Article

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.

Acute agranulocytosis and aseptic meningitis are serious adverse effects (AEs) associated with sulfamethoxazole-trimethoprim. Acute agranulocytosis is a rare, potentially life-threatening blood dyscrasia characterized by a neutrophil count of < 500 cells per μL, with no relevant decrease in hemoglobin or platelet levels.¹ Patients with agranulocytosis may be asymptomatic or experience severe sore throat, pharyngitis, or tonsillitis in combination with high fever, rigors, headaches, or malaise. These AEs are commonly classified as idiosyncratic and, in most cases, attributable to medications. If drug-induced agranulocytosis is suspected, the patient should discontinue the medication immediately.¹

Meningitis is an inflammatory disease typically caused by viral or bacterial infections; however, it may also be attributed to medications or malignancy. Inflammation of the meninges with a negative bacterial cerebrospinal fluid culture is classified as aseptic meningitis. Distinguishing between aseptic and bacterial meningitis is crucial due to differences in illness severity, treatment options, and prognosis.² Symptoms of meningitis may include fever, headache, nuchal rigidity, nausea, or vomiting.³ Several classes of medications can cause drug-induced aseptic meningitis (DIAM), but the most commonly reported antibiotic is sulfamethoxazole-trimethoprim.

DIAM is more prevalent in immunocompromised patients, such as those with a history of HIV/AIDS, organ transplant, collagen vascular disease, or malignancy, who may be prescribed sulfamethoxazoletrimethoprim for prophylaxis or treatment of infection.² The case described in this article serves as a distinctive example of acute agranulocytosis complicated with aseptic meningitis caused by sulfamethoxazole-trimethoprim in an immunocompetent patient.

Case Presentation

A healthy male veteran aged 39 years presented to the Fargo Veterans Affairs Medical Center emergency department (ED) for worsening left testicular pain and increased urinary urgency and frequency for about 48 hours. The patient had no known medication allergies, was current on vaccinations, and his only relevant prescription was valacyclovir for herpes labialis. The evaluation included urinalysis, blood tests, and scrotal ultrasound. The urinalysis, blood tests, and vitals were unremarkable for any signs of systemic infection. The scrotal ultrasound was significant for left focal area of abnormal echogenicity with absent blood flow in the superior left testicle and a significant increase in blood flow around the left epididymis. Mild swelling in the left epididymis was present, with no significant testicular or scrotal swelling or skin changes observed. Urology was consulted and prescribed oral sulfamethoxazole-trimethoprim 800-160 mg every 12 hours for 30 days for the treatment of left epididymo-orchitis.

The patient returned to the ED 2 weeks later with fever, chills, headache, generalized body aches, urinary retention, loose stools, and nonspecific chest pressure. A serum blood test revealed significant neutropenia and leukopenia. The patient was admitted for observation, and sulfamethoxazole-trimethoprim was discontinued. The patient received sodium chloride intravenous (IV) fluid, oral potassium chloride supplementation, IV ondansetron, and analgesics, including oral acetaminophen, oral ibuprofen, and IV hydromorphone as needed. Repeated laboratory tests were completed with no specific findings; serum laboratory work, urinalysis, chest and abdominal X-rays, and echocardiogram were all unremarkable. The patient’s neutrophil count dropped from 5100 cells/µL at the initial ED presentation to 900 cells/µL (reference range, 1500-8000 cells/µL) (Table 1). Agranulocytosis quickly resolved after antibiotic discontinuation.

Upon further investigation, the patient took the prescribed sulfamethoxazole-trimethoprim for 10 days before stopping due to the resolution of testicular pain and epididymal swelling. The patient reported initial AEs of loose stools and generalized myalgias when first taking the medication. The patient restarted the antibiotic to complete the course of therapy after not taking it for 2 days. Within 20 minutes of restarting the medication, he experienced myalgias with pruritus, prompting him to return to the ED. Agranulocytosis and aseptic meningitis developed within 12 days after he was prescribed sulfamethoxazole-trimethoprim, though the exact timeframe is unknown.

The patient’s symptoms, except for a persistent headache, resolved during hospitalization. Infectious disease was consulted, and a lumbar puncture was performed due to prior fever and ongoing headaches to rule out a treatable cause of meningitis. The lumbar puncture showed clear spinal fluid, an elevated white blood cell count with neutrophil predominance, and normal protein and glucose levels. Cultures showed no aerobic, anaerobic, or fungal organisms. Herpes virus simplex and Lyme disease testing was not completed during hospitalization. Respiratory panel, legionella, and hepatitis A, B, and C tests were negative (Table 2). The negative laboratory test results strengthened the suspicion of aseptic meningitis caused by sulfamethoxazole-trimethoprim. The neurology consult recommended no additional treatments or tests.

The patient spontaneously recovered 2 days later, with a normalized complete blood count and resolution of headache. Repeat scrotal ultrasounds showed resolution of the left testicle findings. The patient was discharged and seen for a follow-up 14 days later. The final diagnosis requiring hospitalization was aseptic meningitis secondary to a sulfamethoxazole-trimethoprim.

Discussion

Sulfamethoxazole-trimethoprim is a commonly prescribed antibiotic for urinary tract infections, pneumocystis pneumonia, pneumocystis pneumonia prophylaxis, and methicillin-resistant Staphylococcus aureus skin and soft tissue infections. Empiric antibiotics for epididymo-orchitis caused by enteric organisms include levofloxacin or ofloxacin; however sulfamethoxazole-trimethoprim may be considered as alternative.^5,6 Agranulocytosis induced by sulfamethoxazole-trimethoprim may occur due to the inhibition on folic acid metabolism, which makes the highly proliferating cells of the hematopoietic system more susceptible to neutropenia. Agranulocytosis typically occurs within 7 days of treatment initiation and generally resolves within a month after discontinuation of the offending agent.⁷ In this case, agranulocytosis resolved overnight, resulting in leukocytosis. One explanation for the rapid increase in white blood cell count may be the concurrent diagnosis of aseptic meningitis. Alternatively, the patient’s health and immunocompetence may have helped generate an adequate immune response. Medication-induced agranulocytosis is often a diagnosis of exclusion because it is typically difficult to diagnose.⁷ In more severe or complicated cases of agranulocytosis, filgrastim may be indicated.¹

Sulfamethoxazole-trimethoprim is a lipophilic small-molecule medication that can cross the blood-brain barrier and penetrate the tissues of the bone, prostate, and central nervous system.⁸ Specifically, the medication can pass into the cerebrospinal fluid regardless of meningeal inflammation.⁹ The exact mechanism for aseptic meningitis caused by sulfamethoxazole-trimethoprim is unknown; however, it may accumulate in the choroid plexus, causing destructive inflammation of small blood vessels and resulting in aseptic meningitis.¹⁰ The onset of aseptic meningitis can vary from 10 minutes to 10 days after initiation of the medication. Pre-exposure to the medication typically results in earlier onset of symptoms, though patients do not need to have previously taken the medication to develop aseptic meningitis. Patients generally become afebrile with resolution of headache and mental status changes within 48 to 72 hours after stopping the medication or after about 5 to 7 half-lives of the medication are eliminated.¹¹ Some patients may continue to experience worsening symptoms after discontinuation because the medication is already absorbed into the serum and tissues.

DIAM is an uncommon drug-induced hypersensitivity AE of the central nervous system. Diagnosing aseptic meningitis caused by sulfamethoxazole-trimethoprim can be challenging, as antibiotics are given to treat suspected infections, and the symptoms of aseptic meningitis can be hard to differentiate from those of infectious meningitis.¹¹ Close monitoring between the initiation of the medication and the onset of clinical symptoms is necessary to assist in distinguishing between aseptic and infectious meningitis.³ If the causative agent is not discontinued, symptoms can quickly worsen, progressing from fever and headache to confusion, coma, and respiratory depression. A DIAM diagnosis can only be made with resolution of aseptic meningitis after stopping the contributory agent. If appropriate, this can be proven by rechallenging the medication in a controlled setting. The usual treatment for aseptic meningitis is supportive care, including hydration, antiemetics, electrolyte supplementation, and adequate analgesia.³

Differential diagnoses in this case included viral infection, meningitis, and allergic reaction to sulfamethoxazole-trimethoprim. The patient reported history of experiencing symptoms after restarting his antibiotic, raising strong suspicion for DIAM. Initiation of this antibiotic was the only recent medication change noted. Laboratory testing for infectious agents yielded negative results, including tests for aerobic and anaerobic bacteria as well as viral and fungal infections. A lumbar puncture and cerebrospinal fluid culture was clear, with no organisms shown on gram stain. Bacterial or viral meningitis was presumed less likely due to the duration of symptoms, correlation of symptoms coinciding with restarting the antibiotic, and negative cerebrospinal fluid culture results.

It was concluded that agranulocytosis and aseptic meningitis were likely induced by sulfamethoxazole-trimethoprim as supported by the improvement upon discontinuing the medication and subsequent worsening upon restarting it. Concurrent agranulocytosis and aseptic meningitis is rare, and there is typically no correlation between the 2 reactions. Since agranulocytosis may be asymptomatic, this case highlights the need to monitor blood cell counts in patients using sulfamethoxazole-trimethoprim. The possibility of DIAM should be considered in patients presenting with flu-like symptoms, and a lumbar puncture may be collected to rule out aseptic meningitis if the patient’s AEs are severe following the initiation of an antibiotic, particularly in immunosuppressed patients taking sulfamethoxazole-trimethoprim. This case is unusual because the patient was healthy and immunocompetent.

This case may not be generalizable and may be difficult to compare to other cases. Every case has patient-specific factors affecting subjective information, including the patient’s baseline, severity of symptoms, and treatment options. This report was based on a single patient case and corresponding results may be found in similar patient cases.

Conclusions

This case emphasizes the rare but serious AEs of acute agranulocytosis complicated with aseptic meningitis after prescribed sulfamethoxazole-trimethoprim. This is a unique case of an immunocompetent patient developing both agranulocytosis and aseptic meningitis after restarting the antibiotic to complete therapy. This case highlights the importance of monitoring blood cell counts and monitoring for signs and symptoms of aseptic meningitis, even during short courses of therapy. Further research is needed to recognize characteristics that may increase the risk for these AEs and to develop strategies for their prevention.

Chronic pain is one of the most prevalent public health concerns in the United States, affecting > 51 million adults with about $500 billion in health care costs.¹ Military veterans are among the most vulnerable subpopulations, with 65% of veterans reporting chronic pain in the last 3 months.² Chronic pain is complex, affecting the biopsychosocial-spiritual levels of human health, and requires multimodal and comprehensive treatment approaches.³ Hence, chronic pain treatment can be best delivered via interdisciplinary teams (IDTs) that use a patient-centered approach.^4,5

The Veterans Healthcare Administration (VHA) is a leader in developing and delivering interdisciplinary pain care.^6,7 VHA Directive 2009-053 requires every US Department of Veterans Affairs (VA) medical center to offer an IDT for chronic pain. However, VHA and non-VHA IDT programs vary significantly.^8-11 A recent systematic review found a median of 5 disciplines included on IDTs (range, 2-8), and program content often included exercise and education; only 11% of included IDTs met simultaneously with patients.¹¹ The heterogeneity of IDT programs has made determining best practices challenging.^8,11 The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials has denoted several core measures and measurement domains that were critical for determining the success of pain management interventions, including patient satisfaction.^12,13 Nevertheless, the association of IDTs with high patient satisfaction and improvement in pain measures has been documented.^5,11

The VHA has worked to implement the Whole Health System into health care, which considers well-being across physical, behavioral, spiritual, and socioeconomic domains. As such, the Whole Health System involves an interpersonal, team-based approach, “anchored in trusting longitudinal relationships to promote resilience, prevent disease, and restore health.”¹⁴ It aligns with the patient’s mission, aspiration, and purpose. Surgeon General VADM Vivek H. Murthy, MD, MBA, recently endorsed this approach.^15,16 Other health care systems adopting whole health tend to have higher patient satisfaction, increased access to care, and improved patient-reported outcomes.¹⁵ Within the VHA, the Whole Health System has shifted the conversation between clinicians and patients from “What is the matter with you?” to “What is important to you?” while emphasizing a proactive and personalized approach to health care.¹⁷ Rather than emphasizing passive modalities such as medications and clinician-led services (eg, interventional pain service), the Whole Health System highlights self-care.^3,17 Initial research findings within the VHA have been promising.^18-21 Whole health peer coaching calls appear to be an effective approach for veterans diagnosed with PTSD, and the use of whole health services is associated with a decrease in opioid use.^19,22 However, there are negligible data on patient experiences after meeting with a whole health-focused pain IDT, and studies to date have focused on urban populations.²³ One approach to IDT that has shown promise for other health issues involves a patient meeting simultaneously with all members of the IDT.^24-27 With the integration of the Whole Health System and the VHA priorities to provide veterans with the “soonest and best care,” more data are needed on the experiences of patients and support persons with various approaches to IDT pain care.²⁸ This study aimed to evaluate patient and support person experiences with a whole health-focused pain IDT that met simultaneously with the patient and support person during an initial evaluation. This study was approved by the institutional review board at the Salem VA Health Care System (SVAHCS) in Virginia.

Methods

The PREVAIL IDT Track is a clinical program offered at SVAHCS with a whole health-focused approach that involves patients and their support persons meeting simultaneously with a pain IDT. PREVAIL IDT Track is designed to help veterans more effectively self-manage chronic pain (Table 1).^6,29 Health care practitioners (HCPs) at SVAHCS recommended that veterans with pain persisting for > 3 months participate in PREVAIL IDT Track. After meeting with an advanced practice clinician for an intake, veterans elected to participate in the PREVAIL IDT Track program and completed the initial 6 weeks of pain education. Veterans were then invited to be evaluated by the pain IDT. A team including HCPs from interventional pain, psychology, pharmacy, nutrition, and physical therapy services met with the veteran for 60 minutes. Veterans were also invited to bring a support person to the IDT initial evaluation.

During the IDT initial evaluation, HCPs inquired about the patient’s mission, aspiration, and purpose (“If you were in less pain, what would you be doing more of?”) and about whole health self-care and wellness factors that may contribute to their chronic pain using the Personal Health Inventory.^30,31 Veterans were then invited to select 3 whole health self-care areas to focus on during the 6-month program.³ The IDT HCPs worked with the veteran to establish the treatment plan for the first month in the areas of self-care selected by the patient and made recommendations for additional treatments. If the veteran brought a support person to the IDT initial evaluation, their feedback was elicited throughout and at the end to ensure the final treatment plan and first month’s goals were realistic. At the end of the appointment, the veteran and their support person were asked to complete a program-specific satisfaction survey. The HCPs on the team and the veteran executed the treatment plan developed during the appointment, except for medication prescribing. Recommendations for medication changes are included in clinical notes. Veterans then received 5 monthly coaching calls from a nurse navigator with training in whole health and a 6-month follow-up appointment with the IDT HCPs to discuss a plan for continuity of care.

Participant demographic information was not collected, and participants were not compensated for completing the survey. Veterans in PREVAIL IDT Track are predominantly residents of central Appalachia, White, male, unemployed, have ≥ 1 mental and physical health comorbidity, and have a history of mental health treatment.³² Veterans participating in PREVAIL IDT had a mean age of 57 years, and about 1 in 3 have opioid prescriptions.³²

A program-specific 17-question satisfaction survey was developed, which included questions related to satisfaction with previous SVAHCS pain care and staff interactions. To assess the overall impression of the IDT initial evaluation, 3 yes/no questions and a 0 to 10-point scale were used. The 5 remaining open-ended questions allowed participants to give feedback about the IDT initial evaluation.

Data Analysis

A convergent mixed-methods approach was used to evaluate participant satisfaction with the initial IDT evaluation. The study team collected and analyzed quantitative and qualitative survey data and triangulated the findings.³³ For quantitative responses, frequencies and means were calculated using Python. For qualitative responses, thematic data analysis was conducted by systematic coding, using inductive methods and allowing themes to emerge. Study team members performed a line-by-line analysis of responses using NVivo to identify important codes and reach a consensus. This study adhered to the Consolidated Criteria for Reporting Qualitative Research and followed the National Institute for Health Care Excellence checklist.^34,35

Results

Quantitative Responses

In 2022, 168 veterans completed the initial IDT evaluation, and 144 (85.2%) completed the satisfaction survey and were included in this study. Thirty-two support persons who attended the initial IDT evaluation and completed the survey also were included. Of the 12 quantitative questions, 4 had a 100% completion rate, while 8 had ≤ 3% missing responses. When describing care prior to participating in PREVAIL, participants indicated a mean (SD) response of 4.6 (1.4) with the health care they received at SVAHCS and 4.3 (1.4) with SVAHCS pain management services, both on 6-point scales. All but 2 participants (98.9%) reported always being treated with courtesy and respect by PREVAIL HCPs during the initial IDT evaluation, with a mean (SD) score of 4.0 (0.2) on a 4-point scale. Most respondents (96.6%) reported that PREVAIL HCPs always listened carefully during the initial IDT evaluation, with a mean (SD) 4.0 (0.3) on a 4-point scale. Similarly, 92.6% reported that PREVAIL HCPs explained things clearly during the initial IDT evaluation, with a mean (SD) 3.9 (0.3) on a 4-point scale.

