diseases increases the risk of infection compared with that of other medications used in the treatment of such diseases. Furthermore, the current guidance from the MG expert panel does not suggest that IVIG increases the risk of contracting COVID-19 aside from the risks of exposure to hospital infrastructure.⁶ Yet the guidance does not discuss the use of IVIG for MG in patients who are already symptomatic from COVID-19 or for patients recovering from the clinical disease or does it discuss a possible compounding risk of thromboembolic events associated with IVIG and COVID-19.^6,7 Our patient received his maintenance IVIG during his first admission without any worsening of symptoms or increased oxygen requirements. The day following our patient’s next scheduled IVIG infusion—while asymptomatic—he again developed respiratory symptoms; this could suggest that IVIG did not contribute to his second clinical course nor protect against.

CP is a treatment modality that has been used and studied in previous infectious outbreaks such as the first severe acute respiratory syndrome, and the H1N1 influenza virus.⁸ Current data on CP for COVID-19 are limited, but early descriptive studies have shown a benefit in improvement of symptoms 5 days sooner in those requiring supplemental oxygen, but no benefit for those requiring mechanical ventilation.⁹ Like patients that benefitted in these studies, our patient received CP early, 6 days after first testing positive and onset of symptoms. This patient’s reinfection or return of symptoms draws into question the hindrance or even prevention of long-term immunity from administration of CP.

COVID-19 presents many challenges when managing this patient’s coexisting MG, especially as the patient was already being treated with immunosuppressing therapies. The guidance does recommend continuation of standard MG therapies during hospitalizations, including immunosuppression medications such as MMF.⁶ Immunosuppression is associated with worsened severity of COVID-19 symptoms, although no relation exists to degree of immunosuppression and severity.^7,10 To the best of our knowledge there has been no case report of reinfection or reactivation of COVID-19 associated with immunosuppressive agents used in the treatment of MG.

Our patient also was taking pyridostigmine for the treatment of his MG. There is no evidence this medication increases the risk of infection; but the cholinergic activity can increase bronchial secretions, which could theoretically worsen the COVID-19 respiratory symptoms.^6,11 During both ICU admissions, our patient continued pyridostigmine use, observing complete return to baseline after discharge. Given the possible association with worsened respiratory outcomes after the second ICU admission, the balance between managing MG symptoms and COVID-19 symptoms needs further examination.

The patient was in MC during his third presentation to the ED. Although respiratory symptoms may be difficult to differentiate from COVID-19, the additional neurologic symptoms seen in this patient allowed for quick determination of the need for MC treatment. There are many potential etiologies contributing to the development of the MC presented here, and it was likely due to multifactorial precipitants. A common cause of MC is viral upper respiratory infections, further challenging the care of these patients during this pandemic.¹² Many medications have been cited as causing a MC, 2 of which our patient received during admission for COVID-19: azithromycin and levoquin.¹² Although the patient did not receive hydroxychloroquine, which was still being considered as an appropriate COVID-19 treatment at the time, it also is a drug known for precipitating MC and its use scrutinized in patients with MG.¹²

A key aspect to diagnosing and guiding therapies in myasthenic crisis in addition to the clinical symptoms of acute weakness is respiratory assessment through the nonaerosolizing NIF test.¹² Our patient’s NIF measured < 30 cmH₂O when in MC, while the reference range is < 75 cmH₂O, and for mechanical ventilation is recommended at 20 cmH₂O. Although the patient was maintaining O₂ saturation > 95%, his NIF value was concerning, and preparations were made in case of precipitous decline. Compounding the NIF assessment in this patient is his history of left phrenic nerve palsy. Without a documented baseline NIF, results were limited in determining his diaphragm strength.¹³ Treatment for MC includes IVIG or plasmapheresis, since this patient had failed his maintenance therapy IVIG, plasmapheresis was coordinated for definitive therapy.

Conclusions

Federal facilities have seen an increase in the amount of respiratory complaints over the past months. Although COVID-19 is a concerning diagnosis, it is crucial to consider comorbidities in the diagnostic workup of each, even with a previous recent diagnosis of COVID-19. As treatment recommendations for COVID-19 continue to fluctuate coupled with the limitations and difficulties associated with MG patients, so too treatment and evaluation must be carefully considered at each presentation.

COVID-19 is still in the early stages of understanding, although it is known to be complicated by individual patient comorbidities. The management and treatment of COVID-19 continues to quickly evolve as more is discovered regarding the virus. Multiple treatments have been preliminarily tested and used under a Food and Drug Administration emergency use authorization (EUA) determination. The long-term success of these therapies, however, is yet to be determined. Additionally, if a patient has a second clinical presentation for COVID-19, it is not known whether this represents latency with subsequent reactivation from the previous infection or a second de novo infection. The uncertainty calls into question the duration of immunity, if any, following a primary infection.

COVID-19 management becomes more complicated when patients have complex medical conditions, such as myasthenia gravis (MG). This autoimmune neuromuscular disorder can present with varying weakness, and many patients are on immunomodulator medications. The weakness can worsen into a myasthenic crisis (MC), resulting in profound weakness of the respiratory muscles. Therefore, patients with MG are at increased risk for COVID-19 and may have a more complicated course when infected.

Our patient with MG presented for severe COVID-19 symptoms twice and later developed MC. He received 2 treatment modalities available under an EUA (remdesivir and convalescent plasma) for COVID-19, resulting in symptom resolution and a negative polymerize chain reaction (PCR) test result for the virus. However, after receiving his typical maintenance therapy of IV immunoglobulin (IVIG) for his MG, he again developed symptoms consistent with COVID-19 and tested positive. After recovering from the second episode of COVID-19, the patient went into MC requiring plasmapheresis.

Case Presentation

A 56-year-old male, US Army veteran presented to Carl R. Darnall Army Medical Center emergency department (ED) 6 days after testing positive for COVID-19, with worsening sputum, cough, congestion, dyspnea, and fever. Due to his MG, the patient had a home oxygen monitor and reported that his oxygenation saturation dropped below 90% with minimal exertion. His medical history was significant for MG, status postthymectomy and radiation treatment, left hemidiaphragm paralysis secondary to phrenic nerve injury, and corticosteroid-induced insulin-dependent diabetes mellitus. His current home medications included pyridostigmine 60 mg 3 times a day, mycophenolate (MMF) 1500 mg twice daily, IV immunoglobulin (IVIG) every 3 weeks, insulin aspart up to 16 U per meal, insulin glargine 30 U twice a day, dulaglutide 0.75 mg every week, and metformin 1000 mg twice daily.

On initial examination, the patient’s heart rate (HR) was 111 beats/min, respiratory rate (RR), 22 breaths/min, blood pressure (BP), 138/88 mm Hg, temperature, 100.9 ^oF, and his initial pulse oximetry, 91% on room air. On physical examination, the patient was tachypneic, though without other signs of respiratory distress. Lung auscultation revealed no adventitial lung sounds. His cardiac examination was notable only for tachycardia. His neurologic examination demonstrated intact cranial nerves, with 5 out of 5 (scale 1 to 5) strength throughout the upper and lower extremities, sensation was intact to light touch, and he had normal cerebellar function. The rest of the examination was normal.

Initial laboratory investigation was notable for a white blood cell count of 14.15x10³ cells/mcL with 84% neutrophils, and 6% lymphocytes. Additional tests revealed a C-reactive protein (CRP) level, 17.97 mg/dL (reference range, 0-0.5 mg/dL), ferritin level, 647 ng/mL (reference range, 22-274 ng/mL), d-dimer, 0.64 mcg/mL (reference range, 0-0.47mcg/mL), and a repeated positive COVID-19 PCR test. A portable chest X-ray showed bibasilar opacities (Figure 1).

Discussion

Reinfection with the COVID-19 has been continuously debated with alternative explanations suggested for a positive test after a previous negative PCR test in the setting of symptom resolution.^1,2 Proposed causes include dynamic PCR results due to prolonged viral shedding and inaccurate or poorly sensitive tests. The repeat positive cases in these scenarios, however, occurred in asymptomatic patients.^1,2 COVID-19 shedding averages 20 to 22 days after symptom onset but has been seen up to 36 days after symptom resolution.^2,3 This would suggest that fluctuating results during the immediate postsymptom period may be due to variations in viral shedding load and or sampling error—especially in asymptomatic patients. On the other hand, patients who experience return of symptoms days to weeks after previous convalescence leave clinicians wondering whether this represents clinical latency with reactivation or COVID-19 reinfection. A separate case of initial COVID-19 in a patient that had subsequent clinical recovery with a negative PCR developed recurrent respiratory symptoms and had a positive PCR test only 10 days later, further highlighting the reinfection vs reactivation issue of COVID-19.² Further understanding of this issue may have implications on the extent of natural immunity following primary infection; potential vaccine dosage schedules; and global public health policies.

Although reactivation may be plausible given his immunomodulatory therapy, our patient’s second COVID-19 symptoms started 40 days after the initial symptoms, and 26 days after the initial course resolution; previous cases of return of severe symptoms occurred between 3 and 6 days.¹ Given our patient’s time course between resolution and return of symptoms, if latency is the mechanism at play, this case demonstrates an exceptionally longer latency period than the ones that have been reported. Additionally, if latency is an issue in COVID-19, using remdesivir as a treatment further complicates the understanding of this disease.

Remdesivir, a nucleoside analogue antiviral, was shown to benefit recovery in patients with severe symptoms in the Adaptive COVID-19 Treatment Trial-1 study.⁴ Our patient had originally been placed on a 10-day course; however, on treatment day 8, his symptoms resolved and the remdesivir was discontinued. This is a similar finding to half the patients in the 10-day arm of the study by McCreary and colleagues.⁵ Although our patient was asymptomatic 4 weeks after the start of remdesivir, consistent with the majority of patients in the McCreary 10-day study arm, further comparison of the presented patient is limited due to study length and follow-up considerations.⁵ No previous data exist on reactivation, reinfection, or long-term mortality after being treated with remdesivir for COVID-19 infection.

IVIG is being studied in the treatment of COVID-19 and bears consideration as it relates to our patient. There is no evidence that IVIG used in the treatment of autoimmune diseases increases the risk of infection compared with that of other medications used in the treatment of such diseases. Furthermore, the current guidance from the MG expert panel does not suggest that IVIG increases the risk of contracting COVID-19 aside from the risks of exposure to hospital infrastructure.⁶ Yet the guidance does not discuss the use of IVIG for MG in patients who are already symptomatic from COVID-19 or for patients recovering from the clinical disease or does it discuss a possible compounding risk of thromboembolic events associated with IVIG and COVID-19.^6,7 Our patient received his maintenance IVIG during his first admission without any worsening of symptoms or increased oxygen requirements. The day following our patient’s next scheduled IVIG infusion—while asymptomatic—he again developed respiratory symptoms; this could suggest that IVIG did not contribute to his second clinical course nor protect against.