All respondents agreed that PREVAIL HCPs considered veteran preferences and those of their support persons in deciding their health care needs during the initial IDT evaluation, with a mean (SD) 3.7 (0.5) on a 4-point scale. Most respondents left the appointment with a good understanding of their responsibilities for chronic pain management with 99.4% (n = 169) strongly agreeing or agreeing (mean [SD] 3.6 [0.5]). A total of 135 respondents (79.4%) reported they left appointments with written information on their treatment plan. All 170 respondents reported that they would recommend PREVAIL to a friend, and 169 respondents (98.8%) felt that the initial PREVAIL IDT evaluation was a valuable use of time. Eighty-seven respondents (50.9%) rated the initial IDT evaluation as the “best clinical experience possible” with a mean (SD) score of 9.2 (1.1) on a 10-point scale (Table 2).

Qualitative Responses

Respondents provided complementary feedback on the program, with many participants stating that they enjoyed every aspect (eAppendix, available at doi:10.12788/fp.0503). In terms of positive aspects of the program, several themes emerged: participants appreciated meeting as an IDT, feeling cared for and listened to, learning more about their pain and ways to manage it, and specific services offered. Thirty-three of 144 respondents wanted longer appointment times. Twenty-two respondents suggested logistics improvements (eg, meeting in a larger room, having a written plan at the end, sending paperwork ahead of time, and later appointment times).

Discussion

Veterans and support persons were satisfied with the initial IDT evaluation for the PREVAIL whole health-focused pain clinical program for veterans predominantly residing in central Appalachia. These satisfaction findings are noteworthy since 20% of this same sample reported dissatisfaction with prior pain services, which could affect engagement and outcomes in pain care. In addition to high satisfaction levels, the PREVAIL IDT model may benefit veterans with limited resources. Rather than needing to attend several individual appointments, the PREVAIL IDT Track provides a 1-stop shop approach that decreases patient burden and barriers to care (eg, travel, transportation, and time) as well as health care system burden. For instance, schedulers need only to make 1 appointment for the veteran rather than several. This approach was highly acceptable to veterans served at SVAHCS and may increase the reach and impact of VHA IDT pain care.

The PREVAIL model may foster rapport with HCPs and encourage an active role in self-managing pain.^36,37 Participants noted that their preferences were considered and that they had a good understanding of their responsibilities for managing their chronic pain. This patient-centered approach, emphasizing an active role for the patient, is a hallmark of the VHA Whole Health System and aligns with the overarching PREVAIL IDT Track goal to enhance self-management skills, thus improving functioning through decreased pain interference.^14,38-41

Participants in PREVAIL provided substantial open-ended feedback that has contributed to the program’s improvement and may provide information into preferred components of pain IDT programs, particularly for rural veterans. When asked about their favorite component of the initial IDT evaluation, the most emergent theme was meeting simultaneously with HCPs on the IDT. This finding is significant, given that only 11% of IDTs involve direct patient interaction.

Furthermore, unlike most IDTs, PREVAIL IDT includes a dietitian.^11,42 IDT programs may benefit from dietitian involvement given the importance of the anti-inflammatory diet on chronic pain.^43-46 Participants recommended improvements, (eg, changes to the location and timing, adding a written treatment plan at the end of the appointment, and completing paperwork prior to the appointment) many of which have been addressed. The program now uses validated measures to track progress and comprehensive assessments of pain in response to calls for measurement-based care.^13,47 These process improvement suggestions may be instructive for other VA medical centers with rural populations.

Limitations

This study used a program-specific satisfaction survey with open-ended questions to allow for rich responses; however, the survey has not been validated. It also sought to minimize bias by asking participants to give completed surveys to staff members who were not HCPs on the IDT. However, participants’ responses may still have been influenced by this process. Response rate and demographics for support persons were impossible to determine. The results analyzed the responses of veterans and support persons together, which may have skewed the data. Future studies of pain IDT programs should consider analyzing responses from veterans and their support persons separately and identifying factors (eg, demographics or clinical characteristics) that influence the patients’ experiences while participating.

Conclusions

The initial PREVAIL IDT evaluation at SVAHCS is associated with high-levels of satisfaction. These veterans living in rural Appalachia, similar to the 4.4 million rural US veterans, are more likely to encounter barriers to care (eg, drive time, or transportation concerns) and be prescribed opioids.⁴⁸ These veterans are also at high risk of chronic physical and mental health comorbidities, drug misuse, overdose, and suicide.^49,50 Providing veterans in rural communities the opportunity to attend a single appointment with a pain IDT instead of requiring several individual appointments could improve the reach of evidence-based pain care.

This model of meeting simultaneously with all HCPs on the pain IDT may connect all veterans to the most available and best care, something prioritized by the VHA.28 The initial PREVAIL IDT evaluation also utilizes the Personal Health Inventory and the VHA Whole Health System Circle of Health to design patient-centered treatment plans. Integration of the Whole Health System is currently a high priority within VHA. The PREVAIL IDT Track model warrants additional efficacy research.

Chronic pain is one of the most prevalent public health concerns in the United States, affecting > 51 million adults with about $500 billion in health care costs.¹ Military veterans are among the most vulnerable subpopulations, with 65% of veterans reporting chronic pain in the last 3 months.² Chronic pain is complex, affecting the biopsychosocial-spiritual levels of human health, and requires multimodal and comprehensive treatment approaches.³ Hence, chronic pain treatment can be best delivered via interdisciplinary teams (IDTs) that use a patient-centered approach.^4,5

The Veterans Healthcare Administration (VHA) is a leader in developing and delivering interdisciplinary pain care.^6,7 VHA Directive 2009-053 requires every US Department of Veterans Affairs (VA) medical center to offer an IDT for chronic pain. However, VHA and non-VHA IDT programs vary significantly.^8-11 A recent systematic review found a median of 5 disciplines included on IDTs (range, 2-8), and program content often included exercise and education; only 11% of included IDTs met simultaneously with patients.¹¹ The heterogeneity of IDT programs has made determining best practices challenging.^8,11 The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials has denoted several core measures and measurement domains that were critical for determining the success of pain management interventions, including patient satisfaction.^12,13 Nevertheless, the association of IDTs with high patient satisfaction and improvement in pain measures has been documented.^5,11

The VHA has worked to implement the Whole Health System into health care, which considers well-being across physical, behavioral, spiritual, and socioeconomic domains. As such, the Whole Health System involves an interpersonal, team-based approach, “anchored in trusting longitudinal relationships to promote resilience, prevent disease, and restore health.”¹⁴ It aligns with the patient’s mission, aspiration, and purpose. Surgeon General VADM Vivek H. Murthy, MD, MBA, recently endorsed this approach.^15,16 Other health care systems adopting whole health tend to have higher patient satisfaction, increased access to care, and improved patient-reported outcomes.¹⁵ Within the VHA, the Whole Health System has shifted the conversation between clinicians and patients from “What is the matter with you?” to “What is important to you?” while emphasizing a proactive and personalized approach to health care.¹⁷ Rather than emphasizing passive modalities such as medications and clinician-led services (eg, interventional pain service), the Whole Health System highlights self-care.^3,17 Initial research findings within the VHA have been promising.^18-21 Whole health peer coaching calls appear to be an effective approach for veterans diagnosed with PTSD, and the use of whole health services is associated with a decrease in opioid use.^19,22 However, there are negligible data on patient experiences after meeting with a whole health-focused pain IDT, and studies to date have focused on urban populations.²³ One approach to IDT that has shown promise for other health issues involves a patient meeting simultaneously with all members of the IDT.^24-27 With the integration of the Whole Health System and the VHA priorities to provide veterans with the “soonest and best care,” more data are needed on the experiences of patients and support persons with various approaches to IDT pain care.²⁸ This study aimed to evaluate patient and support person experiences with a whole health-focused pain IDT that met simultaneously with the patient and support person during an initial evaluation. This study was approved by the institutional review board at the Salem VA Health Care System (SVAHCS) in Virginia.

Methods

The PREVAIL IDT Track is a clinical program offered at SVAHCS with a whole health-focused approach that involves patients and their support persons meeting simultaneously with a pain IDT. PREVAIL IDT Track is designed to help veterans more effectively self-manage chronic pain (Table 1).^6,29 Health care practitioners (HCPs) at SVAHCS recommended that veterans with pain persisting for > 3 months participate in PREVAIL IDT Track. After meeting with an advanced practice clinician for an intake, veterans elected to participate in the PREVAIL IDT Track program and completed the initial 6 weeks of pain education. Veterans were then invited to be evaluated by the pain IDT. A team including HCPs from interventional pain, psychology, pharmacy, nutrition, and physical therapy services met with the veteran for 60 minutes. Veterans were also invited to bring a support person to the IDT initial evaluation.

During the IDT initial evaluation, HCPs inquired about the patient’s mission, aspiration, and purpose (“If you were in less pain, what would you be doing more of?”) and about whole health self-care and wellness factors that may contribute to their chronic pain using the Personal Health Inventory.^30,31 Veterans were then invited to select 3 whole health self-care areas to focus on during the 6-month program.³ The IDT HCPs worked with the veteran to establish the treatment plan for the first month in the areas of self-care selected by the patient and made recommendations for additional treatments. If the veteran brought a support person to the IDT initial evaluation, their feedback was elicited throughout and at the end to ensure the final treatment plan and first month’s goals were realistic. At the end of the appointment, the veteran and their support person were asked to complete a program-specific satisfaction survey. The HCPs on the team and the veteran executed the treatment plan developed during the appointment, except for medication prescribing. Recommendations for medication changes are included in clinical notes. Veterans then received 5 monthly coaching calls from a nurse navigator with training in whole health and a 6-month follow-up appointment with the IDT HCPs to discuss a plan for continuity of care.

Participant demographic information was not collected, and participants were not compensated for completing the survey. Veterans in PREVAIL IDT Track are predominantly residents of central Appalachia, White, male, unemployed, have ≥ 1 mental and physical health comorbidity, and have a history of mental health treatment.³² Veterans participating in PREVAIL IDT had a mean age of 57 years, and about 1 in 3 have opioid prescriptions.³²

A program-specific 17-question satisfaction survey was developed, which included questions related to satisfaction with previous SVAHCS pain care and staff interactions. To assess the overall impression of the IDT initial evaluation, 3 yes/no questions and a 0 to 10-point scale were used. The 5 remaining open-ended questions allowed participants to give feedback about the IDT initial evaluation.

Data Analysis

A convergent mixed-methods approach was used to evaluate participant satisfaction with the initial IDT evaluation. The study team collected and analyzed quantitative and qualitative survey data and triangulated the findings.³³ For quantitative responses, frequencies and means were calculated using Python. For qualitative responses, thematic data analysis was conducted by systematic coding, using inductive methods and allowing themes to emerge. Study team members performed a line-by-line analysis of responses using NVivo to identify important codes and reach a consensus. This study adhered to the Consolidated Criteria for Reporting Qualitative Research and followed the National Institute for Health Care Excellence checklist.^34,35

Results

Quantitative Responses

In 2022, 168 veterans completed the initial IDT evaluation, and 144 (85.2%) completed the satisfaction survey and were included in this study. Thirty-two support persons who attended the initial IDT evaluation and completed the survey also were included. Of the 12 quantitative questions, 4 had a 100% completion rate, while 8 had ≤ 3% missing responses. When describing care prior to participating in PREVAIL, participants indicated a mean (SD) response of 4.6 (1.4) with the health care they received at SVAHCS and 4.3 (1.4) with SVAHCS pain management services, both on 6-point scales. All but 2 participants (98.9%) reported always being treated with courtesy and respect by PREVAIL HCPs during the initial IDT evaluation, with a mean (SD) score of 4.0 (0.2) on a 4-point scale. Most respondents (96.6%) reported that PREVAIL HCPs always listened carefully during the initial IDT evaluation, with a mean (SD) 4.0 (0.3) on a 4-point scale. Similarly, 92.6% reported that PREVAIL HCPs explained things clearly during the initial IDT evaluation, with a mean (SD) 3.9 (0.3) on a 4-point scale.

All respondents agreed that PREVAIL HCPs considered veteran preferences and those of their support persons in deciding their health care needs during the initial IDT evaluation, with a mean (SD) 3.7 (0.5) on a 4-point scale. Most respondents left the appointment with a good understanding of their responsibilities for chronic pain management with 99.4% (n = 169) strongly agreeing or agreeing (mean [SD] 3.6 [0.5]). A total of 135 respondents (79.4%) reported they left appointments with written information on their treatment plan. All 170 respondents reported that they would recommend PREVAIL to a friend, and 169 respondents (98.8%) felt that the initial PREVAIL IDT evaluation was a valuable use of time. Eighty-seven respondents (50.9%) rated the initial IDT evaluation as the “best clinical experience possible” with a mean (SD) score of 9.2 (1.1) on a 10-point scale (Table 2).

Qualitative Responses

Respondents provided complementary feedback on the program, with many participants stating that they enjoyed every aspect (eAppendix, available at doi:10.12788/fp.0503). In terms of positive aspects of the program, several themes emerged: participants appreciated meeting as an IDT, feeling cared for and listened to, learning more about their pain and ways to manage it, and specific services offered. Thirty-three of 144 respondents wanted longer appointment times. Twenty-two respondents suggested logistics improvements (eg, meeting in a larger room, having a written plan at the end, sending paperwork ahead of time, and later appointment times).

Discussion

Veterans and support persons were satisfied with the initial IDT evaluation for the PREVAIL whole health-focused pain clinical program for veterans predominantly residing in central Appalachia. These satisfaction findings are noteworthy since 20% of this same sample reported dissatisfaction with prior pain services, which could affect engagement and outcomes in pain care. In addition to high satisfaction levels, the PREVAIL IDT model may benefit veterans with limited resources. Rather than needing to attend several individual appointments, the PREVAIL IDT Track provides a 1-stop shop approach that decreases patient burden and barriers to care (eg, travel, transportation, and time) as well as health care system burden. For instance, schedulers need only to make 1 appointment for the veteran rather than several. This approach was highly acceptable to veterans served at SVAHCS and may increase the reach and impact of VHA IDT pain care.

The PREVAIL model may foster rapport with HCPs and encourage an active role in self-managing pain.^36,37 Participants noted that their preferences were considered and that they had a good understanding of their responsibilities for managing their chronic pain. This patient-centered approach, emphasizing an active role for the patient, is a hallmark of the VHA Whole Health System and aligns with the overarching PREVAIL IDT Track goal to enhance self-management skills, thus improving functioning through decreased pain interference.^14,38-41

Participants in PREVAIL provided substantial open-ended feedback that has contributed to the program’s improvement and may provide information into preferred components of pain IDT programs, particularly for rural veterans. When asked about their favorite component of the initial IDT evaluation, the most emergent theme was meeting simultaneously with HCPs on the IDT. This finding is significant, given that only 11% of IDTs involve direct patient interaction.

Furthermore, unlike most IDTs, PREVAIL IDT includes a dietitian.^11,42 IDT programs may benefit from dietitian involvement given the importance of the anti-inflammatory diet on chronic pain.^43-46 Participants recommended improvements, (eg, changes to the location and timing, adding a written treatment plan at the end of the appointment, and completing paperwork prior to the appointment) many of which have been addressed. The program now uses validated measures to track progress and comprehensive assessments of pain in response to calls for measurement-based care.^13,47 These process improvement suggestions may be instructive for other VA medical centers with rural populations.