CP is a treatment modality that has been used and studied in previous infectious outbreaks such as the first severe acute respiratory syndrome, and the H1N1 influenza virus.⁸ Current data on CP for COVID-19 are limited, but early descriptive studies have shown a benefit in improvement of symptoms 5 days sooner in those requiring supplemental oxygen, but no benefit for those requiring mechanical ventilation.⁹ Like patients that benefitted in these studies, our patient received CP early, 6 days after first testing positive and onset of symptoms. This patient’s reinfection or return of symptoms draws into question the hindrance or even prevention of long-term immunity from administration of CP.

COVID-19 presents many challenges when managing this patient’s coexisting MG, especially as the patient was already being treated with immunosuppressing therapies. The guidance does recommend continuation of standard MG therapies during hospitalizations, including immunosuppression medications such as MMF.⁶ Immunosuppression is associated with worsened severity of COVID-19 symptoms, although no relation exists to degree of immunosuppression and severity.^7,10 To the best of our knowledge there has been no case report of reinfection or reactivation of COVID-19 associated with immunosuppressive agents used in the treatment of MG.

Our patient also was taking pyridostigmine for the treatment of his MG. There is no evidence this medication increases the risk of infection; but the cholinergic activity can increase bronchial secretions, which could theoretically worsen the COVID-19 respiratory symptoms.^6,11 During both ICU admissions, our patient continued pyridostigmine use, observing complete return to baseline after discharge. Given the possible association with worsened respiratory outcomes after the second ICU admission, the balance between managing MG symptoms and COVID-19 symptoms needs further examination.

The patient was in MC during his third presentation to the ED. Although respiratory symptoms may be difficult to differentiate from COVID-19, the additional neurologic symptoms seen in this patient allowed for quick determination of the need for MC treatment. There are many potential etiologies contributing to the development of the MC presented here, and it was likely due to multifactorial precipitants. A common cause of MC is viral upper respiratory infections, further challenging the care of these patients during this pandemic.¹² Many medications have been cited as causing a MC, 2 of which our patient received during admission for COVID-19: azithromycin and levoquin.¹² Although the patient did not receive hydroxychloroquine, which was still being considered as an appropriate COVID-19 treatment at the time, it also is a drug known for precipitating MC and its use scrutinized in patients with MG.¹²

A key aspect to diagnosing and guiding therapies in myasthenic crisis in addition to the clinical symptoms of acute weakness is respiratory assessment through the nonaerosolizing NIF test.¹² Our patient’s NIF measured < 30 cmH₂O when in MC, while the reference range is < 75 cmH₂O, and for mechanical ventilation is recommended at 20 cmH₂O. Although the patient was maintaining O₂ saturation > 95%, his NIF value was concerning, and preparations were made in case of precipitous decline. Compounding the NIF assessment in this patient is his history of left phrenic nerve palsy. Without a documented baseline NIF, results were limited in determining his diaphragm strength.¹³ Treatment for MC includes IVIG or plasmapheresis, since this patient had failed his maintenance therapy IVIG, plasmapheresis was coordinated for definitive therapy.

Conclusions

Federal facilities have seen an increase in the amount of respiratory complaints over the past months. Although COVID-19 is a concerning diagnosis, it is crucial to consider comorbidities in the diagnostic workup of each, even with a previous recent diagnosis of COVID-19. As treatment recommendations for COVID-19 continue to fluctuate coupled with the limitations and difficulties associated with MG patients, so too treatment and evaluation must be carefully considered at each presentation.

The US Department of Veterans Affairs (VA) is the largest health care delivery system in the United States, comprising 1293 sites of care, including 171 medical centers.¹ One of the 4 statutory missions of the VA is to train health care professionals (HCPs) to meet the needs of the VA and the nation.² Through partnerships with more than 1800 accredited colleges, universities, and training programs, the VA provides training annually to nearly 118,000 health professions trainees (HPTs) across a variety of health care professions, and all of whom provide direct clinical care to veterans.³

In the VA, the Office of Academic Affiliations (OAA) is charged with overseeing health professions training and the VA’s partnership with medical and associated health (AH) professions schools, which was first codified in Policy Memorandum No. 2 in 1946.^4,5 Given the scope and breadth of health professions education offered through the VA, OAA is in a unique position to address health care shortage areas as well as influence the educational standards for certain professions.

Many of these health care professions fall under the rubric of AH, which include mental health (MH) specialties, rehabilitative specialties, and others. These professions are critical to address in the expanding world of health care in the United States with its increased specialization and emphasis on coordination of care with interprofessional teams. During the 2019/2020 academic year, the VA provided clinical training to approximately 21,000 AH HPTs from > 40 professions with just over 20% receiving financial support through the OAA. Of the HPTs who train at VA without compensation, most spend shorter amounts of time in clinical rotations in the VA, are in pregraduate-degree education programs where payment for clinical rotations is not expected and may not be eligible for hire immediately on completion of their clinical training experience. The 17 funded professions have been strategically selected by the OAA to ensure a robust pipeline of HCPs to meet the needs of veterans and the nation.

To meet the demands of AH professionals (AHPs), the OAA implemented targeted expansion over the past 10 years. While not exhaustive, this paper describes several expansion efforts based on VA special initiatives, including enhancing clinical access in rural settings and shifting toward postgraduate-degree training and specialization. By aligning expansion with VA priorities as well as trends in health care more broadly, the OAA can ensure that there is a supply of well-trained AHPs who have developed the requisite competencies to contribute to our nation’s health care needs. Further, expansion can help train and recruit health professionals who can be hired into VA positions ready to care for the complex needs of veterans.

Associated Health Professionals

Overseen by the OAA, AH expansion is designed to address the specific needs of the VA and the US health care system. Data from the VA Workforce Management and Consulting (WMC) shows that the VA employment of AHPs has grown from 87,351 AHPs hired in fiscal year (FY) 2010 to 119,120 as of April 2020. This represents an average yearly growth rate of 3.4% and a total growth rate of 36%. The Bureau of Labor Statistics predictions for 2019/2029 suggest that certain AHPs are expected to have a 10-year growth rates of 20% or more to meet the changing health care needs of patients especially as the population ages; the growth rates for many AHPs far surpasses that of physicians, which is anticipated to be 4% (Table).^6,7 The VA WMC expects an additional 52,283 AHPs will be hired by the VA by FY 2030 based on the 10-year average growth rate (Kali Clark, Veterans Health Administration Workforce Management and Consulting Office, email communication, May 28, 2020).

One of the driving forces behind the growth rate is the move toward using AHPs to supplement health care for a variety of health conditions.^8,9 Examples include the integration of rehabilitation professionals, alternative care professionals (eg, massage therapists, practitioners who offer training in yoga and meditation), chiropractors, MH professionals, and pharmacists in the treatment of chronic pain, the use of a wider range of professionals in the treatment of MH conditions, and the integration of MH professionals into traditional medical settings, such as primary care. This intentional move to a more well-integrated model of interprofessional care is apparent in many other health care systems throughout the United States. Within the VA, this shift may be most evident through the introduction of the Whole Health model of care. The Whole Health model of care uses an interprofessional team to assess and care for veterans, using a personalized health plan addressing medical and MH conditions as well as behavioral, social, or spiritual concerns.¹⁰ The Whole Health model of care provides veterans with access to a variety of health care services, including but not limited to MH services, spiritual interventions, exercise-based programs, yoga, meditation, and nutrition counseling.

The OAA and AH education division have focused expansion to meet the increased need for MH and rehabilitation providers, to enhance interprofessional education, and to emphasize postgraduate-degree clinical training. This focus reflects the trends seen in health care training broadly throughout the nation and the intentional pivot is a model of these trends and a model for how to intentionally address these trends. Specific to the VA, focused expansion plans have allowed OAA to address VA strategic initiatives such as pain management and caring for rural veterans.

Funded Training Positions

As a result of recent AH expansion efforts, there has been a 33% increase in stipend-funded positions during the past 10 years, a rate that directly corresponds with the growth of AHPs in the VA. Recent AH expansion efforts can contribute to a particularly positive impact in highly rural and underserved areas where recruiting providers remains challenging.

The OAA launched the Mental Health Education Expansion (MHEE) initiative in 2012, which has now added 782 funded training slots across 10 health professions, 8 of which are psychology, pharmacy, chaplaincy, professional MH counseling, marriage and family therapy (MFT), social work (SW), occupational therapy (OT), and physician assistant (PA). Through the MHEE initiative, the VA has established funded internships for licensed professional mental health counselors and marriage and family therapists, as these professions are targeted for expanding the overall MH workforce in the VA. The OAA currently funds more than 50 total HPT positions for these 2 professions with an aim of increasing their recruitment to the VA MH workforce over the next decade. The MHEE is aligned with specified VA priorities to train a future VA workforce prepared for interprofessional collaboration and clinical care in an increasingly integrated and complex environment. This expansion effort also aligns with an increasing understanding of the importance of addressing the MH needs of our nation by ensuring there is an adequate supply of competent, well-trained clinicians entering the workforce.

The OAA has created and expanded residencies and fellowships in multiple rehabilitation professions, including chiropractic, physical therapy (PT), and OT. With the increased focus on the management of chronic pain in the nation combined with a specific emphasis on this clinical need in the VA, chiropractors have been deemed essential HCPs. In 2014, the VA established 5 chiropractic residency programs while partnering with the Council on Chiropractic Education to develop accreditation standards for residency training. OAA’s efforts have yielded 5 accredited residency programs, the first in the United States. In 2020, the VA doubled the number of available chiropractic residency programs, and future expansion is anticipated. Since 2010, PT residencies have expanded from 1 to 28 programs (42 funded positions) across 4 board certification specialties: cardiovascular-pulmonary, geriatric, neurologic, and orthopedic. Similarly, the VA was one of the first organizations to achieve accreditation for OT fellowships; there are currently 5 accredited OT fellowship programs across 3 areas of practice: assistive technology, MH, and physical rehabilitation. The VA OT fellowship program focused on assistive technology is the only program in the United States at this time.

Interprofessional Education

As one of the primary focus areas for AH expansion, interprofessional education (IPE) has been recognized as increasingly important for the provision of health care and the development of HPT programs. IPE can develop professionals who appreciate the roles of diverse professions and can use teamwork to enhance clinical outcomes for patients.¹¹ There also are a growing number of professional organizations supporting the Interprofessional Education Collaborative with many representing AHPs.¹² Collaboration across HCPs is an important way of reducing health care costs by enhancing clinical outcomes, communication, and teamwork.^13-16 The VA and the nation’s health care system benefit from the by-products of interprofessional collaboration through investment in targeted training programs. In each phase of the AH expansion, special consideration was given to applicant programs offering unique and innovative clinical and educational experiences consistent with the promotion of interprofessional care. In doing so, increased numbers of AH HPTs have engaged in team-based clinical care.

Pain Management Pharmacy

The efforts of AH to align expansion with high-priority agency-wide efforts has resulted in the growth of pharmacy residency positions focused on pain management. Pharmacy postgraduate year (PGY) 2 residencies focusing on opioid reduction are an example of VA efforts to improve response to managing chronic pain and the long-term risks from opioid use during this national public health crisis.¹⁷ These residency programs focus on strategies to reduce the use of opioid medications in the clinical setting and teaching effective clinical interventions for reducing the rates of opioid addiction in veterans while still recognizing the need to identify and treat chronic pain. Before expansion efforts in 2018, there were 6 pharmacy residency programs focused on opioid use reduction in the VA, 8 pharmacy PGY2 residency positions were added in academic year 2019/2020, an additional 5 positions are being added in academic year 2021/2022 with the explicit goal of managing patients with high-risk chronic pain.