Limitations

This study used a program-specific satisfaction survey with open-ended questions to allow for rich responses; however, the survey has not been validated. It also sought to minimize bias by asking participants to give completed surveys to staff members who were not HCPs on the IDT. However, participants’ responses may still have been influenced by this process. Response rate and demographics for support persons were impossible to determine. The results analyzed the responses of veterans and support persons together, which may have skewed the data. Future studies of pain IDT programs should consider analyzing responses from veterans and their support persons separately and identifying factors (eg, demographics or clinical characteristics) that influence the patients’ experiences while participating.

Conclusions

The initial PREVAIL IDT evaluation at SVAHCS is associated with high-levels of satisfaction. These veterans living in rural Appalachia, similar to the 4.4 million rural US veterans, are more likely to encounter barriers to care (eg, drive time, or transportation concerns) and be prescribed opioids.⁴⁸ These veterans are also at high risk of chronic physical and mental health comorbidities, drug misuse, overdose, and suicide.^49,50 Providing veterans in rural communities the opportunity to attend a single appointment with a pain IDT instead of requiring several individual appointments could improve the reach of evidence-based pain care.

This model of meeting simultaneously with all HCPs on the pain IDT may connect all veterans to the most available and best care, something prioritized by the VHA.28 The initial PREVAIL IDT evaluation also utilizes the Personal Health Inventory and the VHA Whole Health System Circle of Health to design patient-centered treatment plans. Integration of the Whole Health System is currently a high priority within VHA. The PREVAIL IDT Track model warrants additional efficacy research.

Chronic pain is one of the most prevalent public health concerns in the United States, affecting > 51 million adults with about $500 billion in health care costs.¹ Military veterans are among the most vulnerable subpopulations, with 65% of veterans reporting chronic pain in the last 3 months.² Chronic pain is complex, affecting the biopsychosocial-spiritual levels of human health, and requires multimodal and comprehensive treatment approaches.³ Hence, chronic pain treatment can be best delivered via interdisciplinary teams (IDTs) that use a patient-centered approach.^4,5

The Veterans Healthcare Administration (VHA) is a leader in developing and delivering interdisciplinary pain care.^6,7 VHA Directive 2009-053 requires every US Department of Veterans Affairs (VA) medical center to offer an IDT for chronic pain. However, VHA and non-VHA IDT programs vary significantly.^8-11 A recent systematic review found a median of 5 disciplines included on IDTs (range, 2-8), and program content often included exercise and education; only 11% of included IDTs met simultaneously with patients.¹¹ The heterogeneity of IDT programs has made determining best practices challenging.^8,11 The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials has denoted several core measures and measurement domains that were critical for determining the success of pain management interventions, including patient satisfaction.^12,13 Nevertheless, the association of IDTs with high patient satisfaction and improvement in pain measures has been documented.^5,11

The VHA has worked to implement the Whole Health System into health care, which considers well-being across physical, behavioral, spiritual, and socioeconomic domains. As such, the Whole Health System involves an interpersonal, team-based approach, “anchored in trusting longitudinal relationships to promote resilience, prevent disease, and restore health.”¹⁴ It aligns with the patient’s mission, aspiration, and purpose. Surgeon General VADM Vivek H. Murthy, MD, MBA, recently endorsed this approach.^15,16 Other health care systems adopting whole health tend to have higher patient satisfaction, increased access to care, and improved patient-reported outcomes.¹⁵ Within the VHA, the Whole Health System has shifted the conversation between clinicians and patients from “What is the matter with you?” to “What is important to you?” while emphasizing a proactive and personalized approach to health care.¹⁷ Rather than emphasizing passive modalities such as medications and clinician-led services (eg, interventional pain service), the Whole Health System highlights self-care.^3,17 Initial research findings within the VHA have been promising.^18-21 Whole health peer coaching calls appear to be an effective approach for veterans diagnosed with PTSD, and the use of whole health services is associated with a decrease in opioid use.^19,22 However, there are negligible data on patient experiences after meeting with a whole health-focused pain IDT, and studies to date have focused on urban populations.²³ One approach to IDT that has shown promise for other health issues involves a patient meeting simultaneously with all members of the IDT.^24-27 With the integration of the Whole Health System and the VHA priorities to provide veterans with the “soonest and best care,” more data are needed on the experiences of patients and support persons with various approaches to IDT pain care.²⁸ This study aimed to evaluate patient and support person experiences with a whole health-focused pain IDT that met simultaneously with the patient and support person during an initial evaluation. This study was approved by the institutional review board at the Salem VA Health Care System (SVAHCS) in Virginia.

Methods

The PREVAIL IDT Track is a clinical program offered at SVAHCS with a whole health-focused approach that involves patients and their support persons meeting simultaneously with a pain IDT. PREVAIL IDT Track is designed to help veterans more effectively self-manage chronic pain (Table 1).^6,29 Health care practitioners (HCPs) at SVAHCS recommended that veterans with pain persisting for > 3 months participate in PREVAIL IDT Track. After meeting with an advanced practice clinician for an intake, veterans elected to participate in the PREVAIL IDT Track program and completed the initial 6 weeks of pain education. Veterans were then invited to be evaluated by the pain IDT. A team including HCPs from interventional pain, psychology, pharmacy, nutrition, and physical therapy services met with the veteran for 60 minutes. Veterans were also invited to bring a support person to the IDT initial evaluation.

During the IDT initial evaluation, HCPs inquired about the patient’s mission, aspiration, and purpose (“If you were in less pain, what would you be doing more of?”) and about whole health self-care and wellness factors that may contribute to their chronic pain using the Personal Health Inventory.^30,31 Veterans were then invited to select 3 whole health self-care areas to focus on during the 6-month program.³ The IDT HCPs worked with the veteran to establish the treatment plan for the first month in the areas of self-care selected by the patient and made recommendations for additional treatments. If the veteran brought a support person to the IDT initial evaluation, their feedback was elicited throughout and at the end to ensure the final treatment plan and first month’s goals were realistic. At the end of the appointment, the veteran and their support person were asked to complete a program-specific satisfaction survey. The HCPs on the team and the veteran executed the treatment plan developed during the appointment, except for medication prescribing. Recommendations for medication changes are included in clinical notes. Veterans then received 5 monthly coaching calls from a nurse navigator with training in whole health and a 6-month follow-up appointment with the IDT HCPs to discuss a plan for continuity of care.

Participant demographic information was not collected, and participants were not compensated for completing the survey. Veterans in PREVAIL IDT Track are predominantly residents of central Appalachia, White, male, unemployed, have ≥ 1 mental and physical health comorbidity, and have a history of mental health treatment.³² Veterans participating in PREVAIL IDT had a mean age of 57 years, and about 1 in 3 have opioid prescriptions.³²

A program-specific 17-question satisfaction survey was developed, which included questions related to satisfaction with previous SVAHCS pain care and staff interactions. To assess the overall impression of the IDT initial evaluation, 3 yes/no questions and a 0 to 10-point scale were used. The 5 remaining open-ended questions allowed participants to give feedback about the IDT initial evaluation.

Data Analysis

A convergent mixed-methods approach was used to evaluate participant satisfaction with the initial IDT evaluation. The study team collected and analyzed quantitative and qualitative survey data and triangulated the findings.³³ For quantitative responses, frequencies and means were calculated using Python. For qualitative responses, thematic data analysis was conducted by systematic coding, using inductive methods and allowing themes to emerge. Study team members performed a line-by-line analysis of responses using NVivo to identify important codes and reach a consensus. This study adhered to the Consolidated Criteria for Reporting Qualitative Research and followed the National Institute for Health Care Excellence checklist.^34,35

Results

Quantitative Responses

In 2022, 168 veterans completed the initial IDT evaluation, and 144 (85.2%) completed the satisfaction survey and were included in this study. Thirty-two support persons who attended the initial IDT evaluation and completed the survey also were included. Of the 12 quantitative questions, 4 had a 100% completion rate, while 8 had ≤ 3% missing responses. When describing care prior to participating in PREVAIL, participants indicated a mean (SD) response of 4.6 (1.4) with the health care they received at SVAHCS and 4.3 (1.4) with SVAHCS pain management services, both on 6-point scales. All but 2 participants (98.9%) reported always being treated with courtesy and respect by PREVAIL HCPs during the initial IDT evaluation, with a mean (SD) score of 4.0 (0.2) on a 4-point scale. Most respondents (96.6%) reported that PREVAIL HCPs always listened carefully during the initial IDT evaluation, with a mean (SD) 4.0 (0.3) on a 4-point scale. Similarly, 92.6% reported that PREVAIL HCPs explained things clearly during the initial IDT evaluation, with a mean (SD) 3.9 (0.3) on a 4-point scale.

All respondents agreed that PREVAIL HCPs considered veteran preferences and those of their support persons in deciding their health care needs during the initial IDT evaluation, with a mean (SD) 3.7 (0.5) on a 4-point scale. Most respondents left the appointment with a good understanding of their responsibilities for chronic pain management with 99.4% (n = 169) strongly agreeing or agreeing (mean [SD] 3.6 [0.5]). A total of 135 respondents (79.4%) reported they left appointments with written information on their treatment plan. All 170 respondents reported that they would recommend PREVAIL to a friend, and 169 respondents (98.8%) felt that the initial PREVAIL IDT evaluation was a valuable use of time. Eighty-seven respondents (50.9%) rated the initial IDT evaluation as the “best clinical experience possible” with a mean (SD) score of 9.2 (1.1) on a 10-point scale (Table 2).

Qualitative Responses

Respondents provided complementary feedback on the program, with many participants stating that they enjoyed every aspect (eAppendix, available at doi:10.12788/fp.0503). In terms of positive aspects of the program, several themes emerged: participants appreciated meeting as an IDT, feeling cared for and listened to, learning more about their pain and ways to manage it, and specific services offered. Thirty-three of 144 respondents wanted longer appointment times. Twenty-two respondents suggested logistics improvements (eg, meeting in a larger room, having a written plan at the end, sending paperwork ahead of time, and later appointment times).

Discussion

Veterans and support persons were satisfied with the initial IDT evaluation for the PREVAIL whole health-focused pain clinical program for veterans predominantly residing in central Appalachia. These satisfaction findings are noteworthy since 20% of this same sample reported dissatisfaction with prior pain services, which could affect engagement and outcomes in pain care. In addition to high satisfaction levels, the PREVAIL IDT model may benefit veterans with limited resources. Rather than needing to attend several individual appointments, the PREVAIL IDT Track provides a 1-stop shop approach that decreases patient burden and barriers to care (eg, travel, transportation, and time) as well as health care system burden. For instance, schedulers need only to make 1 appointment for the veteran rather than several. This approach was highly acceptable to veterans served at SVAHCS and may increase the reach and impact of VHA IDT pain care.

The PREVAIL model may foster rapport with HCPs and encourage an active role in self-managing pain.^36,37 Participants noted that their preferences were considered and that they had a good understanding of their responsibilities for managing their chronic pain. This patient-centered approach, emphasizing an active role for the patient, is a hallmark of the VHA Whole Health System and aligns with the overarching PREVAIL IDT Track goal to enhance self-management skills, thus improving functioning through decreased pain interference.^14,38-41

Participants in PREVAIL provided substantial open-ended feedback that has contributed to the program’s improvement and may provide information into preferred components of pain IDT programs, particularly for rural veterans. When asked about their favorite component of the initial IDT evaluation, the most emergent theme was meeting simultaneously with HCPs on the IDT. This finding is significant, given that only 11% of IDTs involve direct patient interaction.

Furthermore, unlike most IDTs, PREVAIL IDT includes a dietitian.^11,42 IDT programs may benefit from dietitian involvement given the importance of the anti-inflammatory diet on chronic pain.^43-46 Participants recommended improvements, (eg, changes to the location and timing, adding a written treatment plan at the end of the appointment, and completing paperwork prior to the appointment) many of which have been addressed. The program now uses validated measures to track progress and comprehensive assessments of pain in response to calls for measurement-based care.^13,47 These process improvement suggestions may be instructive for other VA medical centers with rural populations.

Limitations

This study used a program-specific satisfaction survey with open-ended questions to allow for rich responses; however, the survey has not been validated. It also sought to minimize bias by asking participants to give completed surveys to staff members who were not HCPs on the IDT. However, participants’ responses may still have been influenced by this process. Response rate and demographics for support persons were impossible to determine. The results analyzed the responses of veterans and support persons together, which may have skewed the data. Future studies of pain IDT programs should consider analyzing responses from veterans and their support persons separately and identifying factors (eg, demographics or clinical characteristics) that influence the patients’ experiences while participating.

Conclusions

The initial PREVAIL IDT evaluation at SVAHCS is associated with high-levels of satisfaction. These veterans living in rural Appalachia, similar to the 4.4 million rural US veterans, are more likely to encounter barriers to care (eg, drive time, or transportation concerns) and be prescribed opioids.⁴⁸ These veterans are also at high risk of chronic physical and mental health comorbidities, drug misuse, overdose, and suicide.^49,50 Providing veterans in rural communities the opportunity to attend a single appointment with a pain IDT instead of requiring several individual appointments could improve the reach of evidence-based pain care.

This model of meeting simultaneously with all HCPs on the pain IDT may connect all veterans to the most available and best care, something prioritized by the VHA.28 The initial PREVAIL IDT evaluation also utilizes the Personal Health Inventory and the VHA Whole Health System Circle of Health to design patient-centered treatment plans. Integration of the Whole Health System is currently a high priority within VHA. The PREVAIL IDT Track model warrants additional efficacy research.

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

We have a tradition at Federal Practitioner where the December editorial usually features some version of the “best and worst” of the last 12 months in government health care. As we close out a difficult year, instead I offer a cautionary yet promising story that epitomizes both risk and benefit.

In some quarters, 2024 has been the year of AI (artificial intelligence).² While in science fiction, superhuman machines, like the Terminator, are often associated with apocalyptic threats, we often forget the positive models of human-technology interaction, such as the protective robot in Lost in Space. While AI is not yet as advanced as what has already been depicted on the screen, it is inextricably interwoven into the daily fabric of our lives. Almost any website you go to for business or pleasure has a chatbot waiting to help (or frustrate) you. Most of us have Alexa, Siri, or another digital assistant organizing our homes and schedules. When I Google “everyday uses of artificial intelligence,” it is AI that responds with an overview.

Medicine is not immune. Renowned physician and scientist Eric Topol, MD, suggests that AI represents a “fourth industrial revolution in medicine” that can dramatically improve health care.³ The US Department of Veterans Affairs (VA) has been at the forefront of this new space.⁴ The story recounted below encapsulates the enormous benefits AI can bring to health care and the vigilance we must exercise to anticipate and mitigate risk for this to be an overall positive transition.

The story begins with a key element of AI change—the machine learning predictive algorithm. In this case, the algorithm was designed to predict—and thereby prevent—the top public health priority in federal practice: suicide. The Recovery Engagement and Coordination for Health-Veterans Enhanced Treatment (REACH VET) program was launched in 2017 to assist in identifying the top 0.1% of veterans at the highest risk for suicide.⁵

At least at this stage of AI in medicine, the safest and most ethical efforts come from collaborations between health care professionals and AI developers that maximize the very different strengths of each partner. REACH VET is an exemplar of this kind of teamwork. Once the algorithm analyzes > 60 variables to identify veterans at high risk for suicide, data are communicated to a REACH VET program coordinator, who then notifies the practitioner responsible for the veteran’s care so they can put into action evidence-based suicide prevention strategies.⁵

VA researchers in 2021 published a study of 173,313 veterans comparing outcomes before and after entry into the program using a triple differences design. Veterans participating in the program reported an increase in outpatient visits and documentation of safety plans, and a decrease in emergency department visits, inpatient mental health admissions, and recorded suicide attempts.⁶

A US Government Accounting Office analysis found that “REACH VET had identified veterans who had not been identified through other methods.”⁷ This was not just an example of AI hype: as a relatively rare and statistically complicated phenomenon, suicide is notoriously difficult to predict and model. Machine learning algorithms like REACH VET have unprecedented potential to assist and augment suicide prevention.⁸

In 2023, veteran service organizations and journalists raised concerns that the AI algorithm was biased and ignored critical risk factors that put some veterans at increased risk. Based on their analysis, they claimed that the algorithm did not account for risk factors uniquely associated with women veterans, namely military sexual trauma and intimate partner violence.⁹ Women are the most rapidly growing VA population, yet too often they encounter health care disparities, harassment, and stigmatization when seeking care. The Congressional Veterans Affairs committees investigated and introduced legislation to update the algorithm.¹⁰

VA experts dispute these claims, and a computer science PhD may be required to understand the debate. But as the history of medicine has shown us, every treatment and procedure has benefits and risks. No matter how bright and shiny the technology initially appears, a soft scientific underbelly emerges sooner or later. Just as with REACH VET, algorithm bias is often discovered during deployment when the logic of the laboratory encounters the unpredictable variety of humankind.¹¹ Frequently, those problems are—as with REACH VET— not solely or even primarily technical ones. The data mirror society and reflect its biases.

For learning organizations like the VA and the US Department of Defense (DoD), the criticisms of REACH VET signal the need to engage in continuous performance improvement. AI requires the human trainers and supervisors who teach the machines to continuously revise and update their lesson plans. The most recent VA data show that in 2021, 6392 veterans died by suicide.¹² In Congressional testimony, VA leaders reported that as of May 2024, REACH VET was operating in 28 VA facilities and had identified 6700 high-risk veterans.13 REACH VET can save veteran’s lives, which is the sine qua non for our federal health care systems.

The algorithm should be improved to identify ALL veterans so they receive lifesaving interventions. Every veteran’s life is sacred; the algorithm that may prevent suicide must be continuously improved. That is why our representatives did not propose to ban REACH VET or enforce an AI winter on the VA and DoD. Instead, they called for an update to the algorithm, underscoring the value of machine learning for suicide prediction and prevention.

The epigraph from one of the top AI ethicists and scientists in the world makes the point that AI is not the moral agent here: it is fallible humans who must keep learning along with machines. That is why, at the end of 2024, VA experts are revising the algorithm so REACH VET can help prevent even more veteran suicides in 2025 and beyond.¹⁴

It is known that there are health-related consequences of migraine, as well as migraine-related comorbidities. Three recent studies examined the relationship between migraine and stroke, with nuanced results, suggesting that migraine does not necessarily increase stroke risk for all populations and may even be associated with a decreased risk for stroke for some patients. But it is clear that migraine is associated with an increased stroke risk for some specific populations, including during pregnancy.

Migraine is also known to have a negative impact on quality of life, affecting many different areas of well-being, including relationships, work productivity, and emotional health. Results from a recent study published in Cephalgia provided evidence that migraine can also increase the risk for occupational burnout.¹

Yet, there’s some good news for migraine patients who have a genetic predisposition for migraine. Results of a recent study published in the Journal of Clinical Medicine showed that hereditary predisposition to migraine does not necessarily correlate with development of chronic migraine.²

An observational study, with results published in Cephalgia in November 2024, included 646 patients aged 18-54 years who were hospitalized with their first stroke.³ It showed no significant association between cerebral small-vessel disease and migraine with aura among the study population. Interestingly, migraine with aura is generally more closely linked with stroke risk than migraine without aura, so the results do not align with previously held beliefs about migraine and stroke risk.⁴

A larger study examined the relationship between migraine and cardiovascular risk scores.⁴ This cohort study included 140,915 Dutch adults with a mean age of 44 years. Results, published in JAMA Network Open in October 2024, revealed that the odds of having prevalent or incident migraine decreased with increasing cardiovascular risk score categories, especially for women. The authors suggested that having migraine could be associated with a healthier cardiovascular system and suggested several potential mechanisms for this inverse relationship, including alterations in the activity of calcitonin gene–related peptide activity, changes in nitric oxide effects, or cortical spreading depression in response to atherosclerosis.

Although the results of these studies, which were focused on young patients, are interesting and could provide a sense of relief for patients with migraine, the authors of the JAMA Network Open article acknowledged that these results should not be extrapolated to other populations.⁴ Specifically, they noted that it has been established in other studies that older patients with migraine have an increased cardiovascular risk.

The relationship between migraine and stroke risk is important for pregnant women. Results of a large analysis including 19,825,525 pregnant patients, with data obtained from 2016 to 2020, were published in November 2024 in the Journal of Women’s Health.⁵ The analysis revealed that a history of migraine substantially increases the risk for hemorrhagic or ischemic stroke during pregnancy. They reported that “acute ischemic stroke was most strongly associated with migraine with aura (odds ratio [OR], 23.26; 95% confidence interval [CI], 18.46-29.31), followed by migraine without aura (OR, 8.15; 95% CI, 4.79-13.88).” The authors advised that stroke risk should be addressed in pregnant women who have migraine or who have a migraine history, especially if they have migraine with aura.

It is well known that migraine risk has a hereditary component, but hereditary factors might not play a role in the time of onset of migraines. In a retrospective clinical genetic case-control study that included over 15,000 participants, researchers identified migraine polygenic risk scores using genome-wide association studies.² The results were published in October 2024 in the Journal of Clinical Medicine. The study authors noted “a higher genetic risk was associated with earlier onset and increased risk for migraine well into adulthood, but not with chronification.” These results support the benefits of a diligent pursuit of effective migraine treatment, even for patients who might feel hopeless about achieving migraine control due to their own family history of migraine. As migraine therapies have evolved over the past decades, patients who had parents or other older family members with migraine may have a pessimistic outlook on the potential for effective treatment. However, newer therapies are far more effective than migraine treatments of the past, and patients should be informed and given encouragement that they can have a better prognosis and better migraine control than past generations.

The value of effective treatment cannot be underestimated. A study, with results published in Cephalgia in October 2024, included data from a subset of participants from the Negev Migraine Cohort, including 675 migraine patients and 232 control participants without migraine.¹ The authors reported that migraine patients reported “significantly higher levels of occupational burnout, with a mean burnout score of 3.46 vs a mean of 2.82 among controls.” They also noted that migraine patients worked longer hours, with 40 hours of work weekly vs 36 for controls. The authors suggested accommodations for migraine patients, such as working from home or flexible scheduling. Although this could be beneficial, achieving migraine relief would be even better for patients, who could eventually be able to enjoy having a 36-hour work week rather than a 40-hour work week. Admittedly, this potential outcome is an overly literal interpretation of the research results, but it emphasizes the potential value of having “more time” in patients’ lives as a result of effective migraine relief.

References

1. Peles I, Sharvit S, Zlotnik Y, et al. Migraine and work — beyond absenteeism: Migraine severity and occupational burnout — a cohort study. Cephalalgia. October 18, 2024. Source 

2. Chase BA, Frigerio R, Rubin S, et al. An integrative migraine polygenic risk score is associated with age at onset but not with chronification. J Clin Med. October 29, 2024. Source 

3. Cloet F, Gueyraud G, Lerebours F, Munio M, Larrue V, Gollion C. Stroke due to small-vessel disease and migraine: a case-control study of a young adult with ischemic stroke population. Cephalalgia. 2024;44:1-8. Source 

4. Al-Hassany L, MaassenVanDenBrink A, Kurth T. Cardiovascular risk scores and migraine status. JAMA Netw Open. October 22, 2024. Source 

5. Reddy M, Vazquez S, Nolan B, et al. Migraine and its association with stroke in pregnancy: A national examination. J Womens Health. 2024;33:1476-1481. Source 

It is known that there are health-related consequences of migraine, as well as migraine-related comorbidities. Three recent studies examined the relationship between migraine and stroke, with nuanced results, suggesting that migraine does not necessarily increase stroke risk for all populations and may even be associated with a decreased risk for stroke for some patients. But it is clear that migraine is associated with an increased stroke risk for some specific populations, including during pregnancy.

Migraine is also known to have a negative impact on quality of life, affecting many different areas of well-being, including relationships, work productivity, and emotional health. Results from a recent study published in Cephalgia provided evidence that migraine can also increase the risk for occupational burnout.¹

Yet, there’s some good news for migraine patients who have a genetic predisposition for migraine. Results of a recent study published in the Journal of Clinical Medicine showed that hereditary predisposition to migraine does not necessarily correlate with development of chronic migraine.²

An observational study, with results published in Cephalgia in November 2024, included 646 patients aged 18-54 years who were hospitalized with their first stroke.³ It showed no significant association between cerebral small-vessel disease and migraine with aura among the study population. Interestingly, migraine with aura is generally more closely linked with stroke risk than migraine without aura, so the results do not align with previously held beliefs about migraine and stroke risk.⁴

A larger study examined the relationship between migraine and cardiovascular risk scores.⁴ This cohort study included 140,915 Dutch adults with a mean age of 44 years. Results, published in JAMA Network Open in October 2024, revealed that the odds of having prevalent or incident migraine decreased with increasing cardiovascular risk score categories, especially for women. The authors suggested that having migraine could be associated with a healthier cardiovascular system and suggested several potential mechanisms for this inverse relationship, including alterations in the activity of calcitonin gene–related peptide activity, changes in nitric oxide effects, or cortical spreading depression in response to atherosclerosis.

Although the results of these studies, which were focused on young patients, are interesting and could provide a sense of relief for patients with migraine, the authors of the JAMA Network Open article acknowledged that these results should not be extrapolated to other populations.⁴ Specifically, they noted that it has been established in other studies that older patients with migraine have an increased cardiovascular risk.

The relationship between migraine and stroke risk is important for pregnant women. Results of a large analysis including 19,825,525 pregnant patients, with data obtained from 2016 to 2020, were published in November 2024 in the Journal of Women’s Health.⁵ The analysis revealed that a history of migraine substantially increases the risk for hemorrhagic or ischemic stroke during pregnancy. They reported that “acute ischemic stroke was most strongly associated with migraine with aura (odds ratio [OR], 23.26; 95% confidence interval [CI], 18.46-29.31), followed by migraine without aura (OR, 8.15; 95% CI, 4.79-13.88).” The authors advised that stroke risk should be addressed in pregnant women who have migraine or who have a migraine history, especially if they have migraine with aura.

It is well known that migraine risk has a hereditary component, but hereditary factors might not play a role in the time of onset of migraines. In a retrospective clinical genetic case-control study that included over 15,000 participants, researchers identified migraine polygenic risk scores using genome-wide association studies.² The results were published in October 2024 in the Journal of Clinical Medicine. The study authors noted “a higher genetic risk was associated with earlier onset and increased risk for migraine well into adulthood, but not with chronification.” These results support the benefits of a diligent pursuit of effective migraine treatment, even for patients who might feel hopeless about achieving migraine control due to their own family history of migraine. As migraine therapies have evolved over the past decades, patients who had parents or other older family members with migraine may have a pessimistic outlook on the potential for effective treatment. However, newer therapies are far more effective than migraine treatments of the past, and patients should be informed and given encouragement that they can have a better prognosis and better migraine control than past generations.

The value of effective treatment cannot be underestimated. A study, with results published in Cephalgia in October 2024, included data from a subset of participants from the Negev Migraine Cohort, including 675 migraine patients and 232 control participants without migraine.¹ The authors reported that migraine patients reported “significantly higher levels of occupational burnout, with a mean burnout score of 3.46 vs a mean of 2.82 among controls.” They also noted that migraine patients worked longer hours, with 40 hours of work weekly vs 36 for controls. The authors suggested accommodations for migraine patients, such as working from home or flexible scheduling. Although this could be beneficial, achieving migraine relief would be even better for patients, who could eventually be able to enjoy having a 36-hour work week rather than a 40-hour work week. Admittedly, this potential outcome is an overly literal interpretation of the research results, but it emphasizes the potential value of having “more time” in patients’ lives as a result of effective migraine relief.

References

1. Peles I, Sharvit S, Zlotnik Y, et al. Migraine and work — beyond absenteeism: Migraine severity and occupational burnout — a cohort study. Cephalalgia. October 18, 2024. Source 

2. Chase BA, Frigerio R, Rubin S, et al. An integrative migraine polygenic risk score is associated with age at onset but not with chronification. J Clin Med. October 29, 2024. Source 

3. Cloet F, Gueyraud G, Lerebours F, Munio M, Larrue V, Gollion C. Stroke due to small-vessel disease and migraine: a case-control study of a young adult with ischemic stroke population. Cephalalgia. 2024;44:1-8. Source 

4. Al-Hassany L, MaassenVanDenBrink A, Kurth T. Cardiovascular risk scores and migraine status. JAMA Netw Open. October 22, 2024. Source 

5. Reddy M, Vazquez S, Nolan B, et al. Migraine and its association with stroke in pregnancy: A national examination. J Womens Health. 2024;33:1476-1481. Source 

It is known that there are health-related consequences of migraine, as well as migraine-related comorbidities. Three recent studies examined the relationship between migraine and stroke, with nuanced results, suggesting that migraine does not necessarily increase stroke risk for all populations and may even be associated with a decreased risk for stroke for some patients. But it is clear that migraine is associated with an increased stroke risk for some specific populations, including during pregnancy.

Migraine is also known to have a negative impact on quality of life, affecting many different areas of well-being, including relationships, work productivity, and emotional health. Results from a recent study published in Cephalgia provided evidence that migraine can also increase the risk for occupational burnout.¹

Yet, there’s some good news for migraine patients who have a genetic predisposition for migraine. Results of a recent study published in the Journal of Clinical Medicine showed that hereditary predisposition to migraine does not necessarily correlate with development of chronic migraine.²

An observational study, with results published in Cephalgia in November 2024, included 646 patients aged 18-54 years who were hospitalized with their first stroke.³ It showed no significant association between cerebral small-vessel disease and migraine with aura among the study population. Interestingly, migraine with aura is generally more closely linked with stroke risk than migraine without aura, so the results do not align with previously held beliefs about migraine and stroke risk.⁴

A larger study examined the relationship between migraine and cardiovascular risk scores.⁴ This cohort study included 140,915 Dutch adults with a mean age of 44 years. Results, published in JAMA Network Open in October 2024, revealed that the odds of having prevalent or incident migraine decreased with increasing cardiovascular risk score categories, especially for women. The authors suggested that having migraine could be associated with a healthier cardiovascular system and suggested several potential mechanisms for this inverse relationship, including alterations in the activity of calcitonin gene–related peptide activity, changes in nitric oxide effects, or cortical spreading depression in response to atherosclerosis.

Although the results of these studies, which were focused on young patients, are interesting and could provide a sense of relief for patients with migraine, the authors of the JAMA Network Open article acknowledged that these results should not be extrapolated to other populations.⁴ Specifically, they noted that it has been established in other studies that older patients with migraine have an increased cardiovascular risk.

The relationship between migraine and stroke risk is important for pregnant women. Results of a large analysis including 19,825,525 pregnant patients, with data obtained from 2016 to 2020, were published in November 2024 in the Journal of Women’s Health.⁵ The analysis revealed that a history of migraine substantially increases the risk for hemorrhagic or ischemic stroke during pregnancy. They reported that “acute ischemic stroke was most strongly associated with migraine with aura (odds ratio [OR], 23.26; 95% confidence interval [CI], 18.46-29.31), followed by migraine without aura (OR, 8.15; 95% CI, 4.79-13.88).” The authors advised that stroke risk should be addressed in pregnant women who have migraine or who have a migraine history, especially if they have migraine with aura.

It is well known that migraine risk has a hereditary component, but hereditary factors might not play a role in the time of onset of migraines. In a retrospective clinical genetic case-control study that included over 15,000 participants, researchers identified migraine polygenic risk scores using genome-wide association studies.² The results were published in October 2024 in the Journal of Clinical Medicine. The study authors noted “a higher genetic risk was associated with earlier onset and increased risk for migraine well into adulthood, but not with chronification.” These results support the benefits of a diligent pursuit of effective migraine treatment, even for patients who might feel hopeless about achieving migraine control due to their own family history of migraine. As migraine therapies have evolved over the past decades, patients who had parents or other older family members with migraine may have a pessimistic outlook on the potential for effective treatment. However, newer therapies are far more effective than migraine treatments of the past, and patients should be informed and given encouragement that they can have a better prognosis and better migraine control than past generations.

The value of effective treatment cannot be underestimated. A study, with results published in Cephalgia in October 2024, included data from a subset of participants from the Negev Migraine Cohort, including 675 migraine patients and 232 control participants without migraine.¹ The authors reported that migraine patients reported “significantly higher levels of occupational burnout, with a mean burnout score of 3.46 vs a mean of 2.82 among controls.” They also noted that migraine patients worked longer hours, with 40 hours of work weekly vs 36 for controls. The authors suggested accommodations for migraine patients, such as working from home or flexible scheduling. Although this could be beneficial, achieving migraine relief would be even better for patients, who could eventually be able to enjoy having a 36-hour work week rather than a 40-hour work week. Admittedly, this potential outcome is an overly literal interpretation of the research results, but it emphasizes the potential value of having “more time” in patients’ lives as a result of effective migraine relief.