Rural Health

The lack of MH providers in rural areas has received much attention and is particularly important in the VA because veterans are more likely to live in less populated areas.¹⁸ The VA mandate to address this population was codified by the creation of the Office of Rural Health in 2006 via 38 USC § 7308.¹⁹Creating health professions training programs in rural settings provides HPTs the opportunity to learn professional competencies and train with faculty knowledgeable about this population—all of which provide a comprehensive training experience and serve as a recruitment pathway to hire HPTs into staff positions at these sites.¹⁹

When MHEE was initiated, not all regions of the country had funded VA psychology training programs, and this geographic gap in psychology training was a contributing factor to recruitment difficulties for psychologists in rural areas. As a result, the request for proposal process in the OAA highlighted and incentivized rurality when considering funding for new training programs. The OAA defined rurality as the number of patients served by the proposed health care facility who lived in a rural or highly rural zip code according to VA Support Service Center Capital Assets data.²⁰ As a result, VA psychology doctoral internships expanded to be available in all states, the District of Columbia, and Puerto Rico. MH training programs were started in the highly rural states of Montana and Wyoming. These expansion efforts promise to be an essential component to addressing the gaps in coverage in rural settings as noted in recent research.²¹

Pregraduate to Postgraduate Programs

The OAA AH education division supports a significant number of pregraduate-degree and postgraduate-degree training. Some professions, such as psychology, pharmacy, SW, PT, speech pathology, OT, and nutrition/dietetics receive funding at both levels of training. More recent, the OAA has started to move funding from pregraduate to postgraduate-degree positions, specifically within professions where pregraduate funding is uncommon for both federal and nonfederal training positions. The effort is designed to better align stipend-paid training programs with the VA Professional Qualification Standards and the final level of training required for employment in the VA.²²This means that HPTs receive stipend support during the highest level of their clinical training before degree conferral, eligibility for VA employment, or while participating in a postgraduate-degree residency or fellowship.

Additionally, this shift in focus and the resulting internal assessment of professions has allowed the OAA to fund more specialized training opportunities, which sometimes go beyond what is required by accrediting bodies or for recruitment into VA positions. For example, the OAA is supporting SW fellowship programs and PA residency positions to allow for greater specialization within these professions; the accrediting agencies for both professions have recently finalized their accreditation standards, and the OAA played a role in moving these standards forward.

While postgraduate residencies and fellowships are not required for all AH HPTs or for employment in the VA, there is a shift in some professions to encourage postgraduate training in advanced competencies in specialized areas. Participation in a residency or fellowship training program affords HPTs additional time and diverse clinical experiences to acquire clinical skills, all while under the supervision of a highly trained practitioner. This additional training also allows for a longitudinal assessment of the HPT to ensure an alignment of the HPTs’ knowledge, abilities, and skills with the expectation should they pursue VA employment.

In academic year 2019/2020, the OAA AH education division in conjunction with the PA national program office transitioned the entirety of the PA pregraduate-degree student positions (415 funded positions) to residency positions, increasing residency positions from 19 to 32 funded positions. This shift in emphasis for funding did not negatively impact the total number of pregraduate PA students receiving training in the VA and has created a pipeline of residency graduates who are ready to enter VA staff positions. To date, the VA has 14 PA residency programs across 3 specialties: emergency medicine (EM), MH, and primary care/geriatrics. Of these tracks, the VA offers 5 EM and 4 MH residencies that position graduates to be eligible for specialty certification. The National Commission on Certification of Physician Assistants established Certificates of Added Qualifications (CAQ) to recognize and document specialty knowledge, skills, and experience. The VA MH residency programs have been established to align with the CAQ expectations, and residents immediately qualify to take the CAQ examination after the completion of training.

Currently, the same process to move pregraduate to postgraduate funding is being implemented for PT and OT. Within the PT profession, there is increased momentum toward residency and fellowship training programs to respond to the changing complexity of the health care systemand reduce the need of complex care to be provided by non-VA providers in the community.²³ Both PT and OT have entered the initial phases of transitioning to residency or fellowship-funded positions. The OAA is partnering with these professions to move positions to postgraduate degree within the next 3 years with a commensurate increase in funding. The initial data indicate that 80% of graduated VA PT residents are board-certification eligible, and 89% of those who are eligible passed the examination on their first attempt.

Since 2013, the VA psychology training also has realized a growth in postgraduate-degree residencies. Psychology residency positions have increased 99% to 453 funded positions. This growth represents increased specialization in neuropsychology, geropsychology, rehabilitation psychology, and health psychology. Additionally, postgraduate residencies meet most jurisdictional requirements for postdoctoral supervised experience and better prepare HPTs to enter specialty staff positions that are necessary to care for aging veterans.

Additional professions are being targeted for postgraduate-degree training programs, including dietetics and speech pathology, to align with upcoming changes in the qualification standards for employment. While the process to transition positions to postgraduate-degree training programs can take 3 to 5 years, the outcomes are expected to result in better prepared HPTs who can fill staff vacancies in the VA.

Conclusions

Through its funding and oversight of numerous professions, the OAA is uniquely situated to adapt its portfolio to meet the needs of the VA and the nation. Over the past 10 years, the OAA has expanded its total number of HPT positions to enhance interprofessional care, respond to the VA’s strategic initiatives, address the care needs of rural veterans, and shift positions to postgraduate training programs. The OAA’s investment in high-quality training programs builds a strong health care workforce ready to meet the needs of an increasingly complex and integrated health care environment.

The OAA anticipates future expansion, especially related to promoting rural training opportunities and shifting to postgraduate training programs as a means of promoting advanced health care and health system competencies while continuing to align with workforce projections. Furthermore, while there are data on the percentage of VA staff who participated in OAA training program through the VA All Employee Survey (AES), the range for AH professions is wide. For example, about 37% of rehabilitative staff reported participating in an OAA training program, and 72% of VA psychologists reported having an OAA training experience. To maximize the hiring of HPTs, OAA will continue its partnership with WMC to enact programs aimed at streamlining the hiring process so that veterans have access to HCPs who are specifically trained to work with them.

The US Department of Veterans Affairs (VA) is the largest health care delivery system in the United States, comprising 1293 sites of care, including 171 medical centers.¹ One of the 4 statutory missions of the VA is to train health care professionals (HCPs) to meet the needs of the VA and the nation.² Through partnerships with more than 1800 accredited colleges, universities, and training programs, the VA provides training annually to nearly 118,000 health professions trainees (HPTs) across a variety of health care professions, and all of whom provide direct clinical care to veterans.³

In the VA, the Office of Academic Affiliations (OAA) is charged with overseeing health professions training and the VA’s partnership with medical and associated health (AH) professions schools, which was first codified in Policy Memorandum No. 2 in 1946.^4,5 Given the scope and breadth of health professions education offered through the VA, OAA is in a unique position to address health care shortage areas as well as influence the educational standards for certain professions.

Many of these health care professions fall under the rubric of AH, which include mental health (MH) specialties, rehabilitative specialties, and others. These professions are critical to address in the expanding world of health care in the United States with its increased specialization and emphasis on coordination of care with interprofessional teams. During the 2019/2020 academic year, the VA provided clinical training to approximately 21,000 AH HPTs from > 40 professions with just over 20% receiving financial support through the OAA. Of the HPTs who train at VA without compensation, most spend shorter amounts of time in clinical rotations in the VA, are in pregraduate-degree education programs where payment for clinical rotations is not expected and may not be eligible for hire immediately on completion of their clinical training experience. The 17 funded professions have been strategically selected by the OAA to ensure a robust pipeline of HCPs to meet the needs of veterans and the nation.

To meet the demands of AH professionals (AHPs), the OAA implemented targeted expansion over the past 10 years. While not exhaustive, this paper describes several expansion efforts based on VA special initiatives, including enhancing clinical access in rural settings and shifting toward postgraduate-degree training and specialization. By aligning expansion with VA priorities as well as trends in health care more broadly, the OAA can ensure that there is a supply of well-trained AHPs who have developed the requisite competencies to contribute to our nation’s health care needs. Further, expansion can help train and recruit health professionals who can be hired into VA positions ready to care for the complex needs of veterans.

Associated Health Professionals

Overseen by the OAA, AH expansion is designed to address the specific needs of the VA and the US health care system. Data from the VA Workforce Management and Consulting (WMC) shows that the VA employment of AHPs has grown from 87,351 AHPs hired in fiscal year (FY) 2010 to 119,120 as of April 2020. This represents an average yearly growth rate of 3.4% and a total growth rate of 36%. The Bureau of Labor Statistics predictions for 2019/2029 suggest that certain AHPs are expected to have a 10-year growth rates of 20% or more to meet the changing health care needs of patients especially as the population ages; the growth rates for many AHPs far surpasses that of physicians, which is anticipated to be 4% (Table).^6,7 The VA WMC expects an additional 52,283 AHPs will be hired by the VA by FY 2030 based on the 10-year average growth rate (Kali Clark, Veterans Health Administration Workforce Management and Consulting Office, email communication, May 28, 2020).

One of the driving forces behind the growth rate is the move toward using AHPs to supplement health care for a variety of health conditions.^8,9 Examples include the integration of rehabilitation professionals, alternative care professionals (eg, massage therapists, practitioners who offer training in yoga and meditation), chiropractors, MH professionals, and pharmacists in the treatment of chronic pain, the use of a wider range of professionals in the treatment of MH conditions, and the integration of MH professionals into traditional medical settings, such as primary care. This intentional move to a more well-integrated model of interprofessional care is apparent in many other health care systems throughout the United States. Within the VA, this shift may be most evident through the introduction of the Whole Health model of care. The Whole Health model of care uses an interprofessional team to assess and care for veterans, using a personalized health plan addressing medical and MH conditions as well as behavioral, social, or spiritual concerns.¹⁰ The Whole Health model of care provides veterans with access to a variety of health care services, including but not limited to MH services, spiritual interventions, exercise-based programs, yoga, meditation, and nutrition counseling.

The OAA and AH education division have focused expansion to meet the increased need for MH and rehabilitation providers, to enhance interprofessional education, and to emphasize postgraduate-degree clinical training. This focus reflects the trends seen in health care training broadly throughout the nation and the intentional pivot is a model of these trends and a model for how to intentionally address these trends. Specific to the VA, focused expansion plans have allowed OAA to address VA strategic initiatives such as pain management and caring for rural veterans.

Funded Training Positions

As a result of recent AH expansion efforts, there has been a 33% increase in stipend-funded positions during the past 10 years, a rate that directly corresponds with the growth of AHPs in the VA. Recent AH expansion efforts can contribute to a particularly positive impact in highly rural and underserved areas where recruiting providers remains challenging.

The OAA launched the Mental Health Education Expansion (MHEE) initiative in 2012, which has now added 782 funded training slots across 10 health professions, 8 of which are psychology, pharmacy, chaplaincy, professional MH counseling, marriage and family therapy (MFT), social work (SW), occupational therapy (OT), and physician assistant (PA). Through the MHEE initiative, the VA has established funded internships for licensed professional mental health counselors and marriage and family therapists, as these professions are targeted for expanding the overall MH workforce in the VA. The OAA currently funds more than 50 total HPT positions for these 2 professions with an aim of increasing their recruitment to the VA MH workforce over the next decade. The MHEE is aligned with specified VA priorities to train a future VA workforce prepared for interprofessional collaboration and clinical care in an increasingly integrated and complex environment. This expansion effort also aligns with an increasing understanding of the importance of addressing the MH needs of our nation by ensuring there is an adequate supply of competent, well-trained clinicians entering the workforce.

The OAA has created and expanded residencies and fellowships in multiple rehabilitation professions, including chiropractic, physical therapy (PT), and OT. With the increased focus on the management of chronic pain in the nation combined with a specific emphasis on this clinical need in the VA, chiropractors have been deemed essential HCPs. In 2014, the VA established 5 chiropractic residency programs while partnering with the Council on Chiropractic Education to develop accreditation standards for residency training. OAA’s efforts have yielded 5 accredited residency programs, the first in the United States. In 2020, the VA doubled the number of available chiropractic residency programs, and future expansion is anticipated. Since 2010, PT residencies have expanded from 1 to 28 programs (42 funded positions) across 4 board certification specialties: cardiovascular-pulmonary, geriatric, neurologic, and orthopedic. Similarly, the VA was one of the first organizations to achieve accreditation for OT fellowships; there are currently 5 accredited OT fellowship programs across 3 areas of practice: assistive technology, MH, and physical rehabilitation. The VA OT fellowship program focused on assistive technology is the only program in the United States at this time.

Interprofessional Education

As one of the primary focus areas for AH expansion, interprofessional education (IPE) has been recognized as increasingly important for the provision of health care and the development of HPT programs. IPE can develop professionals who appreciate the roles of diverse professions and can use teamwork to enhance clinical outcomes for patients.¹¹ There also are a growing number of professional organizations supporting the Interprofessional Education Collaborative with many representing AHPs.¹² Collaboration across HCPs is an important way of reducing health care costs by enhancing clinical outcomes, communication, and teamwork.^13-16 The VA and the nation’s health care system benefit from the by-products of interprofessional collaboration through investment in targeted training programs. In each phase of the AH expansion, special consideration was given to applicant programs offering unique and innovative clinical and educational experiences consistent with the promotion of interprofessional care. In doing so, increased numbers of AH HPTs have engaged in team-based clinical care.

Pain Management Pharmacy

The efforts of AH to align expansion with high-priority agency-wide efforts has resulted in the growth of pharmacy residency positions focused on pain management. Pharmacy postgraduate year (PGY) 2 residencies focusing on opioid reduction are an example of VA efforts to improve response to managing chronic pain and the long-term risks from opioid use during this national public health crisis.¹⁷ These residency programs focus on strategies to reduce the use of opioid medications in the clinical setting and teaching effective clinical interventions for reducing the rates of opioid addiction in veterans while still recognizing the need to identify and treat chronic pain. Before expansion efforts in 2018, there were 6 pharmacy residency programs focused on opioid use reduction in the VA, 8 pharmacy PGY2 residency positions were added in academic year 2019/2020, an additional 5 positions are being added in academic year 2021/2022 with the explicit goal of managing patients with high-risk chronic pain.

Rural Health

The lack of MH providers in rural areas has received much attention and is particularly important in the VA because veterans are more likely to live in less populated areas.¹⁸ The VA mandate to address this population was codified by the creation of the Office of Rural Health in 2006 via 38 USC § 7308.¹⁹Creating health professions training programs in rural settings provides HPTs the opportunity to learn professional competencies and train with faculty knowledgeable about this population—all of which provide a comprehensive training experience and serve as a recruitment pathway to hire HPTs into staff positions at these sites.¹⁹

When MHEE was initiated, not all regions of the country had funded VA psychology training programs, and this geographic gap in psychology training was a contributing factor to recruitment difficulties for psychologists in rural areas. As a result, the request for proposal process in the OAA highlighted and incentivized rurality when considering funding for new training programs. The OAA defined rurality as the number of patients served by the proposed health care facility who lived in a rural or highly rural zip code according to VA Support Service Center Capital Assets data.²⁰ As a result, VA psychology doctoral internships expanded to be available in all states, the District of Columbia, and Puerto Rico. MH training programs were started in the highly rural states of Montana and Wyoming. These expansion efforts promise to be an essential component to addressing the gaps in coverage in rural settings as noted in recent research.²¹

Pregraduate to Postgraduate Programs

The OAA AH education division supports a significant number of pregraduate-degree and postgraduate-degree training. Some professions, such as psychology, pharmacy, SW, PT, speech pathology, OT, and nutrition/dietetics receive funding at both levels of training. More recent, the OAA has started to move funding from pregraduate to postgraduate-degree positions, specifically within professions where pregraduate funding is uncommon for both federal and nonfederal training positions. The effort is designed to better align stipend-paid training programs with the VA Professional Qualification Standards and the final level of training required for employment in the VA.²²This means that HPTs receive stipend support during the highest level of their clinical training before degree conferral, eligibility for VA employment, or while participating in a postgraduate-degree residency or fellowship.

Additionally, this shift in focus and the resulting internal assessment of professions has allowed the OAA to fund more specialized training opportunities, which sometimes go beyond what is required by accrediting bodies or for recruitment into VA positions. For example, the OAA is supporting SW fellowship programs and PA residency positions to allow for greater specialization within these professions; the accrediting agencies for both professions have recently finalized their accreditation standards, and the OAA played a role in moving these standards forward.

While postgraduate residencies and fellowships are not required for all AH HPTs or for employment in the VA, there is a shift in some professions to encourage postgraduate training in advanced competencies in specialized areas. Participation in a residency or fellowship training program affords HPTs additional time and diverse clinical experiences to acquire clinical skills, all while under the supervision of a highly trained practitioner. This additional training also allows for a longitudinal assessment of the HPT to ensure an alignment of the HPTs’ knowledge, abilities, and skills with the expectation should they pursue VA employment.

In academic year 2019/2020, the OAA AH education division in conjunction with the PA national program office transitioned the entirety of the PA pregraduate-degree student positions (415 funded positions) to residency positions, increasing residency positions from 19 to 32 funded positions. This shift in emphasis for funding did not negatively impact the total number of pregraduate PA students receiving training in the VA and has created a pipeline of residency graduates who are ready to enter VA staff positions. To date, the VA has 14 PA residency programs across 3 specialties: emergency medicine (EM), MH, and primary care/geriatrics. Of these tracks, the VA offers 5 EM and 4 MH residencies that position graduates to be eligible for specialty certification. The National Commission on Certification of Physician Assistants established Certificates of Added Qualifications (CAQ) to recognize and document specialty knowledge, skills, and experience. The VA MH residency programs have been established to align with the CAQ expectations, and residents immediately qualify to take the CAQ examination after the completion of training.

Currently, the same process to move pregraduate to postgraduate funding is being implemented for PT and OT. Within the PT profession, there is increased momentum toward residency and fellowship training programs to respond to the changing complexity of the health care systemand reduce the need of complex care to be provided by non-VA providers in the community.²³ Both PT and OT have entered the initial phases of transitioning to residency or fellowship-funded positions. The OAA is partnering with these professions to move positions to postgraduate degree within the next 3 years with a commensurate increase in funding. The initial data indicate that 80% of graduated VA PT residents are board-certification eligible, and 89% of those who are eligible passed the examination on their first attempt.

Since 2013, the VA psychology training also has realized a growth in postgraduate-degree residencies. Psychology residency positions have increased 99% to 453 funded positions. This growth represents increased specialization in neuropsychology, geropsychology, rehabilitation psychology, and health psychology. Additionally, postgraduate residencies meet most jurisdictional requirements for postdoctoral supervised experience and better prepare HPTs to enter specialty staff positions that are necessary to care for aging veterans.

Additional professions are being targeted for postgraduate-degree training programs, including dietetics and speech pathology, to align with upcoming changes in the qualification standards for employment. While the process to transition positions to postgraduate-degree training programs can take 3 to 5 years, the outcomes are expected to result in better prepared HPTs who can fill staff vacancies in the VA.

Conclusions

Through its funding and oversight of numerous professions, the OAA is uniquely situated to adapt its portfolio to meet the needs of the VA and the nation. Over the past 10 years, the OAA has expanded its total number of HPT positions to enhance interprofessional care, respond to the VA’s strategic initiatives, address the care needs of rural veterans, and shift positions to postgraduate training programs. The OAA’s investment in high-quality training programs builds a strong health care workforce ready to meet the needs of an increasingly complex and integrated health care environment.

The OAA anticipates future expansion, especially related to promoting rural training opportunities and shifting to postgraduate training programs as a means of promoting advanced health care and health system competencies while continuing to align with workforce projections. Furthermore, while there are data on the percentage of VA staff who participated in OAA training program through the VA All Employee Survey (AES), the range for AH professions is wide. For example, about 37% of rehabilitative staff reported participating in an OAA training program, and 72% of VA psychologists reported having an OAA training experience. To maximize the hiring of HPTs, OAA will continue its partnership with WMC to enact programs aimed at streamlining the hiring process so that veterans have access to HCPs who are specifically trained to work with them.

The US Department of Veterans Affairs (VA) is the largest health care delivery system in the United States, comprising 1293 sites of care, including 171 medical centers.¹ One of the 4 statutory missions of the VA is to train health care professionals (HCPs) to meet the needs of the VA and the nation.² Through partnerships with more than 1800 accredited colleges, universities, and training programs, the VA provides training annually to nearly 118,000 health professions trainees (HPTs) across a variety of health care professions, and all of whom provide direct clinical care to veterans.³

In the VA, the Office of Academic Affiliations (OAA) is charged with overseeing health professions training and the VA’s partnership with medical and associated health (AH) professions schools, which was first codified in Policy Memorandum No. 2 in 1946.^4,5 Given the scope and breadth of health professions education offered through the VA, OAA is in a unique position to address health care shortage areas as well as influence the educational standards for certain professions.

Many of these health care professions fall under the rubric of AH, which include mental health (MH) specialties, rehabilitative specialties, and others. These professions are critical to address in the expanding world of health care in the United States with its increased specialization and emphasis on coordination of care with interprofessional teams. During the 2019/2020 academic year, the VA provided clinical training to approximately 21,000 AH HPTs from > 40 professions with just over 20% receiving financial support through the OAA. Of the HPTs who train at VA without compensation, most spend shorter amounts of time in clinical rotations in the VA, are in pregraduate-degree education programs where payment for clinical rotations is not expected and may not be eligible for hire immediately on completion of their clinical training experience. The 17 funded professions have been strategically selected by the OAA to ensure a robust pipeline of HCPs to meet the needs of veterans and the nation.