References

1. Peles I, Sharvit S, Zlotnik Y, et al. Migraine and work — beyond absenteeism: Migraine severity and occupational burnout — a cohort study. Cephalalgia. October 18, 2024. Source 

2. Chase BA, Frigerio R, Rubin S, et al. An integrative migraine polygenic risk score is associated with age at onset but not with chronification. J Clin Med. October 29, 2024. Source 

3. Cloet F, Gueyraud G, Lerebours F, Munio M, Larrue V, Gollion C. Stroke due to small-vessel disease and migraine: a case-control study of a young adult with ischemic stroke population. Cephalalgia. 2024;44:1-8. Source 

4. Al-Hassany L, MaassenVanDenBrink A, Kurth T. Cardiovascular risk scores and migraine status. JAMA Netw Open. October 22, 2024. Source 

5. Reddy M, Vazquez S, Nolan B, et al. Migraine and its association with stroke in pregnancy: A national examination. J Womens Health. 2024;33:1476-1481. Source 

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

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Formaldehyde (FA) is a colorless, flammable, highly pungent gas that remains ubiquitous in the environment despite being a known carcinogen and allergen.¹ In the cosmetic industry, FA commonly is used as both a preservative and active ingredient in hairstraightening products. Due to its toxicity and the thermal instability of FA releasers (ie, the release of FA at high temperatures), the US Food and Drug Administration has proposed a ban on formaldehyde and other FA-releasing chemicals (eg, methylene glycol) as an ingredient in hairsmoothing or hair-straightening products marketed in the United States.² However, the implementation of this ban is not yet in effect.

Hair-straightening products that are referred to as chemical relaxers typically contain alkaline derivatives. Alkaline hair straighteners—which include lye relaxers (active ingredient: sodium hydroxide), nolye relaxers (active ingredients: potassium hydroxide, lithium hydroxide, calcium hydroxide, guanidine hydroxide, or ammonium thioglycolate), and the Japanese hair straightening process (active ingredient: ammonium thioglycolate)—do not contain FA or FA-derivatives as active ingredients.³ Alternatively, acidic hair straighteners—popularly known as keratin treatments—contain either FA or FA-releasers and will be the primary focus of this discussion. As many patients are exposed to these products, we aim to highlight the cutaneous and systemic manifestations of acute and chronic exposure.

How Hair-Straightening Products Work

Hair straighteners that include FA or its derivatives generally contain high and low molecular weights of keratin peptides. The keratin peptides with high molecular weights diffuse into the cuticle while the low-molecular-weight peptides can penetrate further into the cortex of the hair shaft.⁴ Formaldehyde forms cross-links with the keratin amino acids (eg, tyrosine, arginine), and the application of heat via blow-drying enhances its ability to cross-link the hydrolyzed keratin from the straightening product to the natural keratin in the hair fibers; the use of a heated flat iron further enhances the cross-linking and seals the cuticle.⁵ The same mechanism of action applies for “safe keratin” (marketing terminology used for FA releasers) treatments, whereby the hydrogen and salt bonds of the hair are weakened, allowing for interconversion of the cysteine bonds of the hair fibers. This chemical conversion allows for the hair shafts to have a stable straight configuration. Of note, this mechanism of action differs from the action of chemical relaxers, which have a high pH and straighten the hair by opening the cuticles and permanently breaking the disulfide bonds in the cortex of the hair shaft—a process that restructures the keratin bonds without requiring heat application.⁵

The outcome of a keratin treatment, as seen on light microscopy, is the replenishment of gaps in the hair’s cuticle, therefore increasing its mechanical and thermal properties.⁶ This can give the appearance of increased shine, softness, and tensile strength. However, Sanad et al⁶ report that, as viewed on transmission electron microscopy, these keratin treatments do not repair lost cuticles, cuticle splitting, or detached cuticle layers from damaged strands.

Lastly, some patients notice lightening of their hair color after a hair-straightening treatment, which is possibly due to inhibition of the enzymatic synthesis of melanin, decomposition of melanin granules, or a direct reaction from chemical neutralizers with a high pH.⁶ Knowledge of the mechanism of action of hair-straightening treatments will aid dermatologists in educating patients about their immediate and long-term effects. This education subsequently will help patients avoid inappropriate hair care techniques that further damage the hair.

Environmental Distribution and Systemic Absorption of Formaldehyde

Atmospheric FA is absorbed via cutaneous and mucosal surfaces. Atmospheric FA concentrations produced when hair-straightening products are used cannot routinely be predicted because the amount generated depends on factors such as the pH of the preparation, the temperature to which the product is heated during straightening, duration of storage, and aeration and size of the environment in which the product is being used, among others.⁷

Peteffi et al⁷ and Aglan et al⁸ detected a moderate positive correlation between environmental FA concentrations and those in cosmetic products, particularly after blow-drying the hair or using other heat applications; however, the products examined by Peteffi et al⁷ contained exceedingly high concentrations of FA (up to 5.9%, which is higher than the legal limit of 0.1% in the United States).⁹ Of note, some products in this study were labelled as “formaldehyde free” but still contained high concentrations of FA.⁷ This is consistent with data published by the Occupational Health and Safety Administration, which citied salons with exposure limits outside the national recommendations (2.0 FA ppm/air).¹⁰ These findings highlight the inadvertent exposure that consumers face from products that are not regulated consistently.

Interestingly, Henault et al¹¹ observed that products with a high concentration of FA dispersed more airborne particles during hair brushing than hair straightening/ironing.¹¹ Further studies are needed to clarify the different routes and methods contributing to FA dispersion and the molecular instability of FA-releasers.

Clinical Correlation

Products that contain low (ie, less than the legal limit) levels of FA are not mandated to declare its presence on the product label; however, many products are contaminated with FA or inappropriately omit FA from the ingredient list, even at elevated concentrations. Consumers therefore may be inadvertently exposed to FA particles. Additionally, occupations with frequent exposure to FA include hairdressers, barbers, beauticians and related workers (33.6% exposure rate); sewers and embroiderers (26.1%); and cooks (19.1%).¹²

Adverse health effects associated with acute FA exposure include but are not limited to headache, eye irritation, allergic/irritant contact dermatitis, psoriasiform reactions, and acute kidney and respiratory tract injuries. Frontal fibrosing alopecia; non-Hodgkin lymphoma; and cancers of the upper digestive tract, lungs, and bladder also have been associated with chronic FA exposure.^7,13 In a cohort of female hairdressers, a longer duration of FA exposure (>8 years) as well as cumulative exposure were associated with an increase in ovarian cancer (OR, 1.48 [0.88 to 2.51]).¹² Formalin, the aqueous derivative of FA, also contains phenolic products that can mediate inflammatory response, DNA methylation, and carcinogenesis even with chronic low-level exposure.¹⁴ However, evidence supporting a direct correlation of FA exposure with breast carcinoma in both hairstylists and consumers remains controversial.⁷

Sanchez-Duenas et al¹⁵ described a case series of patients who were found to have psoriasiform scalp reactions after exposure to keratin treatments containing FA. The time to development of the lesions was inversely correlated with the number of treatments received, although the mean time to development was 12 months postprocedure.¹⁵ These researchers also identified no allergies to the substance on contact testing, which suggests an alternate pathogenesis as a consequence of FA exposure, resulting in the development of a psoriasiform reaction.¹⁵

Following adjustment for sex, age, menopause status, and skin color, frontal fibrosing alopecia also has been associated with the use of formalin and FA in hair straighteners.¹⁴ This is possibly related to the ability of FA and many phenolic products to induce chronic inflammation; however, a cumulative effect has not been noted consistently across the literature.

Future Directives

Continuous industry regulation is needed to ensure that use of FA is reduced and it is eventually eliminated from consumer products. Additionally, strict regulations are required to ensure products containing FA and FA-releasers are accurately labeled. Physicians and consumers should be aware of the potential health hazards associated with FA and advocate for effective legislation. While there is controversy regarding the level of absorption from environmental exposure and the subsequent biologic effects of absorption, both consumers and workers in industries such as hairdressing and barbering should reduce exposure time to FA and limit the application of heat and contact with products containing FA and FA releasers.

Formaldehyde (FA) is a colorless, flammable, highly pungent gas that remains ubiquitous in the environment despite being a known carcinogen and allergen.¹ In the cosmetic industry, FA commonly is used as both a preservative and active ingredient in hairstraightening products. Due to its toxicity and the thermal instability of FA releasers (ie, the release of FA at high temperatures), the US Food and Drug Administration has proposed a ban on formaldehyde and other FA-releasing chemicals (eg, methylene glycol) as an ingredient in hairsmoothing or hair-straightening products marketed in the United States.² However, the implementation of this ban is not yet in effect.

Hair-straightening products that are referred to as chemical relaxers typically contain alkaline derivatives. Alkaline hair straighteners—which include lye relaxers (active ingredient: sodium hydroxide), nolye relaxers (active ingredients: potassium hydroxide, lithium hydroxide, calcium hydroxide, guanidine hydroxide, or ammonium thioglycolate), and the Japanese hair straightening process (active ingredient: ammonium thioglycolate)—do not contain FA or FA-derivatives as active ingredients.³ Alternatively, acidic hair straighteners—popularly known as keratin treatments—contain either FA or FA-releasers and will be the primary focus of this discussion. As many patients are exposed to these products, we aim to highlight the cutaneous and systemic manifestations of acute and chronic exposure.

How Hair-Straightening Products Work

Hair straighteners that include FA or its derivatives generally contain high and low molecular weights of keratin peptides. The keratin peptides with high molecular weights diffuse into the cuticle while the low-molecular-weight peptides can penetrate further into the cortex of the hair shaft.⁴ Formaldehyde forms cross-links with the keratin amino acids (eg, tyrosine, arginine), and the application of heat via blow-drying enhances its ability to cross-link the hydrolyzed keratin from the straightening product to the natural keratin in the hair fibers; the use of a heated flat iron further enhances the cross-linking and seals the cuticle.⁵ The same mechanism of action applies for “safe keratin” (marketing terminology used for FA releasers) treatments, whereby the hydrogen and salt bonds of the hair are weakened, allowing for interconversion of the cysteine bonds of the hair fibers. This chemical conversion allows for the hair shafts to have a stable straight configuration. Of note, this mechanism of action differs from the action of chemical relaxers, which have a high pH and straighten the hair by opening the cuticles and permanently breaking the disulfide bonds in the cortex of the hair shaft—a process that restructures the keratin bonds without requiring heat application.⁵

The outcome of a keratin treatment, as seen on light microscopy, is the replenishment of gaps in the hair’s cuticle, therefore increasing its mechanical and thermal properties.⁶ This can give the appearance of increased shine, softness, and tensile strength. However, Sanad et al⁶ report that, as viewed on transmission electron microscopy, these keratin treatments do not repair lost cuticles, cuticle splitting, or detached cuticle layers from damaged strands.

Lastly, some patients notice lightening of their hair color after a hair-straightening treatment, which is possibly due to inhibition of the enzymatic synthesis of melanin, decomposition of melanin granules, or a direct reaction from chemical neutralizers with a high pH.⁶ Knowledge of the mechanism of action of hair-straightening treatments will aid dermatologists in educating patients about their immediate and long-term effects. This education subsequently will help patients avoid inappropriate hair care techniques that further damage the hair.

Environmental Distribution and Systemic Absorption of Formaldehyde

Atmospheric FA is absorbed via cutaneous and mucosal surfaces. Atmospheric FA concentrations produced when hair-straightening products are used cannot routinely be predicted because the amount generated depends on factors such as the pH of the preparation, the temperature to which the product is heated during straightening, duration of storage, and aeration and size of the environment in which the product is being used, among others.⁷

Peteffi et al⁷ and Aglan et al⁸ detected a moderate positive correlation between environmental FA concentrations and those in cosmetic products, particularly after blow-drying the hair or using other heat applications; however, the products examined by Peteffi et al⁷ contained exceedingly high concentrations of FA (up to 5.9%, which is higher than the legal limit of 0.1% in the United States).⁹ Of note, some products in this study were labelled as “formaldehyde free” but still contained high concentrations of FA.⁷ This is consistent with data published by the Occupational Health and Safety Administration, which citied salons with exposure limits outside the national recommendations (2.0 FA ppm/air).¹⁰ These findings highlight the inadvertent exposure that consumers face from products that are not regulated consistently.

Interestingly, Henault et al¹¹ observed that products with a high concentration of FA dispersed more airborne particles during hair brushing than hair straightening/ironing.¹¹ Further studies are needed to clarify the different routes and methods contributing to FA dispersion and the molecular instability of FA-releasers.

Clinical Correlation

Products that contain low (ie, less than the legal limit) levels of FA are not mandated to declare its presence on the product label; however, many products are contaminated with FA or inappropriately omit FA from the ingredient list, even at elevated concentrations. Consumers therefore may be inadvertently exposed to FA particles. Additionally, occupations with frequent exposure to FA include hairdressers, barbers, beauticians and related workers (33.6% exposure rate); sewers and embroiderers (26.1%); and cooks (19.1%).¹²

Adverse health effects associated with acute FA exposure include but are not limited to headache, eye irritation, allergic/irritant contact dermatitis, psoriasiform reactions, and acute kidney and respiratory tract injuries. Frontal fibrosing alopecia; non-Hodgkin lymphoma; and cancers of the upper digestive tract, lungs, and bladder also have been associated with chronic FA exposure.^7,13 In a cohort of female hairdressers, a longer duration of FA exposure (>8 years) as well as cumulative exposure were associated with an increase in ovarian cancer (OR, 1.48 [0.88 to 2.51]).¹² Formalin, the aqueous derivative of FA, also contains phenolic products that can mediate inflammatory response, DNA methylation, and carcinogenesis even with chronic low-level exposure.¹⁴ However, evidence supporting a direct correlation of FA exposure with breast carcinoma in both hairstylists and consumers remains controversial.⁷

Sanchez-Duenas et al¹⁵ described a case series of patients who were found to have psoriasiform scalp reactions after exposure to keratin treatments containing FA. The time to development of the lesions was inversely correlated with the number of treatments received, although the mean time to development was 12 months postprocedure.¹⁵ These researchers also identified no allergies to the substance on contact testing, which suggests an alternate pathogenesis as a consequence of FA exposure, resulting in the development of a psoriasiform reaction.¹⁵

Following adjustment for sex, age, menopause status, and skin color, frontal fibrosing alopecia also has been associated with the use of formalin and FA in hair straighteners.¹⁴ This is possibly related to the ability of FA and many phenolic products to induce chronic inflammation; however, a cumulative effect has not been noted consistently across the literature.

Future Directives

Continuous industry regulation is needed to ensure that use of FA is reduced and it is eventually eliminated from consumer products. Additionally, strict regulations are required to ensure products containing FA and FA-releasers are accurately labeled. Physicians and consumers should be aware of the potential health hazards associated with FA and advocate for effective legislation. While there is controversy regarding the level of absorption from environmental exposure and the subsequent biologic effects of absorption, both consumers and workers in industries such as hairdressing and barbering should reduce exposure time to FA and limit the application of heat and contact with products containing FA and FA releasers.

Formaldehyde (FA) is a colorless, flammable, highly pungent gas that remains ubiquitous in the environment despite being a known carcinogen and allergen.¹ In the cosmetic industry, FA commonly is used as both a preservative and active ingredient in hairstraightening products. Due to its toxicity and the thermal instability of FA releasers (ie, the release of FA at high temperatures), the US Food and Drug Administration has proposed a ban on formaldehyde and other FA-releasing chemicals (eg, methylene glycol) as an ingredient in hairsmoothing or hair-straightening products marketed in the United States.² However, the implementation of this ban is not yet in effect.

Hair-straightening products that are referred to as chemical relaxers typically contain alkaline derivatives. Alkaline hair straighteners—which include lye relaxers (active ingredient: sodium hydroxide), nolye relaxers (active ingredients: potassium hydroxide, lithium hydroxide, calcium hydroxide, guanidine hydroxide, or ammonium thioglycolate), and the Japanese hair straightening process (active ingredient: ammonium thioglycolate)—do not contain FA or FA-derivatives as active ingredients.³ Alternatively, acidic hair straighteners—popularly known as keratin treatments—contain either FA or FA-releasers and will be the primary focus of this discussion. As many patients are exposed to these products, we aim to highlight the cutaneous and systemic manifestations of acute and chronic exposure.