To meet the demands of AH professionals (AHPs), the OAA implemented targeted expansion over the past 10 years. While not exhaustive, this paper describes several expansion efforts based on VA special initiatives, including enhancing clinical access in rural settings and shifting toward postgraduate-degree training and specialization. By aligning expansion with VA priorities as well as trends in health care more broadly, the OAA can ensure that there is a supply of well-trained AHPs who have developed the requisite competencies to contribute to our nation’s health care needs. Further, expansion can help train and recruit health professionals who can be hired into VA positions ready to care for the complex needs of veterans.

Associated Health Professionals

Overseen by the OAA, AH expansion is designed to address the specific needs of the VA and the US health care system. Data from the VA Workforce Management and Consulting (WMC) shows that the VA employment of AHPs has grown from 87,351 AHPs hired in fiscal year (FY) 2010 to 119,120 as of April 2020. This represents an average yearly growth rate of 3.4% and a total growth rate of 36%. The Bureau of Labor Statistics predictions for 2019/2029 suggest that certain AHPs are expected to have a 10-year growth rates of 20% or more to meet the changing health care needs of patients especially as the population ages; the growth rates for many AHPs far surpasses that of physicians, which is anticipated to be 4% (Table).^6,7 The VA WMC expects an additional 52,283 AHPs will be hired by the VA by FY 2030 based on the 10-year average growth rate (Kali Clark, Veterans Health Administration Workforce Management and Consulting Office, email communication, May 28, 2020).

One of the driving forces behind the growth rate is the move toward using AHPs to supplement health care for a variety of health conditions.^8,9 Examples include the integration of rehabilitation professionals, alternative care professionals (eg, massage therapists, practitioners who offer training in yoga and meditation), chiropractors, MH professionals, and pharmacists in the treatment of chronic pain, the use of a wider range of professionals in the treatment of MH conditions, and the integration of MH professionals into traditional medical settings, such as primary care. This intentional move to a more well-integrated model of interprofessional care is apparent in many other health care systems throughout the United States. Within the VA, this shift may be most evident through the introduction of the Whole Health model of care. The Whole Health model of care uses an interprofessional team to assess and care for veterans, using a personalized health plan addressing medical and MH conditions as well as behavioral, social, or spiritual concerns.¹⁰ The Whole Health model of care provides veterans with access to a variety of health care services, including but not limited to MH services, spiritual interventions, exercise-based programs, yoga, meditation, and nutrition counseling.

The OAA and AH education division have focused expansion to meet the increased need for MH and rehabilitation providers, to enhance interprofessional education, and to emphasize postgraduate-degree clinical training. This focus reflects the trends seen in health care training broadly throughout the nation and the intentional pivot is a model of these trends and a model for how to intentionally address these trends. Specific to the VA, focused expansion plans have allowed OAA to address VA strategic initiatives such as pain management and caring for rural veterans.

Funded Training Positions

As a result of recent AH expansion efforts, there has been a 33% increase in stipend-funded positions during the past 10 years, a rate that directly corresponds with the growth of AHPs in the VA. Recent AH expansion efforts can contribute to a particularly positive impact in highly rural and underserved areas where recruiting providers remains challenging.

The OAA launched the Mental Health Education Expansion (MHEE) initiative in 2012, which has now added 782 funded training slots across 10 health professions, 8 of which are psychology, pharmacy, chaplaincy, professional MH counseling, marriage and family therapy (MFT), social work (SW), occupational therapy (OT), and physician assistant (PA). Through the MHEE initiative, the VA has established funded internships for licensed professional mental health counselors and marriage and family therapists, as these professions are targeted for expanding the overall MH workforce in the VA. The OAA currently funds more than 50 total HPT positions for these 2 professions with an aim of increasing their recruitment to the VA MH workforce over the next decade. The MHEE is aligned with specified VA priorities to train a future VA workforce prepared for interprofessional collaboration and clinical care in an increasingly integrated and complex environment. This expansion effort also aligns with an increasing understanding of the importance of addressing the MH needs of our nation by ensuring there is an adequate supply of competent, well-trained clinicians entering the workforce.

The OAA has created and expanded residencies and fellowships in multiple rehabilitation professions, including chiropractic, physical therapy (PT), and OT. With the increased focus on the management of chronic pain in the nation combined with a specific emphasis on this clinical need in the VA, chiropractors have been deemed essential HCPs. In 2014, the VA established 5 chiropractic residency programs while partnering with the Council on Chiropractic Education to develop accreditation standards for residency training. OAA’s efforts have yielded 5 accredited residency programs, the first in the United States. In 2020, the VA doubled the number of available chiropractic residency programs, and future expansion is anticipated. Since 2010, PT residencies have expanded from 1 to 28 programs (42 funded positions) across 4 board certification specialties: cardiovascular-pulmonary, geriatric, neurologic, and orthopedic. Similarly, the VA was one of the first organizations to achieve accreditation for OT fellowships; there are currently 5 accredited OT fellowship programs across 3 areas of practice: assistive technology, MH, and physical rehabilitation. The VA OT fellowship program focused on assistive technology is the only program in the United States at this time.

Interprofessional Education

As one of the primary focus areas for AH expansion, interprofessional education (IPE) has been recognized as increasingly important for the provision of health care and the development of HPT programs. IPE can develop professionals who appreciate the roles of diverse professions and can use teamwork to enhance clinical outcomes for patients.¹¹ There also are a growing number of professional organizations supporting the Interprofessional Education Collaborative with many representing AHPs.¹² Collaboration across HCPs is an important way of reducing health care costs by enhancing clinical outcomes, communication, and teamwork.^13-16 The VA and the nation’s health care system benefit from the by-products of interprofessional collaboration through investment in targeted training programs. In each phase of the AH expansion, special consideration was given to applicant programs offering unique and innovative clinical and educational experiences consistent with the promotion of interprofessional care. In doing so, increased numbers of AH HPTs have engaged in team-based clinical care.

Pain Management Pharmacy

The efforts of AH to align expansion with high-priority agency-wide efforts has resulted in the growth of pharmacy residency positions focused on pain management. Pharmacy postgraduate year (PGY) 2 residencies focusing on opioid reduction are an example of VA efforts to improve response to managing chronic pain and the long-term risks from opioid use during this national public health crisis.¹⁷ These residency programs focus on strategies to reduce the use of opioid medications in the clinical setting and teaching effective clinical interventions for reducing the rates of opioid addiction in veterans while still recognizing the need to identify and treat chronic pain. Before expansion efforts in 2018, there were 6 pharmacy residency programs focused on opioid use reduction in the VA, 8 pharmacy PGY2 residency positions were added in academic year 2019/2020, an additional 5 positions are being added in academic year 2021/2022 with the explicit goal of managing patients with high-risk chronic pain.

Rural Health

The lack of MH providers in rural areas has received much attention and is particularly important in the VA because veterans are more likely to live in less populated areas.¹⁸ The VA mandate to address this population was codified by the creation of the Office of Rural Health in 2006 via 38 USC § 7308.¹⁹Creating health professions training programs in rural settings provides HPTs the opportunity to learn professional competencies and train with faculty knowledgeable about this population—all of which provide a comprehensive training experience and serve as a recruitment pathway to hire HPTs into staff positions at these sites.¹⁹

When MHEE was initiated, not all regions of the country had funded VA psychology training programs, and this geographic gap in psychology training was a contributing factor to recruitment difficulties for psychologists in rural areas. As a result, the request for proposal process in the OAA highlighted and incentivized rurality when considering funding for new training programs. The OAA defined rurality as the number of patients served by the proposed health care facility who lived in a rural or highly rural zip code according to VA Support Service Center Capital Assets data.²⁰ As a result, VA psychology doctoral internships expanded to be available in all states, the District of Columbia, and Puerto Rico. MH training programs were started in the highly rural states of Montana and Wyoming. These expansion efforts promise to be an essential component to addressing the gaps in coverage in rural settings as noted in recent research.²¹

Pregraduate to Postgraduate Programs

The OAA AH education division supports a significant number of pregraduate-degree and postgraduate-degree training. Some professions, such as psychology, pharmacy, SW, PT, speech pathology, OT, and nutrition/dietetics receive funding at both levels of training. More recent, the OAA has started to move funding from pregraduate to postgraduate-degree positions, specifically within professions where pregraduate funding is uncommon for both federal and nonfederal training positions. The effort is designed to better align stipend-paid training programs with the VA Professional Qualification Standards and the final level of training required for employment in the VA.²²This means that HPTs receive stipend support during the highest level of their clinical training before degree conferral, eligibility for VA employment, or while participating in a postgraduate-degree residency or fellowship.

Additionally, this shift in focus and the resulting internal assessment of professions has allowed the OAA to fund more specialized training opportunities, which sometimes go beyond what is required by accrediting bodies or for recruitment into VA positions. For example, the OAA is supporting SW fellowship programs and PA residency positions to allow for greater specialization within these professions; the accrediting agencies for both professions have recently finalized their accreditation standards, and the OAA played a role in moving these standards forward.

While postgraduate residencies and fellowships are not required for all AH HPTs or for employment in the VA, there is a shift in some professions to encourage postgraduate training in advanced competencies in specialized areas. Participation in a residency or fellowship training program affords HPTs additional time and diverse clinical experiences to acquire clinical skills, all while under the supervision of a highly trained practitioner. This additional training also allows for a longitudinal assessment of the HPT to ensure an alignment of the HPTs’ knowledge, abilities, and skills with the expectation should they pursue VA employment.

In academic year 2019/2020, the OAA AH education division in conjunction with the PA national program office transitioned the entirety of the PA pregraduate-degree student positions (415 funded positions) to residency positions, increasing residency positions from 19 to 32 funded positions. This shift in emphasis for funding did not negatively impact the total number of pregraduate PA students receiving training in the VA and has created a pipeline of residency graduates who are ready to enter VA staff positions. To date, the VA has 14 PA residency programs across 3 specialties: emergency medicine (EM), MH, and primary care/geriatrics. Of these tracks, the VA offers 5 EM and 4 MH residencies that position graduates to be eligible for specialty certification. The National Commission on Certification of Physician Assistants established Certificates of Added Qualifications (CAQ) to recognize and document specialty knowledge, skills, and experience. The VA MH residency programs have been established to align with the CAQ expectations, and residents immediately qualify to take the CAQ examination after the completion of training.

Currently, the same process to move pregraduate to postgraduate funding is being implemented for PT and OT. Within the PT profession, there is increased momentum toward residency and fellowship training programs to respond to the changing complexity of the health care systemand reduce the need of complex care to be provided by non-VA providers in the community.²³ Both PT and OT have entered the initial phases of transitioning to residency or fellowship-funded positions. The OAA is partnering with these professions to move positions to postgraduate degree within the next 3 years with a commensurate increase in funding. The initial data indicate that 80% of graduated VA PT residents are board-certification eligible, and 89% of those who are eligible passed the examination on their first attempt.

Since 2013, the VA psychology training also has realized a growth in postgraduate-degree residencies. Psychology residency positions have increased 99% to 453 funded positions. This growth represents increased specialization in neuropsychology, geropsychology, rehabilitation psychology, and health psychology. Additionally, postgraduate residencies meet most jurisdictional requirements for postdoctoral supervised experience and better prepare HPTs to enter specialty staff positions that are necessary to care for aging veterans.