How Hair-Straightening Products Work

Hair straighteners that include FA or its derivatives generally contain high and low molecular weights of keratin peptides. The keratin peptides with high molecular weights diffuse into the cuticle while the low-molecular-weight peptides can penetrate further into the cortex of the hair shaft.⁴ Formaldehyde forms cross-links with the keratin amino acids (eg, tyrosine, arginine), and the application of heat via blow-drying enhances its ability to cross-link the hydrolyzed keratin from the straightening product to the natural keratin in the hair fibers; the use of a heated flat iron further enhances the cross-linking and seals the cuticle.⁵ The same mechanism of action applies for “safe keratin” (marketing terminology used for FA releasers) treatments, whereby the hydrogen and salt bonds of the hair are weakened, allowing for interconversion of the cysteine bonds of the hair fibers. This chemical conversion allows for the hair shafts to have a stable straight configuration. Of note, this mechanism of action differs from the action of chemical relaxers, which have a high pH and straighten the hair by opening the cuticles and permanently breaking the disulfide bonds in the cortex of the hair shaft—a process that restructures the keratin bonds without requiring heat application.⁵

The outcome of a keratin treatment, as seen on light microscopy, is the replenishment of gaps in the hair’s cuticle, therefore increasing its mechanical and thermal properties.⁶ This can give the appearance of increased shine, softness, and tensile strength. However, Sanad et al⁶ report that, as viewed on transmission electron microscopy, these keratin treatments do not repair lost cuticles, cuticle splitting, or detached cuticle layers from damaged strands.

Lastly, some patients notice lightening of their hair color after a hair-straightening treatment, which is possibly due to inhibition of the enzymatic synthesis of melanin, decomposition of melanin granules, or a direct reaction from chemical neutralizers with a high pH.⁶ Knowledge of the mechanism of action of hair-straightening treatments will aid dermatologists in educating patients about their immediate and long-term effects. This education subsequently will help patients avoid inappropriate hair care techniques that further damage the hair.

Environmental Distribution and Systemic Absorption of Formaldehyde

Atmospheric FA is absorbed via cutaneous and mucosal surfaces. Atmospheric FA concentrations produced when hair-straightening products are used cannot routinely be predicted because the amount generated depends on factors such as the pH of the preparation, the temperature to which the product is heated during straightening, duration of storage, and aeration and size of the environment in which the product is being used, among others.⁷

Peteffi et al⁷ and Aglan et al⁸ detected a moderate positive correlation between environmental FA concentrations and those in cosmetic products, particularly after blow-drying the hair or using other heat applications; however, the products examined by Peteffi et al⁷ contained exceedingly high concentrations of FA (up to 5.9%, which is higher than the legal limit of 0.1% in the United States).⁹ Of note, some products in this study were labelled as “formaldehyde free” but still contained high concentrations of FA.⁷ This is consistent with data published by the Occupational Health and Safety Administration, which citied salons with exposure limits outside the national recommendations (2.0 FA ppm/air).¹⁰ These findings highlight the inadvertent exposure that consumers face from products that are not regulated consistently.

Interestingly, Henault et al¹¹ observed that products with a high concentration of FA dispersed more airborne particles during hair brushing than hair straightening/ironing.¹¹ Further studies are needed to clarify the different routes and methods contributing to FA dispersion and the molecular instability of FA-releasers.

Clinical Correlation

Products that contain low (ie, less than the legal limit) levels of FA are not mandated to declare its presence on the product label; however, many products are contaminated with FA or inappropriately omit FA from the ingredient list, even at elevated concentrations. Consumers therefore may be inadvertently exposed to FA particles. Additionally, occupations with frequent exposure to FA include hairdressers, barbers, beauticians and related workers (33.6% exposure rate); sewers and embroiderers (26.1%); and cooks (19.1%).¹²

Adverse health effects associated with acute FA exposure include but are not limited to headache, eye irritation, allergic/irritant contact dermatitis, psoriasiform reactions, and acute kidney and respiratory tract injuries. Frontal fibrosing alopecia; non-Hodgkin lymphoma; and cancers of the upper digestive tract, lungs, and bladder also have been associated with chronic FA exposure.^7,13 In a cohort of female hairdressers, a longer duration of FA exposure (>8 years) as well as cumulative exposure were associated with an increase in ovarian cancer (OR, 1.48 [0.88 to 2.51]).¹² Formalin, the aqueous derivative of FA, also contains phenolic products that can mediate inflammatory response, DNA methylation, and carcinogenesis even with chronic low-level exposure.¹⁴ However, evidence supporting a direct correlation of FA exposure with breast carcinoma in both hairstylists and consumers remains controversial.⁷

Sanchez-Duenas et al¹⁵ described a case series of patients who were found to have psoriasiform scalp reactions after exposure to keratin treatments containing FA. The time to development of the lesions was inversely correlated with the number of treatments received, although the mean time to development was 12 months postprocedure.¹⁵ These researchers also identified no allergies to the substance on contact testing, which suggests an alternate pathogenesis as a consequence of FA exposure, resulting in the development of a psoriasiform reaction.¹⁵

Following adjustment for sex, age, menopause status, and skin color, frontal fibrosing alopecia also has been associated with the use of formalin and FA in hair straighteners.¹⁴ This is possibly related to the ability of FA and many phenolic products to induce chronic inflammation; however, a cumulative effect has not been noted consistently across the literature.

Future Directives

Continuous industry regulation is needed to ensure that use of FA is reduced and it is eventually eliminated from consumer products. Additionally, strict regulations are required to ensure products containing FA and FA-releasers are accurately labeled. Physicians and consumers should be aware of the potential health hazards associated with FA and advocate for effective legislation. While there is controversy regarding the level of absorption from environmental exposure and the subsequent biologic effects of absorption, both consumers and workers in industries such as hairdressing and barbering should reduce exposure time to FA and limit the application of heat and contact with products containing FA and FA releasers.

Androgenetic alopecia (AGA) is the most common type of hair loss after adolescence, with a high prevalence of 21.3% among males and 6.0% among females in China.¹ In men, AGA manifests as diffuse hair loss in the frontal and temporal areas of the scalp; in women, it is characterized by thinning of the hair on the top of the head with a wide part and less recession of the frontal line. Although the specific pathogenesis of AGA still is unclear, it is believed to be related mainly to genetics and androgen levels.¹ Androgenetic alopecia is not considered a life-threatening medical condition, but it can have a major impact on patients’ self-esteem and quality of life.

The prevalence of pediatric AGA has been steadily rising over the past few decades and is thought to be correlated to a hyperinsulinemic diet and elevated circulating androgens at younger ages, resulting in early onset in genetically susceptible children and adolescents.^2,3 Additionally, studies have shown that early-onset AGA is associated with metabolic syndrome,^4-6 which includes conditions such as obesity, insulin resistance, hyperglycemia, and dyslipidemia.^7,8 Furthermore, polycystic ovary syndrome (PCOS) is commonly observed in adolescent girls with early-onset AGA. The condition is associated with hormonal imbalances, particularly elevated androgens, which can contribute to the early onset of AGA. In girls, these hormonal changes may accelerate hair thinning and hair loss, making AGA a potential early indicator of underlying PCOS.^9,10

Available research on early-onset AGA in pediatric patients is limited, with most studies having a relatively small sample size and generalized findings. Data on pediatric AGA in China is scarce; therefore, the objective of this retrospective study was to analyze the clinical, laboratory, and trichoscopic features of AGA in 133 pediatric patients with AGA who visited the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University (Nanjing, China), from January 2010 to December 2023.

Methods

Study Population—Pediatric patients with early-onset AGA who were registered for outpatient consultations at the hair disease clinic of the Department of Dermatology at The First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were included. Patients aged 18 years and younger with a definitive diagnosis of AGA were selected for data collection and analysis. Any uncertain information was confirmed through telephone follow-up with patients.

Collection of Demographic Information and Laboratory Tests—Patient demographics and medical history including age, sex, age at disease onset, and duration of AGA were collected from the electronic medical record. Height and weight also were collected to calculate patients’ body mass index (BMI). Detailed laboratory test results were recorded, including assessments of sex hormone—binding globulin (SHBG), vitamin D, testosterone, and ferritin.

Analysis of Comorbidities—Due to the influence of genetic factors on body composition, there are differences in how obesity is defined across racial populations. The World Health Organization international standard defines the term overweight as a BMI greater than 25 and obese as a BMI greater than 30; however, the World Health Organization recommends a lower definition standard for these classifications in the Chinese population. China established specific BMI standards for classification of patients as overweight (24.0.27.9 kg/m²) and obese (≥28 kg/m²).¹¹ During outpatient consultations, a comprehensive medical history was obtained from each patient, including the presence of PCOS, acne, seborrheic dermatitis, hirsutism, and sleeping disorders. During routine outpatient assessments, experienced dermatologists (including W.F.) determined the presence of symptoms and confirmed the diagnosis.

Hair Loss Classification and Trichoscopy—Hair loss patterns for male patients were assessed using the basic and specific classification system, while the Ludwig scale was utilized for female patients.^12,13 Trichoscopy was utilized with high-resolution imaging systems and advanced software for image analysis, enabling precise assessment of hair in different scalp regions. Parameters such as hair density, hair diameter, percentage of terminal hairs, and percentage of vellus hair were recorded to monitor changes in hair growth for the patients.

Statistical Analysis—Categorical data were analyzed using the x² test. A P value less than .05 was considered statistically significant. All statistical analyses were conducted using SPSS software version 26 (IBM).

Results

Patient Characteristics and Hair Loss Patterns—A sample of 133 pediatric patients (60 males, 73 females) who were diagnosed with AGA at the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were selected. The mean age of the patients was 15.5 years (range, 10–18 years). The mean age was slightly lower in females compared with males (15.05 vs 16.19 years, respectively). Additionally, females showed earlier onset of the disease, with a mean age at onset of 13.41 years compared to 14.44 years in males. The time between onset of AGA symptoms and first seeking medical care ranged from 4 months to 3 years, with a mean disease duration of 1.72 years. There was no significant difference in the duration of disease between males and females (1.76 and 1.70 years, respectively). Patient characteristics by age group are summarized in eTable 1.

The pediatric patients in our study exhibited hair loss patterns similar to those typically observed in adults. Male patients typically showed diffuse thinning on the crown and varying degrees of temporal thinning, while female patients demonstrated diffuse thinning on the crown with a preserved frontal hairline; however, 5 (8.3%) male patients presented with Christmas tree– like pattern of hair loss with a preserved hairline and a thinning crown (Figures 1 and 2).

BMI and Comorbidities—Among our study sample, 27.1% (36/133) of patients were identified as overweight or obese. It came to our attention that the prevalence of patients who were overweight and obese was notably higher in patients aged older than 14 but younger than 18 years compared with those aged 14 years or younger (24.1% vs 3.0% [32/133 vs 4/133]). A more detailed analysis of patients who were overweight and obese is outlined in eTable 2.

Seborrheic dermatitis was identified as the most prevalent comorbidity associated with pediatric AGA (51.9% [69/133]), followed by acne (42.8% [57/133]), hirsutism (33.1% [44/133]), and sleep disturbances/insomnia (28.6% [38/133]). The prevalence of these comorbidities varied by age group, with a higher incidence observed among patients aged older than 14 years as compared to those aged 14 years or younger.

Family History of AGA—Our study results indicated that most (78.2% [104/133]) patients had a family history of AGA. Among males and females, 81.7% and 75.3% (49/60 and 55/73) had a positive family history, respectively. Further analysis showed that 43.3% (26/60) of males and 21.9% (16/73) of females reported AGA in their father, while 16.7% (10/60) of males and 35.6% insert (26/73) of females reported AGA in their mother. Both parents were affected in 21.7% (13/60) of male patients and 17.8% (13/73) of female patients (eTable 3).

Related Laboratory Tests of Pediatric Patients With AGA—The results of laboratory testing for vitamin D deficiency, low SHBG, high testosterone, and low ferritin levels in the study sample are outlined in eTable 4. Among the study participants, 15.9% (10/63) of females exhibited increased levels of both free and total testosterone. Low SHBG was observed in 47.1% (56/119) of patients, with a slightly higher proportion in males (48.2% [27/56] than females (46.0% [29/63]). Vitamin D deficiency was prevalent in 60.5% (72/119) of the study population, with a higher incidence rate in females (71.4%[45/63]) compared to males (48.2%[27/56]). Moreover, 21.8% (26/119) of pediatric patients had low ferritin levels, with a higher incidence rate in females (33.3%[21/63]) compared to males (8.9%[5/56]).

Female Patients With PCOS—In our study, 6 (8.2%) female patients with AGA had been diagnosed with PCOS prior to their referral to the First Affiliated Hospital of Nanjing Medical University. Information regarding their age at treatment, hair loss grade, comorbidities, and laboratory test results is provided in eTable 5.

Degree of Hair Loss at First Visit—In male pediatric patients with AGA, the majority were classified as M type according to the basic and specific classification. Specifically, the main hairloss level in males was concentrated in M1 and M2 (80.0% [48/60]), while specific type F was mainly distributed in F1 and F2 (81.7% [49/60]), and specific type V was mainly distributed in V1 and V2 (80.0% [48/60]). On the other hand, female patients were mainly (87.7% [64/73]) classified as type I or II in the Ludwig scale.

Clinical Features of Trichoscopy Examinations at First Visit—We present the trichoscopic findings of our study regarding hair characteristics, including hair density, hair diameter, terminal hair ratio, and vellus hair ratio, among male and female pediatric participants stratified into 2 age groups: 14 years or younger, and older than 14 but younger than 18 years. In males, those aged 14 years or younger had a lower average hair density than those older than 14 years but thicker hair diameter. Conversely, males aged 14 years and older were more likely to seek treatment of hair loss than those aged 14 years or younger. Among females, those older than 14 years had higher hair density, hair diameter, and terminal hair ratio than those younger than 14 years. Hair trichoscopy characteristics among pediatric patients with AGA in our study population were similar to those of adults with AGA (Figure 3).

Efficacy and Adverse Effects of Topical Minoxidil—There were 56 (42.1%) patients who had used topical minoxidil for more than 6 months: 33 (58.9%) males and 23 (41.1%) females. In terms of efficacy, 51 (91.1%) patients responded positively, demonstrating improved scalp coverage, increased hair density, or greater hair diameter. There were 2 (3.6%) cases of minor adverse reactions: 1 case of scalp itching with increased dandruff that improved with local symptomatic treatment, and 1 case of hirsutism, which improved after discontinuing the drug. Among the 28 (50.0%) pediatric patients who used topical minoxidil for more than 12 months, there were no reported adverse reactions. Overall, topical minoxidil was effective and well tolerated in pediatric patients, with mild adverse reactions.

Comment

In our study, the youngest AGA patient was 10 years old, which is slightly older than a 6-year-old patient reported in the literature.¹⁴ Females showed a higher incidence of AGA compared to males, which is consistent with some previous studies^14,15 but contradicts the findings of Gonzalez et al¹⁶ and Kim et al.¹⁷ We speculate that the differences in AGA incidence could be attributed to the diverse genetic background and racial disparities between the populations included in the study by Gonzalez et al¹⁶—primarily White patients from Europe and the United States—and our study, which included individuals from East Asia. Furthermore, variations in lifestyle and environment in Europe and the United States vs Asia (eg, dietary habits, stress, environmental pollution) may contribute to the differing sexspecific incidence rates. Additionally, our study showed that female patients tended to experience AGA at a younger age than male patients, as indicated by younger age of disease onset and at the initial visit. These findings are consistent with other studies reporting a slightly younger age of disease onset in female patients.^14,16,17 The importance lies in raising awareness among both patients and physicians about early-onset AGA, facilitating earlier detection, diagnosis, and treatment. Furthermore, our study revealed a higher prevalence of a positive family history of AGA in our study population (78.2%) compared to other studies.¹⁴ Paternal family history was more commonly observed than maternal history (81.7% and 75.3%, respectively); moreover, 19.5% of patients reported a positive family history of AGA in both parents. Therefore, it is essential to raise awareness among pediatric patients with a positive family history of AGA, as they may experience hair loss at a younger age.

Patients with AGA commonly present with concurrent skin conditions, most notably acne, seborrheic dermatitis, and hirsutism. Therefore, it is important to monitor these associated diseases and adopt appropriate treatments. Moreover, it is worth mentioning that a considerable number of pediatric patients reported experiencing sleep difficulties. It is well known that sleep disturbances can lead to hormonal abnormalities, which are also a risk factor for AGA.^18-20 Therefore, further research is needed to investigate whether treating sleep disturbances can delay onset or progression of pediatric AGA. A previous retrospective study reported a PCOS prevalence of 47.4% (9/19) in adolescent females with AGA,¹⁶ but our study observed a much lower incidence of 4.5%. This discrepancy may be due to the fact that diagnostic imaging was not required for all female patients suspected of having PCOS in our study, which may have resulted in the exclusion of some undiagnosed PCOS cases from the data analysis.