Additional professions are being targeted for postgraduate-degree training programs, including dietetics and speech pathology, to align with upcoming changes in the qualification standards for employment. While the process to transition positions to postgraduate-degree training programs can take 3 to 5 years, the outcomes are expected to result in better prepared HPTs who can fill staff vacancies in the VA.

Conclusions

Through its funding and oversight of numerous professions, the OAA is uniquely situated to adapt its portfolio to meet the needs of the VA and the nation. Over the past 10 years, the OAA has expanded its total number of HPT positions to enhance interprofessional care, respond to the VA’s strategic initiatives, address the care needs of rural veterans, and shift positions to postgraduate training programs. The OAA’s investment in high-quality training programs builds a strong health care workforce ready to meet the needs of an increasingly complex and integrated health care environment.

The OAA anticipates future expansion, especially related to promoting rural training opportunities and shifting to postgraduate training programs as a means of promoting advanced health care and health system competencies while continuing to align with workforce projections. Furthermore, while there are data on the percentage of VA staff who participated in OAA training program through the VA All Employee Survey (AES), the range for AH professions is wide. For example, about 37% of rehabilitative staff reported participating in an OAA training program, and 72% of VA psychologists reported having an OAA training experience. To maximize the hiring of HPTs, OAA will continue its partnership with WMC to enact programs aimed at streamlining the hiring process so that veterans have access to HCPs who are specifically trained to work with them.

Infection with hepatitis B virus (HBV) is associated with risk of potentially lethal, chronic infection and is a major public health problem. Infection from HBV has the potential to lead to liver failure, cirrhosis, and cancer.^1,2 Chronic HBV infection exists in as many as 2.2 million Americans, and in 2015 alone, HBV was estimated to be associated with 887,000 deaths worldwide.^1,3 Suppression of viral load is the basis of treatment, necessitating long-term use of medication for treatment.⁴ Nucleoside reverse transcriptase inhibitors (entecavir, lamivudine, telbivudine) and nucleotide reverse transcriptase inhibitors (adefovir, tenofovir), have improved the efficacy and tolerability of chronic HBV treatment compared with interferon-based agents.^4-7 However, concerns remain regarding long-term risk of nephrotoxicity, in particular with tenofovir disoproxil fumarate (TDF), which could lead to a limitation of safe and effective options for certain populations.^5,6,8 A newer formulation, tenofovir alafenamide fumarate (TAF), has improved the kidney risks, but expense remains a limiting factor for this agent.⁹

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) have demonstrated efficacy in reducing HBV viral load and other markers of improvement in chronic HBV, but entecavir and tenofovir have tended to demonstrate greater efficacy in clinical trials.^5-7 Several studies have suggested potential benefits of tenofovir-based treatment over other NRTIs, including greater viral load achievement compared with adefovir, efficacy in patients with previous failure of lamivudine or adefovir, and long-term efficacy in chronic HBV infection.^10-12 A 2019 systematic review suggests TDF and TAF are more effective than other NRTIs for achieving viral load suppression.¹³ Other NRTIs are not without their own risks, including mitochondrial dysfunction, mostly with lamivudine and telbivudine.⁴

Despite these data, guidelines have varied in their treatment recommendations in the context of chronic kidney disease partly due to variations in the evidence regarding nephrotoxicity.^7,14 Cohort studies and case reports have suggested association between TDF and acute kidney injury in patients with HIV infection as well as long-term reductions in kidney function.^15,16 In one study, 58% of patients treated with TDF did not return to baseline kidney function after an event of acute kidney injury.¹⁷ However, little data are available on whether this association exists for chronic HBV treatment in the absence of HIV infection. One retrospective analysis comparing TDF and entecavir in chronic HBV without HIV showed greater incidence of creatinine clearance < 60 mL/min with TDF but greater incidence of serum creatinine (SCr) ≥ 2.5 mg/dL in the entacavir group, making it difficult to reach a clear conclusion on risks.¹⁸ Other studies have either suffered from small cohorts with TDF or included patients with HIV coinfection.^19,20 Although a retrospective comparison of TDF and entecavir, randomly matched 1:2 to account for differences between groups, showed lower estimated glomerular filtration rate (eGFR) in the TDF group, more data are needed.²¹ Entecavir remains an option for many patient, but for those who have failed nucleosides, few options remain.

With the advantages available from TDF and the continued expense of TAF, more data regarding the risks of nephrotoxicity with TDF would be beneficial. The objective of this study was to compare treatment with TDF and other NRTIs in chronic HBV monoinfection to distinguish any differences in kidney function changes over time. With hopes of gathering enough data to distinguish between groups, information was gathered from across the Veterans Health Administration (VHA) system.

Methods

A nationwide, multicenter, retrospective, cohort study of veterans with HBV infection was conducted to compare the effects of various NRTIs on renal function. Patient were identified through the US Department of Veterans Affairs Corporate Data Warehouse (CDW), using data from July 1, 2005 to July 31, 2015. Patients were included who had positive HBV surface antigen (HBsAg) or newly prescribed NRTI. Multiple drug episodes could be included for each patient. That is, if a patient who had previously been included had another instance of a newly prescribed NRTI, this would be included in the analysis. Exclusion criteria were patients aged < 18 years, those with NRTI prescription for ≤ 1 month, and concurrent HIV infection. All patients with HBsAg were included for the study for increasing the sensitivity in gathering patients; however, those patients were included only if they received NRTI concurrent with the laboratory test results used for the primary endpoint (ie, SCr) to be included in the analysis.

How data are received from CDW bears some explanation. A basic way to understand the way data are received is that questions can be asked such as “for X population, at this point in time, was the patient on Y drug and what was the SCr value.” Therefore, inclusion and exclusion must first be specified to define the population, after which point certain data points can be received depending on the specifications made. For this reason, there is no way to determine, for example, whether a certain patient continued TDF use for the duration of the study, only at the defined points in time (described below) to receive the specific data.

For the patients included, information was retrieved from the first receipt of the NRTI prescription to 36 months after initiation. Baseline characteristics included age, sex, race, and ethnicity, and were defined at time of NRTI initiation. Values for SCr were compared at baseline, 3, 6, 12, 24, and 36 months after prescription of NRTI. The date of laboratory results was associated with the nearest date of comparison. Values for eGFR were determined by the modification of diet in renal disease equation. Values for eGFR are available in the CDW, whereas there is no direct means to calculate creatinine clearance with the available data, so eGFR was used for this study.

The primary endpoint was a change in eGFR in patients taking TDF after adjustment for time with the full cohort. Secondary analyses included the overall effect of time for the full cohort and change in renal function for each NRTI group. Mean and standard deviation for eGFR were determined for each NRTI group using the available data points. Analyses of the primary and secondary endpoints were completed using a linear mixed model with terms for time, to account for fixed effects, and specific NRTI used to account for random effects. A 2-sided α of .05 was used to determine statistical significance.

Results

A total of 413 drug episodes from 308 subjects met inclusion criteria for the study. Of these subjects, 229 were still living at the time of query. Most study participants were male (96%), the mean age was 62.1 years for males and 55.9 years for females; 49.5% were White and 39.7% were Black veterans (Table 1).

The NRTIs received by patients during the study period included TDF, TDF/emtricitabine, adefovir, entecavir, and lamivudine. No patients were on telbivudine. Formulations including TAF had not been approved by the US Food and Drug Administration (FDA) by the end of the study period, and as such were not found in the study.¹³ A plurality of participants received entecavir (94 of 223 at baseline), followed by TDF (n = 38) (Table 2). Of note, only 8 participants received TDF/emtricitabine at baseline. Differences were found between the groups in number of SCr data points available at 36 months vs baseline. The TDF group had the greatest reduction in data points available with 38 laboratory values at baseline vs 15 at 36 months (39.5% of baseline). From the available data, it is not possible to determine whether these represent medication discontinuations, missing values, lost to follow-up, or some other cause. Baseline eGFR was highest in the 2 TDF groups, with TDF alone at 77.7 mL/min (1.4-5.5 mL/min higher than the nontenofovir groups) and TDF/emtricitabine at 89.7 mL/min (13.4-17.5 mL/min higher than nontenofovir groups) (Table 3).

Discussion

This study demonstrated a decline in eGFR over time in a similar fashion for all NRTIs used in patients treated for HBV monoinfection, but no greater decline in renal function was found with use of TDF vs other NRTIs. A statistically significant decline in eGFR of −4.55 mL/min over the 36-month time frame of the study was demonstrated for the full cohort, but no statistically significant change in eGFR was found for any individual NRTI after accounting for the fixed effect of time. If TDF is not associated with additional risk of nephrotoxicity compared with other NRTIs, this could have important implications for treatment when considering the evidence that tenofovir-based treatment seems to be more effective than other medications for suppressing viral load.¹³

This result runs contrary to data in patients given NRTIs for HIV infection as well as a more recent cohort study in chronic HBV infectioin, which showed a statistically significant difference in kidney dysfunction between TDF and entecavir (-15.73 vs -5.96 mL/min/m², P < .001).^5-7,21 Possible mechanism for differences in response between HIV and HBV patients has not been elucidated, but the inherent risk of developing chronic kidney disease from HIV disease may play a role.²² The possibility remains that all NRTIs cause a degree of kidney impairment in patients treated for chronic HBV infection as evidenced by the statistically significant fixed effect for time in the present study. The cause of this effect is unknown but may be independently related to HBV infection or may be specific to NRTI therapy. No control group of patients not receiving NRTI therapy was included in this study, so conclusions cannot be drawn regarding whether all NRTIs are associated with decline in renal function in chronic HBV infection.

Limitations

Although this study did not detect a difference in change in eGFR between TDF and other NRTI treatments, it is possible that the length of data collection was not adequate to account for possible kidney injury from TDF. A study assessing renal tubular dysfunction in patients receiving adefovir or TDF showed a mean onset of dysfunction of 49 months.¹⁵ It is possible that participants in this study would go on to develop renal dysfunction in the future. This potential also was observed in a more recent retrospective cohort study in chronic HBV infection, which showed the greatest degree of decline in kidney function between 36 and 48 months (−11.87 to −15.73 mL/min/m² for the TDF group).²¹

The retrospective design created additional limitations. We attempted to account for some by using a matched cohort for the entecavir group, and there was no statistically significant difference between the groups in baseline characteristics. In HIV patients, a 10-year follow-up study continued to show decline in eGFR throughout the study, though the greatest degree of reduction occurred in the first year of the study.¹⁰ The higher baseline eGFR of the TDF recipients, 77.7 mL/min for the TDF alone group and 89.7 mL/min for the TDF/emtricitabine group vs 72.2 to 76.3 mL/min in the other NRTI groups, suggests high potential for selection bias. Some health care providers were likely to avoid TDF in patients with lower eGFR due to the data suggesting nephrotoxicity in other populations. Another limitation is that the reason for the missing laboratory values could not be determined. The TDF group had the greatest disparity in SCr data availability at baseline vs 36 months, with 39.5% concurrence with TDF alone compared with 50.0 to 63.6% in the other groups. Other treatment received outside the VHA system also could have influenced results.

Conclusions

This retrospective, multicenter, cohort study did not find a difference between TDF and other NRTIs for changes in renal function over time in patients with HBV infection without HIV. There was a fixed effect for time, ie, all NRTI groups showed some decline in renal function over time (−4.6 mL/min), but the effects were similar across groups. The results appear contrary to studies with comorbid HIV showing a decline in renal function with TDF, but present studies in HBV monotherapy have mixed results.

Further studies are needed to validate these results, as this and previous studies have several limitations. If these results are confirmed, a possible mechanism for these differences between patients with and without HIV should be examined. In addition, a study looking specifically at incidence of acute kidney injury rather than overall decline in renal function would add important data. If the results of this study are confirmed, there could be clinical implications in choice of agent with treatment of HBV monoinfection. This would add to the overall armament of medications available for chronic HBV infection and could create cost savings in certain situations if providers feel more comfortable continuing to use TDF instead of switching to the more expensive TAF.

Acknowledgments
Funding for this study was provided by the Veterans Health Administration.

Infection with hepatitis B virus (HBV) is associated with risk of potentially lethal, chronic infection and is a major public health problem. Infection from HBV has the potential to lead to liver failure, cirrhosis, and cancer.^1,2 Chronic HBV infection exists in as many as 2.2 million Americans, and in 2015 alone, HBV was estimated to be associated with 887,000 deaths worldwide.^1,3 Suppression of viral load is the basis of treatment, necessitating long-term use of medication for treatment.⁴ Nucleoside reverse transcriptase inhibitors (entecavir, lamivudine, telbivudine) and nucleotide reverse transcriptase inhibitors (adefovir, tenofovir), have improved the efficacy and tolerability of chronic HBV treatment compared with interferon-based agents.^4-7 However, concerns remain regarding long-term risk of nephrotoxicity, in particular with tenofovir disoproxil fumarate (TDF), which could lead to a limitation of safe and effective options for certain populations.^5,6,8 A newer formulation, tenofovir alafenamide fumarate (TAF), has improved the kidney risks, but expense remains a limiting factor for this agent.⁹

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) have demonstrated efficacy in reducing HBV viral load and other markers of improvement in chronic HBV, but entecavir and tenofovir have tended to demonstrate greater efficacy in clinical trials.^5-7 Several studies have suggested potential benefits of tenofovir-based treatment over other NRTIs, including greater viral load achievement compared with adefovir, efficacy in patients with previous failure of lamivudine or adefovir, and long-term efficacy in chronic HBV infection.^10-12 A 2019 systematic review suggests TDF and TAF are more effective than other NRTIs for achieving viral load suppression.¹³ Other NRTIs are not without their own risks, including mitochondrial dysfunction, mostly with lamivudine and telbivudine.⁴

Despite these data, guidelines have varied in their treatment recommendations in the context of chronic kidney disease partly due to variations in the evidence regarding nephrotoxicity.^7,14 Cohort studies and case reports have suggested association between TDF and acute kidney injury in patients with HIV infection as well as long-term reductions in kidney function.^15,16 In one study, 58% of patients treated with TDF did not return to baseline kidney function after an event of acute kidney injury.¹⁷ However, little data are available on whether this association exists for chronic HBV treatment in the absence of HIV infection. One retrospective analysis comparing TDF and entecavir in chronic HBV without HIV showed greater incidence of creatinine clearance < 60 mL/min with TDF but greater incidence of serum creatinine (SCr) ≥ 2.5 mg/dL in the entacavir group, making it difficult to reach a clear conclusion on risks.¹⁸ Other studies have either suffered from small cohorts with TDF or included patients with HIV coinfection.^19,20 Although a retrospective comparison of TDF and entecavir, randomly matched 1:2 to account for differences between groups, showed lower estimated glomerular filtration rate (eGFR) in the TDF group, more data are needed.²¹ Entecavir remains an option for many patient, but for those who have failed nucleosides, few options remain.

With the advantages available from TDF and the continued expense of TAF, more data regarding the risks of nephrotoxicity with TDF would be beneficial. The objective of this study was to compare treatment with TDF and other NRTIs in chronic HBV monoinfection to distinguish any differences in kidney function changes over time. With hopes of gathering enough data to distinguish between groups, information was gathered from across the Veterans Health Administration (VHA) system.

Methods

A nationwide, multicenter, retrospective, cohort study of veterans with HBV infection was conducted to compare the effects of various NRTIs on renal function. Patient were identified through the US Department of Veterans Affairs Corporate Data Warehouse (CDW), using data from July 1, 2005 to July 31, 2015. Patients were included who had positive HBV surface antigen (HBsAg) or newly prescribed NRTI. Multiple drug episodes could be included for each patient. That is, if a patient who had previously been included had another instance of a newly prescribed NRTI, this would be included in the analysis. Exclusion criteria were patients aged < 18 years, those with NRTI prescription for ≤ 1 month, and concurrent HIV infection. All patients with HBsAg were included for the study for increasing the sensitivity in gathering patients; however, those patients were included only if they received NRTI concurrent with the laboratory test results used for the primary endpoint (ie, SCr) to be included in the analysis.

How data are received from CDW bears some explanation. A basic way to understand the way data are received is that questions can be asked such as “for X population, at this point in time, was the patient on Y drug and what was the SCr value.” Therefore, inclusion and exclusion must first be specified to define the population, after which point certain data points can be received depending on the specifications made. For this reason, there is no way to determine, for example, whether a certain patient continued TDF use for the duration of the study, only at the defined points in time (described below) to receive the specific data.

For the patients included, information was retrieved from the first receipt of the NRTI prescription to 36 months after initiation. Baseline characteristics included age, sex, race, and ethnicity, and were defined at time of NRTI initiation. Values for SCr were compared at baseline, 3, 6, 12, 24, and 36 months after prescription of NRTI. The date of laboratory results was associated with the nearest date of comparison. Values for eGFR were determined by the modification of diet in renal disease equation. Values for eGFR are available in the CDW, whereas there is no direct means to calculate creatinine clearance with the available data, so eGFR was used for this study.

The primary endpoint was a change in eGFR in patients taking TDF after adjustment for time with the full cohort. Secondary analyses included the overall effect of time for the full cohort and change in renal function for each NRTI group. Mean and standard deviation for eGFR were determined for each NRTI group using the available data points. Analyses of the primary and secondary endpoints were completed using a linear mixed model with terms for time, to account for fixed effects, and specific NRTI used to account for random effects. A 2-sided α of .05 was used to determine statistical significance.

Results

A total of 413 drug episodes from 308 subjects met inclusion criteria for the study. Of these subjects, 229 were still living at the time of query. Most study participants were male (96%), the mean age was 62.1 years for males and 55.9 years for females; 49.5% were White and 39.7% were Black veterans (Table 1).

The NRTIs received by patients during the study period included TDF, TDF/emtricitabine, adefovir, entecavir, and lamivudine. No patients were on telbivudine. Formulations including TAF had not been approved by the US Food and Drug Administration (FDA) by the end of the study period, and as such were not found in the study.¹³ A plurality of participants received entecavir (94 of 223 at baseline), followed by TDF (n = 38) (Table 2). Of note, only 8 participants received TDF/emtricitabine at baseline. Differences were found between the groups in number of SCr data points available at 36 months vs baseline. The TDF group had the greatest reduction in data points available with 38 laboratory values at baseline vs 15 at 36 months (39.5% of baseline). From the available data, it is not possible to determine whether these represent medication discontinuations, missing values, lost to follow-up, or some other cause. Baseline eGFR was highest in the 2 TDF groups, with TDF alone at 77.7 mL/min (1.4-5.5 mL/min higher than the nontenofovir groups) and TDF/emtricitabine at 89.7 mL/min (13.4-17.5 mL/min higher than nontenofovir groups) (Table 3).

Discussion

This study demonstrated a decline in eGFR over time in a similar fashion for all NRTIs used in patients treated for HBV monoinfection, but no greater decline in renal function was found with use of TDF vs other NRTIs. A statistically significant decline in eGFR of −4.55 mL/min over the 36-month time frame of the study was demonstrated for the full cohort, but no statistically significant change in eGFR was found for any individual NRTI after accounting for the fixed effect of time. If TDF is not associated with additional risk of nephrotoxicity compared with other NRTIs, this could have important implications for treatment when considering the evidence that tenofovir-based treatment seems to be more effective than other medications for suppressing viral load.¹³

This result runs contrary to data in patients given NRTIs for HIV infection as well as a more recent cohort study in chronic HBV infectioin, which showed a statistically significant difference in kidney dysfunction between TDF and entecavir (-15.73 vs -5.96 mL/min/m², P < .001).^5-7,21 Possible mechanism for differences in response between HIV and HBV patients has not been elucidated, but the inherent risk of developing chronic kidney disease from HIV disease may play a role.²² The possibility remains that all NRTIs cause a degree of kidney impairment in patients treated for chronic HBV infection as evidenced by the statistically significant fixed effect for time in the present study. The cause of this effect is unknown but may be independently related to HBV infection or may be specific to NRTI therapy. No control group of patients not receiving NRTI therapy was included in this study, so conclusions cannot be drawn regarding whether all NRTIs are associated with decline in renal function in chronic HBV infection.

Limitations

Although this study did not detect a difference in change in eGFR between TDF and other NRTI treatments, it is possible that the length of data collection was not adequate to account for possible kidney injury from TDF. A study assessing renal tubular dysfunction in patients receiving adefovir or TDF showed a mean onset of dysfunction of 49 months.¹⁵ It is possible that participants in this study would go on to develop renal dysfunction in the future. This potential also was observed in a more recent retrospective cohort study in chronic HBV infection, which showed the greatest degree of decline in kidney function between 36 and 48 months (−11.87 to −15.73 mL/min/m² for the TDF group).²¹

The retrospective design created additional limitations. We attempted to account for some by using a matched cohort for the entecavir group, and there was no statistically significant difference between the groups in baseline characteristics. In HIV patients, a 10-year follow-up study continued to show decline in eGFR throughout the study, though the greatest degree of reduction occurred in the first year of the study.¹⁰ The higher baseline eGFR of the TDF recipients, 77.7 mL/min for the TDF alone group and 89.7 mL/min for the TDF/emtricitabine group vs 72.2 to 76.3 mL/min in the other NRTI groups, suggests high potential for selection bias. Some health care providers were likely to avoid TDF in patients with lower eGFR due to the data suggesting nephrotoxicity in other populations. Another limitation is that the reason for the missing laboratory values could not be determined. The TDF group had the greatest disparity in SCr data availability at baseline vs 36 months, with 39.5% concurrence with TDF alone compared with 50.0 to 63.6% in the other groups. Other treatment received outside the VHA system also could have influenced results.

Conclusions

This retrospective, multicenter, cohort study did not find a difference between TDF and other NRTIs for changes in renal function over time in patients with HBV infection without HIV. There was a fixed effect for time, ie, all NRTI groups showed some decline in renal function over time (−4.6 mL/min), but the effects were similar across groups. The results appear contrary to studies with comorbid HIV showing a decline in renal function with TDF, but present studies in HBV monotherapy have mixed results.