In our study, a considerable proportion of patients exhibited moderate hair loss at their first visit, and there were differences in hair density and diameter among different age groups, with female patients having finer hair than male patients. Therefore, it is necessary to raise awareness of and perform early diagnosis and treatment of AGA in pediatric patients presenting with hair loss. Upon evaluation of laboratory results, we observed a notable proportion of pediatric patients with AGA who had low levels of vitamin D, SHBG, and ferritin. Notably, female patients were more susceptible to low vitamin D levels compared with males. Screening for these indicators, particularly in female patients, could aid in the diagnosis and treatment of pediatric AGA. Surprisingly, testosterone levels did not show a significant increase in male patients with AGA. Furthermore, only a small percentage of female patients exhibited elevated testosterone levels, indicating that androgens may not play a dominant role in the pathogenesis of male pediatric AGA and that other factors and mechanisms may be involved. Although AGA has been extensively studied in adults, there is limited knowledge about its occurrence and characteristics in children and adolescents. Our study represents one of the few investigations into AGA in this population and is among the largest to explore the clinical features, laboratory testing and results, trichoscopic characteristics, and comorbidities in Chinese pediatric patients with AGA. Our findings offer valuable insights into early clinical characteristics of pediatric AGA in this specific demographic population to inform future research directions and clinical practice guidelines.

Given that we conducted a retrospective study with a relatively small sample size from a single clinic site, the generalizability of our research findings may be limited. In addition, the patients included in our study did not have frequent routine testing for metabolic and hormonal indicators to analyze further correlations between hormonal changes with severity of pediatric AGA. Future research with prospective multicenter designs and larger sample sizes are needed to increase representativeness and generalizability, and comprehensive testing is needed to validate and extend our findings. Furthermore, the psychological impact among pediatric patients with AGA warrants further investigation on early intervention to reduce psychological stress.

Besides enhancing the understanding of AGA in children and adolescents among dermatologists and pediatricians, there is a need for individualized, step-by-step, and comprehensive treatment. Initial assessment generally includes addressing hormonal disorders such as seborrheic dermatitis, folliculitis, PCOS, and acne. Some adult treatments may be effective in pediatric cases. In one study of 15 pediatric patients using minoxidil 5% daily (6 females, 4 males), 4 (66.7%) females had stable alopecia (follow-up, >6 months); 4 (44.4%) males using minoxidil 5% daily and 1 mg finasteride and 5 (55.6%) taking 1 mg of finasteride alone showed hair density gains.¹⁶ In another study,²¹ 373 adolescents with AGA (286 boys, 87 girls; age range, 10–17 years) were treated with topical minoxidil solution over an 18-month period, with 95.0% responding positively: 54.0% showed improved scalp coverage, and 41.0% experienced slower hair thinning. Topical minoxidil generally is well tolerated in pediatric patients with no significant impact on blood pressure, pulse rate, or other vital signs.²¹ The primary adverse reactions to topical minoxidil observed in clinical practice are mild scalp irritation and increased facial hair, which usually resolve upon discontinuation.²² In China, topical minoxidil (available in 2% or 5% concentrations) commonly is used in children and adolescents, with adjustments made based on treatment response and adverse effects. Despite its proven efficacy and tolerability, it is essential that adverse effects be promptly communicated to health care providers for appropriate dosage adjustments, and that concurrent conditions, such as vitamin D and iron deficiencies, be adequately managed. Encouraging patients to adhere to prescribed medications and undergo long-term follow-up typically results in favorable outcomes.

Androgenetic alopecia (AGA) is the most common type of hair loss after adolescence, with a high prevalence of 21.3% among males and 6.0% among females in China.¹ In men, AGA manifests as diffuse hair loss in the frontal and temporal areas of the scalp; in women, it is characterized by thinning of the hair on the top of the head with a wide part and less recession of the frontal line. Although the specific pathogenesis of AGA still is unclear, it is believed to be related mainly to genetics and androgen levels.¹ Androgenetic alopecia is not considered a life-threatening medical condition, but it can have a major impact on patients’ self-esteem and quality of life.

The prevalence of pediatric AGA has been steadily rising over the past few decades and is thought to be correlated to a hyperinsulinemic diet and elevated circulating androgens at younger ages, resulting in early onset in genetically susceptible children and adolescents.^2,3 Additionally, studies have shown that early-onset AGA is associated with metabolic syndrome,^4-6 which includes conditions such as obesity, insulin resistance, hyperglycemia, and dyslipidemia.^7,8 Furthermore, polycystic ovary syndrome (PCOS) is commonly observed in adolescent girls with early-onset AGA. The condition is associated with hormonal imbalances, particularly elevated androgens, which can contribute to the early onset of AGA. In girls, these hormonal changes may accelerate hair thinning and hair loss, making AGA a potential early indicator of underlying PCOS.^9,10

Available research on early-onset AGA in pediatric patients is limited, with most studies having a relatively small sample size and generalized findings. Data on pediatric AGA in China is scarce; therefore, the objective of this retrospective study was to analyze the clinical, laboratory, and trichoscopic features of AGA in 133 pediatric patients with AGA who visited the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University (Nanjing, China), from January 2010 to December 2023.

Methods

Study Population—Pediatric patients with early-onset AGA who were registered for outpatient consultations at the hair disease clinic of the Department of Dermatology at The First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were included. Patients aged 18 years and younger with a definitive diagnosis of AGA were selected for data collection and analysis. Any uncertain information was confirmed through telephone follow-up with patients.

Collection of Demographic Information and Laboratory Tests—Patient demographics and medical history including age, sex, age at disease onset, and duration of AGA were collected from the electronic medical record. Height and weight also were collected to calculate patients’ body mass index (BMI). Detailed laboratory test results were recorded, including assessments of sex hormone—binding globulin (SHBG), vitamin D, testosterone, and ferritin.

Analysis of Comorbidities—Due to the influence of genetic factors on body composition, there are differences in how obesity is defined across racial populations. The World Health Organization international standard defines the term overweight as a BMI greater than 25 and obese as a BMI greater than 30; however, the World Health Organization recommends a lower definition standard for these classifications in the Chinese population. China established specific BMI standards for classification of patients as overweight (24.0.27.9 kg/m²) and obese (≥28 kg/m²).¹¹ During outpatient consultations, a comprehensive medical history was obtained from each patient, including the presence of PCOS, acne, seborrheic dermatitis, hirsutism, and sleeping disorders. During routine outpatient assessments, experienced dermatologists (including W.F.) determined the presence of symptoms and confirmed the diagnosis.

Hair Loss Classification and Trichoscopy—Hair loss patterns for male patients were assessed using the basic and specific classification system, while the Ludwig scale was utilized for female patients.^12,13 Trichoscopy was utilized with high-resolution imaging systems and advanced software for image analysis, enabling precise assessment of hair in different scalp regions. Parameters such as hair density, hair diameter, percentage of terminal hairs, and percentage of vellus hair were recorded to monitor changes in hair growth for the patients.

Statistical Analysis—Categorical data were analyzed using the x² test. A P value less than .05 was considered statistically significant. All statistical analyses were conducted using SPSS software version 26 (IBM).

Results

Patient Characteristics and Hair Loss Patterns—A sample of 133 pediatric patients (60 males, 73 females) who were diagnosed with AGA at the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were selected. The mean age of the patients was 15.5 years (range, 10–18 years). The mean age was slightly lower in females compared with males (15.05 vs 16.19 years, respectively). Additionally, females showed earlier onset of the disease, with a mean age at onset of 13.41 years compared to 14.44 years in males. The time between onset of AGA symptoms and first seeking medical care ranged from 4 months to 3 years, with a mean disease duration of 1.72 years. There was no significant difference in the duration of disease between males and females (1.76 and 1.70 years, respectively). Patient characteristics by age group are summarized in eTable 1.

The pediatric patients in our study exhibited hair loss patterns similar to those typically observed in adults. Male patients typically showed diffuse thinning on the crown and varying degrees of temporal thinning, while female patients demonstrated diffuse thinning on the crown with a preserved frontal hairline; however, 5 (8.3%) male patients presented with Christmas tree– like pattern of hair loss with a preserved hairline and a thinning crown (Figures 1 and 2).

BMI and Comorbidities—Among our study sample, 27.1% (36/133) of patients were identified as overweight or obese. It came to our attention that the prevalence of patients who were overweight and obese was notably higher in patients aged older than 14 but younger than 18 years compared with those aged 14 years or younger (24.1% vs 3.0% [32/133 vs 4/133]). A more detailed analysis of patients who were overweight and obese is outlined in eTable 2.

Seborrheic dermatitis was identified as the most prevalent comorbidity associated with pediatric AGA (51.9% [69/133]), followed by acne (42.8% [57/133]), hirsutism (33.1% [44/133]), and sleep disturbances/insomnia (28.6% [38/133]). The prevalence of these comorbidities varied by age group, with a higher incidence observed among patients aged older than 14 years as compared to those aged 14 years or younger.

Family History of AGA—Our study results indicated that most (78.2% [104/133]) patients had a family history of AGA. Among males and females, 81.7% and 75.3% (49/60 and 55/73) had a positive family history, respectively. Further analysis showed that 43.3% (26/60) of males and 21.9% (16/73) of females reported AGA in their father, while 16.7% (10/60) of males and 35.6% insert (26/73) of females reported AGA in their mother. Both parents were affected in 21.7% (13/60) of male patients and 17.8% (13/73) of female patients (eTable 3).

Related Laboratory Tests of Pediatric Patients With AGA—The results of laboratory testing for vitamin D deficiency, low SHBG, high testosterone, and low ferritin levels in the study sample are outlined in eTable 4. Among the study participants, 15.9% (10/63) of females exhibited increased levels of both free and total testosterone. Low SHBG was observed in 47.1% (56/119) of patients, with a slightly higher proportion in males (48.2% [27/56] than females (46.0% [29/63]). Vitamin D deficiency was prevalent in 60.5% (72/119) of the study population, with a higher incidence rate in females (71.4%[45/63]) compared to males (48.2%[27/56]). Moreover, 21.8% (26/119) of pediatric patients had low ferritin levels, with a higher incidence rate in females (33.3%[21/63]) compared to males (8.9%[5/56]).

Female Patients With PCOS—In our study, 6 (8.2%) female patients with AGA had been diagnosed with PCOS prior to their referral to the First Affiliated Hospital of Nanjing Medical University. Information regarding their age at treatment, hair loss grade, comorbidities, and laboratory test results is provided in eTable 5.

Degree of Hair Loss at First Visit—In male pediatric patients with AGA, the majority were classified as M type according to the basic and specific classification. Specifically, the main hairloss level in males was concentrated in M1 and M2 (80.0% [48/60]), while specific type F was mainly distributed in F1 and F2 (81.7% [49/60]), and specific type V was mainly distributed in V1 and V2 (80.0% [48/60]). On the other hand, female patients were mainly (87.7% [64/73]) classified as type I or II in the Ludwig scale.

Clinical Features of Trichoscopy Examinations at First Visit—We present the trichoscopic findings of our study regarding hair characteristics, including hair density, hair diameter, terminal hair ratio, and vellus hair ratio, among male and female pediatric participants stratified into 2 age groups: 14 years or younger, and older than 14 but younger than 18 years. In males, those aged 14 years or younger had a lower average hair density than those older than 14 years but thicker hair diameter. Conversely, males aged 14 years and older were more likely to seek treatment of hair loss than those aged 14 years or younger. Among females, those older than 14 years had higher hair density, hair diameter, and terminal hair ratio than those younger than 14 years. Hair trichoscopy characteristics among pediatric patients with AGA in our study population were similar to those of adults with AGA (Figure 3).

Efficacy and Adverse Effects of Topical Minoxidil—There were 56 (42.1%) patients who had used topical minoxidil for more than 6 months: 33 (58.9%) males and 23 (41.1%) females. In terms of efficacy, 51 (91.1%) patients responded positively, demonstrating improved scalp coverage, increased hair density, or greater hair diameter. There were 2 (3.6%) cases of minor adverse reactions: 1 case of scalp itching with increased dandruff that improved with local symptomatic treatment, and 1 case of hirsutism, which improved after discontinuing the drug. Among the 28 (50.0%) pediatric patients who used topical minoxidil for more than 12 months, there were no reported adverse reactions. Overall, topical minoxidil was effective and well tolerated in pediatric patients, with mild adverse reactions.

Comment

In our study, the youngest AGA patient was 10 years old, which is slightly older than a 6-year-old patient reported in the literature.¹⁴ Females showed a higher incidence of AGA compared to males, which is consistent with some previous studies^14,15 but contradicts the findings of Gonzalez et al¹⁶ and Kim et al.¹⁷ We speculate that the differences in AGA incidence could be attributed to the diverse genetic background and racial disparities between the populations included in the study by Gonzalez et al¹⁶—primarily White patients from Europe and the United States—and our study, which included individuals from East Asia. Furthermore, variations in lifestyle and environment in Europe and the United States vs Asia (eg, dietary habits, stress, environmental pollution) may contribute to the differing sexspecific incidence rates. Additionally, our study showed that female patients tended to experience AGA at a younger age than male patients, as indicated by younger age of disease onset and at the initial visit. These findings are consistent with other studies reporting a slightly younger age of disease onset in female patients.^14,16,17 The importance lies in raising awareness among both patients and physicians about early-onset AGA, facilitating earlier detection, diagnosis, and treatment. Furthermore, our study revealed a higher prevalence of a positive family history of AGA in our study population (78.2%) compared to other studies.¹⁴ Paternal family history was more commonly observed than maternal history (81.7% and 75.3%, respectively); moreover, 19.5% of patients reported a positive family history of AGA in both parents. Therefore, it is essential to raise awareness among pediatric patients with a positive family history of AGA, as they may experience hair loss at a younger age.

Patients with AGA commonly present with concurrent skin conditions, most notably acne, seborrheic dermatitis, and hirsutism. Therefore, it is important to monitor these associated diseases and adopt appropriate treatments. Moreover, it is worth mentioning that a considerable number of pediatric patients reported experiencing sleep difficulties. It is well known that sleep disturbances can lead to hormonal abnormalities, which are also a risk factor for AGA.^18-20 Therefore, further research is needed to investigate whether treating sleep disturbances can delay onset or progression of pediatric AGA. A previous retrospective study reported a PCOS prevalence of 47.4% (9/19) in adolescent females with AGA,¹⁶ but our study observed a much lower incidence of 4.5%. This discrepancy may be due to the fact that diagnostic imaging was not required for all female patients suspected of having PCOS in our study, which may have resulted in the exclusion of some undiagnosed PCOS cases from the data analysis.

In our study, a considerable proportion of patients exhibited moderate hair loss at their first visit, and there were differences in hair density and diameter among different age groups, with female patients having finer hair than male patients. Therefore, it is necessary to raise awareness of and perform early diagnosis and treatment of AGA in pediatric patients presenting with hair loss. Upon evaluation of laboratory results, we observed a notable proportion of pediatric patients with AGA who had low levels of vitamin D, SHBG, and ferritin. Notably, female patients were more susceptible to low vitamin D levels compared with males. Screening for these indicators, particularly in female patients, could aid in the diagnosis and treatment of pediatric AGA. Surprisingly, testosterone levels did not show a significant increase in male patients with AGA. Furthermore, only a small percentage of female patients exhibited elevated testosterone levels, indicating that androgens may not play a dominant role in the pathogenesis of male pediatric AGA and that other factors and mechanisms may be involved. Although AGA has been extensively studied in adults, there is limited knowledge about its occurrence and characteristics in children and adolescents. Our study represents one of the few investigations into AGA in this population and is among the largest to explore the clinical features, laboratory testing and results, trichoscopic characteristics, and comorbidities in Chinese pediatric patients with AGA. Our findings offer valuable insights into early clinical characteristics of pediatric AGA in this specific demographic population to inform future research directions and clinical practice guidelines.

Given that we conducted a retrospective study with a relatively small sample size from a single clinic site, the generalizability of our research findings may be limited. In addition, the patients included in our study did not have frequent routine testing for metabolic and hormonal indicators to analyze further correlations between hormonal changes with severity of pediatric AGA. Future research with prospective multicenter designs and larger sample sizes are needed to increase representativeness and generalizability, and comprehensive testing is needed to validate and extend our findings. Furthermore, the psychological impact among pediatric patients with AGA warrants further investigation on early intervention to reduce psychological stress.