Further studies are needed to validate these results, as this and previous studies have several limitations. If these results are confirmed, a possible mechanism for these differences between patients with and without HIV should be examined. In addition, a study looking specifically at incidence of acute kidney injury rather than overall decline in renal function would add important data. If the results of this study are confirmed, there could be clinical implications in choice of agent with treatment of HBV monoinfection. This would add to the overall armament of medications available for chronic HBV infection and could create cost savings in certain situations if providers feel more comfortable continuing to use TDF instead of switching to the more expensive TAF.

Acknowledgments
Funding for this study was provided by the Veterans Health Administration.

Infection with hepatitis B virus (HBV) is associated with risk of potentially lethal, chronic infection and is a major public health problem. Infection from HBV has the potential to lead to liver failure, cirrhosis, and cancer.^1,2 Chronic HBV infection exists in as many as 2.2 million Americans, and in 2015 alone, HBV was estimated to be associated with 887,000 deaths worldwide.^1,3 Suppression of viral load is the basis of treatment, necessitating long-term use of medication for treatment.⁴ Nucleoside reverse transcriptase inhibitors (entecavir, lamivudine, telbivudine) and nucleotide reverse transcriptase inhibitors (adefovir, tenofovir), have improved the efficacy and tolerability of chronic HBV treatment compared with interferon-based agents.^4-7 However, concerns remain regarding long-term risk of nephrotoxicity, in particular with tenofovir disoproxil fumarate (TDF), which could lead to a limitation of safe and effective options for certain populations.^5,6,8 A newer formulation, tenofovir alafenamide fumarate (TAF), has improved the kidney risks, but expense remains a limiting factor for this agent.⁹

Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) have demonstrated efficacy in reducing HBV viral load and other markers of improvement in chronic HBV, but entecavir and tenofovir have tended to demonstrate greater efficacy in clinical trials.^5-7 Several studies have suggested potential benefits of tenofovir-based treatment over other NRTIs, including greater viral load achievement compared with adefovir, efficacy in patients with previous failure of lamivudine or adefovir, and long-term efficacy in chronic HBV infection.^10-12 A 2019 systematic review suggests TDF and TAF are more effective than other NRTIs for achieving viral load suppression.¹³ Other NRTIs are not without their own risks, including mitochondrial dysfunction, mostly with lamivudine and telbivudine.⁴

Despite these data, guidelines have varied in their treatment recommendations in the context of chronic kidney disease partly due to variations in the evidence regarding nephrotoxicity.^7,14 Cohort studies and case reports have suggested association between TDF and acute kidney injury in patients with HIV infection as well as long-term reductions in kidney function.^15,16 In one study, 58% of patients treated with TDF did not return to baseline kidney function after an event of acute kidney injury.¹⁷ However, little data are available on whether this association exists for chronic HBV treatment in the absence of HIV infection. One retrospective analysis comparing TDF and entecavir in chronic HBV without HIV showed greater incidence of creatinine clearance < 60 mL/min with TDF but greater incidence of serum creatinine (SCr) ≥ 2.5 mg/dL in the entacavir group, making it difficult to reach a clear conclusion on risks.¹⁸ Other studies have either suffered from small cohorts with TDF or included patients with HIV coinfection.^19,20 Although a retrospective comparison of TDF and entecavir, randomly matched 1:2 to account for differences between groups, showed lower estimated glomerular filtration rate (eGFR) in the TDF group, more data are needed.²¹ Entecavir remains an option for many patient, but for those who have failed nucleosides, few options remain.

With the advantages available from TDF and the continued expense of TAF, more data regarding the risks of nephrotoxicity with TDF would be beneficial. The objective of this study was to compare treatment with TDF and other NRTIs in chronic HBV monoinfection to distinguish any differences in kidney function changes over time. With hopes of gathering enough data to distinguish between groups, information was gathered from across the Veterans Health Administration (VHA) system.

Methods

A nationwide, multicenter, retrospective, cohort study of veterans with HBV infection was conducted to compare the effects of various NRTIs on renal function. Patient were identified through the US Department of Veterans Affairs Corporate Data Warehouse (CDW), using data from July 1, 2005 to July 31, 2015. Patients were included who had positive HBV surface antigen (HBsAg) or newly prescribed NRTI. Multiple drug episodes could be included for each patient. That is, if a patient who had previously been included had another instance of a newly prescribed NRTI, this would be included in the analysis. Exclusion criteria were patients aged < 18 years, those with NRTI prescription for ≤ 1 month, and concurrent HIV infection. All patients with HBsAg were included for the study for increasing the sensitivity in gathering patients; however, those patients were included only if they received NRTI concurrent with the laboratory test results used for the primary endpoint (ie, SCr) to be included in the analysis.

How data are received from CDW bears some explanation. A basic way to understand the way data are received is that questions can be asked such as “for X population, at this point in time, was the patient on Y drug and what was the SCr value.” Therefore, inclusion and exclusion must first be specified to define the population, after which point certain data points can be received depending on the specifications made. For this reason, there is no way to determine, for example, whether a certain patient continued TDF use for the duration of the study, only at the defined points in time (described below) to receive the specific data.

For the patients included, information was retrieved from the first receipt of the NRTI prescription to 36 months after initiation. Baseline characteristics included age, sex, race, and ethnicity, and were defined at time of NRTI initiation. Values for SCr were compared at baseline, 3, 6, 12, 24, and 36 months after prescription of NRTI. The date of laboratory results was associated with the nearest date of comparison. Values for eGFR were determined by the modification of diet in renal disease equation. Values for eGFR are available in the CDW, whereas there is no direct means to calculate creatinine clearance with the available data, so eGFR was used for this study.

The primary endpoint was a change in eGFR in patients taking TDF after adjustment for time with the full cohort. Secondary analyses included the overall effect of time for the full cohort and change in renal function for each NRTI group. Mean and standard deviation for eGFR were determined for each NRTI group using the available data points. Analyses of the primary and secondary endpoints were completed using a linear mixed model with terms for time, to account for fixed effects, and specific NRTI used to account for random effects. A 2-sided α of .05 was used to determine statistical significance.

Results

A total of 413 drug episodes from 308 subjects met inclusion criteria for the study. Of these subjects, 229 were still living at the time of query. Most study participants were male (96%), the mean age was 62.1 years for males and 55.9 years for females; 49.5% were White and 39.7% were Black veterans (Table 1).

The NRTIs received by patients during the study period included TDF, TDF/emtricitabine, adefovir, entecavir, and lamivudine. No patients were on telbivudine. Formulations including TAF had not been approved by the US Food and Drug Administration (FDA) by the end of the study period, and as such were not found in the study.¹³ A plurality of participants received entecavir (94 of 223 at baseline), followed by TDF (n = 38) (Table 2). Of note, only 8 participants received TDF/emtricitabine at baseline. Differences were found between the groups in number of SCr data points available at 36 months vs baseline. The TDF group had the greatest reduction in data points available with 38 laboratory values at baseline vs 15 at 36 months (39.5% of baseline). From the available data, it is not possible to determine whether these represent medication discontinuations, missing values, lost to follow-up, or some other cause. Baseline eGFR was highest in the 2 TDF groups, with TDF alone at 77.7 mL/min (1.4-5.5 mL/min higher than the nontenofovir groups) and TDF/emtricitabine at 89.7 mL/min (13.4-17.5 mL/min higher than nontenofovir groups) (Table 3).

Discussion

This study demonstrated a decline in eGFR over time in a similar fashion for all NRTIs used in patients treated for HBV monoinfection, but no greater decline in renal function was found with use of TDF vs other NRTIs. A statistically significant decline in eGFR of −4.55 mL/min over the 36-month time frame of the study was demonstrated for the full cohort, but no statistically significant change in eGFR was found for any individual NRTI after accounting for the fixed effect of time. If TDF is not associated with additional risk of nephrotoxicity compared with other NRTIs, this could have important implications for treatment when considering the evidence that tenofovir-based treatment seems to be more effective than other medications for suppressing viral load.¹³

This result runs contrary to data in patients given NRTIs for HIV infection as well as a more recent cohort study in chronic HBV infectioin, which showed a statistically significant difference in kidney dysfunction between TDF and entecavir (-15.73 vs -5.96 mL/min/m², P < .001).^5-7,21 Possible mechanism for differences in response between HIV and HBV patients has not been elucidated, but the inherent risk of developing chronic kidney disease from HIV disease may play a role.²² The possibility remains that all NRTIs cause a degree of kidney impairment in patients treated for chronic HBV infection as evidenced by the statistically significant fixed effect for time in the present study. The cause of this effect is unknown but may be independently related to HBV infection or may be specific to NRTI therapy. No control group of patients not receiving NRTI therapy was included in this study, so conclusions cannot be drawn regarding whether all NRTIs are associated with decline in renal function in chronic HBV infection.

Limitations

Although this study did not detect a difference in change in eGFR between TDF and other NRTI treatments, it is possible that the length of data collection was not adequate to account for possible kidney injury from TDF. A study assessing renal tubular dysfunction in patients receiving adefovir or TDF showed a mean onset of dysfunction of 49 months.¹⁵ It is possible that participants in this study would go on to develop renal dysfunction in the future. This potential also was observed in a more recent retrospective cohort study in chronic HBV infection, which showed the greatest degree of decline in kidney function between 36 and 48 months (−11.87 to −15.73 mL/min/m² for the TDF group).²¹

The retrospective design created additional limitations. We attempted to account for some by using a matched cohort for the entecavir group, and there was no statistically significant difference between the groups in baseline characteristics. In HIV patients, a 10-year follow-up study continued to show decline in eGFR throughout the study, though the greatest degree of reduction occurred in the first year of the study.¹⁰ The higher baseline eGFR of the TDF recipients, 77.7 mL/min for the TDF alone group and 89.7 mL/min for the TDF/emtricitabine group vs 72.2 to 76.3 mL/min in the other NRTI groups, suggests high potential for selection bias. Some health care providers were likely to avoid TDF in patients with lower eGFR due to the data suggesting nephrotoxicity in other populations. Another limitation is that the reason for the missing laboratory values could not be determined. The TDF group had the greatest disparity in SCr data availability at baseline vs 36 months, with 39.5% concurrence with TDF alone compared with 50.0 to 63.6% in the other groups. Other treatment received outside the VHA system also could have influenced results.

Conclusions

This retrospective, multicenter, cohort study did not find a difference between TDF and other NRTIs for changes in renal function over time in patients with HBV infection without HIV. There was a fixed effect for time, ie, all NRTI groups showed some decline in renal function over time (−4.6 mL/min), but the effects were similar across groups. The results appear contrary to studies with comorbid HIV showing a decline in renal function with TDF, but present studies in HBV monotherapy have mixed results.

Further studies are needed to validate these results, as this and previous studies have several limitations. If these results are confirmed, a possible mechanism for these differences between patients with and without HIV should be examined. In addition, a study looking specifically at incidence of acute kidney injury rather than overall decline in renal function would add important data. If the results of this study are confirmed, there could be clinical implications in choice of agent with treatment of HBV monoinfection. This would add to the overall armament of medications available for chronic HBV infection and could create cost savings in certain situations if providers feel more comfortable continuing to use TDF instead of switching to the more expensive TAF.

Acknowledgments
Funding for this study was provided by the Veterans Health Administration.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.