Besides enhancing the understanding of AGA in children and adolescents among dermatologists and pediatricians, there is a need for individualized, step-by-step, and comprehensive treatment. Initial assessment generally includes addressing hormonal disorders such as seborrheic dermatitis, folliculitis, PCOS, and acne. Some adult treatments may be effective in pediatric cases. In one study of 15 pediatric patients using minoxidil 5% daily (6 females, 4 males), 4 (66.7%) females had stable alopecia (follow-up, >6 months); 4 (44.4%) males using minoxidil 5% daily and 1 mg finasteride and 5 (55.6%) taking 1 mg of finasteride alone showed hair density gains.¹⁶ In another study,²¹ 373 adolescents with AGA (286 boys, 87 girls; age range, 10–17 years) were treated with topical minoxidil solution over an 18-month period, with 95.0% responding positively: 54.0% showed improved scalp coverage, and 41.0% experienced slower hair thinning. Topical minoxidil generally is well tolerated in pediatric patients with no significant impact on blood pressure, pulse rate, or other vital signs.²¹ The primary adverse reactions to topical minoxidil observed in clinical practice are mild scalp irritation and increased facial hair, which usually resolve upon discontinuation.²² In China, topical minoxidil (available in 2% or 5% concentrations) commonly is used in children and adolescents, with adjustments made based on treatment response and adverse effects. Despite its proven efficacy and tolerability, it is essential that adverse effects be promptly communicated to health care providers for appropriate dosage adjustments, and that concurrent conditions, such as vitamin D and iron deficiencies, be adequately managed. Encouraging patients to adhere to prescribed medications and undergo long-term follow-up typically results in favorable outcomes.

Androgenetic alopecia (AGA) is the most common type of hair loss after adolescence, with a high prevalence of 21.3% among males and 6.0% among females in China.¹ In men, AGA manifests as diffuse hair loss in the frontal and temporal areas of the scalp; in women, it is characterized by thinning of the hair on the top of the head with a wide part and less recession of the frontal line. Although the specific pathogenesis of AGA still is unclear, it is believed to be related mainly to genetics and androgen levels.¹ Androgenetic alopecia is not considered a life-threatening medical condition, but it can have a major impact on patients’ self-esteem and quality of life.

The prevalence of pediatric AGA has been steadily rising over the past few decades and is thought to be correlated to a hyperinsulinemic diet and elevated circulating androgens at younger ages, resulting in early onset in genetically susceptible children and adolescents.^2,3 Additionally, studies have shown that early-onset AGA is associated with metabolic syndrome,^4-6 which includes conditions such as obesity, insulin resistance, hyperglycemia, and dyslipidemia.^7,8 Furthermore, polycystic ovary syndrome (PCOS) is commonly observed in adolescent girls with early-onset AGA. The condition is associated with hormonal imbalances, particularly elevated androgens, which can contribute to the early onset of AGA. In girls, these hormonal changes may accelerate hair thinning and hair loss, making AGA a potential early indicator of underlying PCOS.^9,10

Available research on early-onset AGA in pediatric patients is limited, with most studies having a relatively small sample size and generalized findings. Data on pediatric AGA in China is scarce; therefore, the objective of this retrospective study was to analyze the clinical, laboratory, and trichoscopic features of AGA in 133 pediatric patients with AGA who visited the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University (Nanjing, China), from January 2010 to December 2023.

Methods

Study Population—Pediatric patients with early-onset AGA who were registered for outpatient consultations at the hair disease clinic of the Department of Dermatology at The First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were included. Patients aged 18 years and younger with a definitive diagnosis of AGA were selected for data collection and analysis. Any uncertain information was confirmed through telephone follow-up with patients.

Collection of Demographic Information and Laboratory Tests—Patient demographics and medical history including age, sex, age at disease onset, and duration of AGA were collected from the electronic medical record. Height and weight also were collected to calculate patients’ body mass index (BMI). Detailed laboratory test results were recorded, including assessments of sex hormone—binding globulin (SHBG), vitamin D, testosterone, and ferritin.

Analysis of Comorbidities—Due to the influence of genetic factors on body composition, there are differences in how obesity is defined across racial populations. The World Health Organization international standard defines the term overweight as a BMI greater than 25 and obese as a BMI greater than 30; however, the World Health Organization recommends a lower definition standard for these classifications in the Chinese population. China established specific BMI standards for classification of patients as overweight (24.0.27.9 kg/m²) and obese (≥28 kg/m²).¹¹ During outpatient consultations, a comprehensive medical history was obtained from each patient, including the presence of PCOS, acne, seborrheic dermatitis, hirsutism, and sleeping disorders. During routine outpatient assessments, experienced dermatologists (including W.F.) determined the presence of symptoms and confirmed the diagnosis.

Hair Loss Classification and Trichoscopy—Hair loss patterns for male patients were assessed using the basic and specific classification system, while the Ludwig scale was utilized for female patients.^12,13 Trichoscopy was utilized with high-resolution imaging systems and advanced software for image analysis, enabling precise assessment of hair in different scalp regions. Parameters such as hair density, hair diameter, percentage of terminal hairs, and percentage of vellus hair were recorded to monitor changes in hair growth for the patients.

Statistical Analysis—Categorical data were analyzed using the x² test. A P value less than .05 was considered statistically significant. All statistical analyses were conducted using SPSS software version 26 (IBM).

Results

Patient Characteristics and Hair Loss Patterns—A sample of 133 pediatric patients (60 males, 73 females) who were diagnosed with AGA at the hair disease clinic of the Department of Dermatology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to December 2023 were selected. The mean age of the patients was 15.5 years (range, 10–18 years). The mean age was slightly lower in females compared with males (15.05 vs 16.19 years, respectively). Additionally, females showed earlier onset of the disease, with a mean age at onset of 13.41 years compared to 14.44 years in males. The time between onset of AGA symptoms and first seeking medical care ranged from 4 months to 3 years, with a mean disease duration of 1.72 years. There was no significant difference in the duration of disease between males and females (1.76 and 1.70 years, respectively). Patient characteristics by age group are summarized in eTable 1.

The pediatric patients in our study exhibited hair loss patterns similar to those typically observed in adults. Male patients typically showed diffuse thinning on the crown and varying degrees of temporal thinning, while female patients demonstrated diffuse thinning on the crown with a preserved frontal hairline; however, 5 (8.3%) male patients presented with Christmas tree– like pattern of hair loss with a preserved hairline and a thinning crown (Figures 1 and 2).

BMI and Comorbidities—Among our study sample, 27.1% (36/133) of patients were identified as overweight or obese. It came to our attention that the prevalence of patients who were overweight and obese was notably higher in patients aged older than 14 but younger than 18 years compared with those aged 14 years or younger (24.1% vs 3.0% [32/133 vs 4/133]). A more detailed analysis of patients who were overweight and obese is outlined in eTable 2.

Seborrheic dermatitis was identified as the most prevalent comorbidity associated with pediatric AGA (51.9% [69/133]), followed by acne (42.8% [57/133]), hirsutism (33.1% [44/133]), and sleep disturbances/insomnia (28.6% [38/133]). The prevalence of these comorbidities varied by age group, with a higher incidence observed among patients aged older than 14 years as compared to those aged 14 years or younger.

Family History of AGA—Our study results indicated that most (78.2% [104/133]) patients had a family history of AGA. Among males and females, 81.7% and 75.3% (49/60 and 55/73) had a positive family history, respectively. Further analysis showed that 43.3% (26/60) of males and 21.9% (16/73) of females reported AGA in their father, while 16.7% (10/60) of males and 35.6% insert (26/73) of females reported AGA in their mother. Both parents were affected in 21.7% (13/60) of male patients and 17.8% (13/73) of female patients (eTable 3).

Related Laboratory Tests of Pediatric Patients With AGA—The results of laboratory testing for vitamin D deficiency, low SHBG, high testosterone, and low ferritin levels in the study sample are outlined in eTable 4. Among the study participants, 15.9% (10/63) of females exhibited increased levels of both free and total testosterone. Low SHBG was observed in 47.1% (56/119) of patients, with a slightly higher proportion in males (48.2% [27/56] than females (46.0% [29/63]). Vitamin D deficiency was prevalent in 60.5% (72/119) of the study population, with a higher incidence rate in females (71.4%[45/63]) compared to males (48.2%[27/56]). Moreover, 21.8% (26/119) of pediatric patients had low ferritin levels, with a higher incidence rate in females (33.3%[21/63]) compared to males (8.9%[5/56]).

Female Patients With PCOS—In our study, 6 (8.2%) female patients with AGA had been diagnosed with PCOS prior to their referral to the First Affiliated Hospital of Nanjing Medical University. Information regarding their age at treatment, hair loss grade, comorbidities, and laboratory test results is provided in eTable 5.

Degree of Hair Loss at First Visit—In male pediatric patients with AGA, the majority were classified as M type according to the basic and specific classification. Specifically, the main hairloss level in males was concentrated in M1 and M2 (80.0% [48/60]), while specific type F was mainly distributed in F1 and F2 (81.7% [49/60]), and specific type V was mainly distributed in V1 and V2 (80.0% [48/60]). On the other hand, female patients were mainly (87.7% [64/73]) classified as type I or II in the Ludwig scale.

Clinical Features of Trichoscopy Examinations at First Visit—We present the trichoscopic findings of our study regarding hair characteristics, including hair density, hair diameter, terminal hair ratio, and vellus hair ratio, among male and female pediatric participants stratified into 2 age groups: 14 years or younger, and older than 14 but younger than 18 years. In males, those aged 14 years or younger had a lower average hair density than those older than 14 years but thicker hair diameter. Conversely, males aged 14 years and older were more likely to seek treatment of hair loss than those aged 14 years or younger. Among females, those older than 14 years had higher hair density, hair diameter, and terminal hair ratio than those younger than 14 years. Hair trichoscopy characteristics among pediatric patients with AGA in our study population were similar to those of adults with AGA (Figure 3).

Efficacy and Adverse Effects of Topical Minoxidil—There were 56 (42.1%) patients who had used topical minoxidil for more than 6 months: 33 (58.9%) males and 23 (41.1%) females. In terms of efficacy, 51 (91.1%) patients responded positively, demonstrating improved scalp coverage, increased hair density, or greater hair diameter. There were 2 (3.6%) cases of minor adverse reactions: 1 case of scalp itching with increased dandruff that improved with local symptomatic treatment, and 1 case of hirsutism, which improved after discontinuing the drug. Among the 28 (50.0%) pediatric patients who used topical minoxidil for more than 12 months, there were no reported adverse reactions. Overall, topical minoxidil was effective and well tolerated in pediatric patients, with mild adverse reactions.

Comment

In our study, the youngest AGA patient was 10 years old, which is slightly older than a 6-year-old patient reported in the literature.¹⁴ Females showed a higher incidence of AGA compared to males, which is consistent with some previous studies^14,15 but contradicts the findings of Gonzalez et al¹⁶ and Kim et al.¹⁷ We speculate that the differences in AGA incidence could be attributed to the diverse genetic background and racial disparities between the populations included in the study by Gonzalez et al¹⁶—primarily White patients from Europe and the United States—and our study, which included individuals from East Asia. Furthermore, variations in lifestyle and environment in Europe and the United States vs Asia (eg, dietary habits, stress, environmental pollution) may contribute to the differing sexspecific incidence rates. Additionally, our study showed that female patients tended to experience AGA at a younger age than male patients, as indicated by younger age of disease onset and at the initial visit. These findings are consistent with other studies reporting a slightly younger age of disease onset in female patients.^14,16,17 The importance lies in raising awareness among both patients and physicians about early-onset AGA, facilitating earlier detection, diagnosis, and treatment. Furthermore, our study revealed a higher prevalence of a positive family history of AGA in our study population (78.2%) compared to other studies.¹⁴ Paternal family history was more commonly observed than maternal history (81.7% and 75.3%, respectively); moreover, 19.5% of patients reported a positive family history of AGA in both parents. Therefore, it is essential to raise awareness among pediatric patients with a positive family history of AGA, as they may experience hair loss at a younger age.

Patients with AGA commonly present with concurrent skin conditions, most notably acne, seborrheic dermatitis, and hirsutism. Therefore, it is important to monitor these associated diseases and adopt appropriate treatments. Moreover, it is worth mentioning that a considerable number of pediatric patients reported experiencing sleep difficulties. It is well known that sleep disturbances can lead to hormonal abnormalities, which are also a risk factor for AGA.^18-20 Therefore, further research is needed to investigate whether treating sleep disturbances can delay onset or progression of pediatric AGA. A previous retrospective study reported a PCOS prevalence of 47.4% (9/19) in adolescent females with AGA,¹⁶ but our study observed a much lower incidence of 4.5%. This discrepancy may be due to the fact that diagnostic imaging was not required for all female patients suspected of having PCOS in our study, which may have resulted in the exclusion of some undiagnosed PCOS cases from the data analysis.

In our study, a considerable proportion of patients exhibited moderate hair loss at their first visit, and there were differences in hair density and diameter among different age groups, with female patients having finer hair than male patients. Therefore, it is necessary to raise awareness of and perform early diagnosis and treatment of AGA in pediatric patients presenting with hair loss. Upon evaluation of laboratory results, we observed a notable proportion of pediatric patients with AGA who had low levels of vitamin D, SHBG, and ferritin. Notably, female patients were more susceptible to low vitamin D levels compared with males. Screening for these indicators, particularly in female patients, could aid in the diagnosis and treatment of pediatric AGA. Surprisingly, testosterone levels did not show a significant increase in male patients with AGA. Furthermore, only a small percentage of female patients exhibited elevated testosterone levels, indicating that androgens may not play a dominant role in the pathogenesis of male pediatric AGA and that other factors and mechanisms may be involved. Although AGA has been extensively studied in adults, there is limited knowledge about its occurrence and characteristics in children and adolescents. Our study represents one of the few investigations into AGA in this population and is among the largest to explore the clinical features, laboratory testing and results, trichoscopic characteristics, and comorbidities in Chinese pediatric patients with AGA. Our findings offer valuable insights into early clinical characteristics of pediatric AGA in this specific demographic population to inform future research directions and clinical practice guidelines.

Given that we conducted a retrospective study with a relatively small sample size from a single clinic site, the generalizability of our research findings may be limited. In addition, the patients included in our study did not have frequent routine testing for metabolic and hormonal indicators to analyze further correlations between hormonal changes with severity of pediatric AGA. Future research with prospective multicenter designs and larger sample sizes are needed to increase representativeness and generalizability, and comprehensive testing is needed to validate and extend our findings. Furthermore, the psychological impact among pediatric patients with AGA warrants further investigation on early intervention to reduce psychological stress.

Besides enhancing the understanding of AGA in children and adolescents among dermatologists and pediatricians, there is a need for individualized, step-by-step, and comprehensive treatment. Initial assessment generally includes addressing hormonal disorders such as seborrheic dermatitis, folliculitis, PCOS, and acne. Some adult treatments may be effective in pediatric cases. In one study of 15 pediatric patients using minoxidil 5% daily (6 females, 4 males), 4 (66.7%) females had stable alopecia (follow-up, >6 months); 4 (44.4%) males using minoxidil 5% daily and 1 mg finasteride and 5 (55.6%) taking 1 mg of finasteride alone showed hair density gains.¹⁶ In another study,²¹ 373 adolescents with AGA (286 boys, 87 girls; age range, 10–17 years) were treated with topical minoxidil solution over an 18-month period, with 95.0% responding positively: 54.0% showed improved scalp coverage, and 41.0% experienced slower hair thinning. Topical minoxidil generally is well tolerated in pediatric patients with no significant impact on blood pressure, pulse rate, or other vital signs.²¹ The primary adverse reactions to topical minoxidil observed in clinical practice are mild scalp irritation and increased facial hair, which usually resolve upon discontinuation.²² In China, topical minoxidil (available in 2% or 5% concentrations) commonly is used in children and adolescents, with adjustments made based on treatment response and adverse effects. Despite its proven efficacy and tolerability, it is essential that adverse effects be promptly communicated to health care providers for appropriate dosage adjustments, and that concurrent conditions, such as vitamin D and iron deficiencies, be adequately managed. Encouraging patients to adhere to prescribed medications and undergo long-term follow-up typically results in favorable outcomes.