Mixed Topics

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

Celery (Apium graveolens)—that lowly vegetable that often languishes in the refrigerator crisper and apparently supplies fewer calories than are required to consume it—contains a myriad of photosensitizing chemicals known as furocoumarins and psoralens that can cause phytophotodermatitis (PPD) when handled prior to exposure to UV light.¹ Individuals who are most likely to develop PPD caused by repeated contact with celery include food industry workers (eg, grocery store workers, farmers) who pick, handle, or prepare celery for consumption. While eating celery as part of a standard diet is highly unlikely to cause PPD, celery infected with Sclerotinia sclerotiorum (known as pink rot) causes more severe generalized sun sensitivity due to an increased amount of furocoumarins produced in response to the fungus.² Contact with celery also can induce cutaneous manifestations unrelated to sun exposure in some individuals, including urticaria, allergic contact dermatitis, and anaphylaxis.³ In this article, we provide an overview of the life cycle and origin of celery as well as its irritant and allergic properties. We also describe cutaneous rashes associated with PPD caused by exposure to celery and highlight treatment options.

Morphology and Distribution

The Apiaceae family features aromatic flowering plants that comprise more than 3500 species, including many economically important vegetables, herbs, and spices.⁴ It also includes many alkaloid-containing species that are known to be poisonous to humans, such as poison hemlock (Conium maculatum) and water hemlock (Cicuta maculate). Most Apiaceae plants that are consumed by humans originate from the Mediterranean region.⁵ While known for their diversity of flavor and aroma, most of the plants from this family have low caloric value and provide minimal amounts of energy.

Members of the Apiaceae family have flowers that create a classic umbel shape mimicking the appearance of an upside-down umbrella (thus the former name for this family, Umbelliferae). The pedicles—the small stems attached to the base of each flower—spread from a common center to form the umbel.⁵ The Apiaceae family also includes the greatest number of plants that cause PPD due to their high concentration of furocoumarins, which deter fungus from harming the plants.⁶

A biennial plant, celery completes its life cycle in 2 years. During the first season, the stems, roots, and leaves sprout; in the second and final year, the flowers, fruits, and seeds proliferate, followed by decomposition. Apium graveolens approaches heights of 2 to 3 ft, growing upright and displaying grooved stems. Each stem terminates in a basal rosette of leaves. The second season brings white flower blooms in terminal or axillary umbels.⁷

Celery originated in the temperate Mediterranean regions of Europe, but farmers now cultivate it globally.⁸ It grows best in rich moist soil with full exposure to sunlight. Plants multiply their numbers through self-seeding. Celery commonly is found in suburban and rural homes, both in refrigerators for consumption as well as in medicine cabinets in capsule form for the treatment of arthritis.⁴

Irritant and Allergenic Properties

Despite the potential health benefits of celery, the Apiaceae family, which includes hogweed, dill, and fennel, prevails as the most common culprit for phytotoxic reactions. The Rutaceae family, including citrus plants and rue, remains runner-up for causes of PPD.⁹ Phytophotodermatitis is not an immunologic reaction, making anyone susceptible to formation of the cutaneous lesions when exposed to UV light after handling celery. Pruritis rarely occurs, unlike in allergic phytodermatitis.¹⁰ Upon photoexcitation from exposure to UVA light, individual psoralen molecules covalently bind to pyrimidine bases, causing interstrand cross-linking that prevents DNA replication and triggering a cascade leading to apoptosis of the cell. Apoptosis induces cell membrane edema, which manifests as cutaneous vesicles and bullae on the skin.¹⁰ Regardless of plant species, PPD reactions have similar appearance.

Celery roots contain the greatest concentration of psoralens, making it the most likely part of the plant to induce PPD.⁶ Phytophotodermatitis caused by celery can occur at any time of the year, but most eruptions occur during the summer months due to increased sunlight exposure and intensity. Among 320 randomly selected Michigan celery harvesters, 163 (51%) displayed evidence of vesicular and bullous dermatitis on the fingers, hands, and forearms.¹¹ In this study, celery infected with pink rot fungus induced an erythematous eruption with vesicles and bullae within 48 hours of contact after just 30 seconds of summer sunlight exposure; however, eruptions are not limited to summer months, as the cutaneous presentation depends solely on exposure to UVA light, which can occur year-round.

Use of tanning beds is a major risk factor for PPD.¹² Tanning beds utilize fluorescent bulbs that primarily emit UVA light, with UVB light emitted to a lesser degree. The UVA radiation produced by tanning beds is more than 3 times as intense as natural sunlight.¹² Among grocery store employees, the combination of these 2 risk factors—regular contact with celery and tanning bed use—resulted in a prevalence ratio for PPD more than 40 times greater than that of individuals with neither risk factor.¹³

Cutaneous Manifestations of PPD

Phytophotodermatitis is a nonimmunologic dermatitis that forms via the interaction between UV light exposure and the photosensitizing chemicals inherent to some plant species. Development of PPD following contact with celery may be caused by the photoactive substances in celery, including the psoralens 8-methoxypsoralen and 5-methoxypsoralen.¹⁴ The psoralens must become activated by UV light with wavelengths between 320 nm and 400 nm (UVA) to initiate biologic effects.¹⁵

Once chemically activated, the photoactive mediators cause an erythematous and edematous sunburnlike reaction. Current hypotheses state that psoralen plus UVA generates reactive oxygen species, which damage the DNA within cells and alter receptors on cell membranes within the epidermis.¹⁴ The cutaneous eruption usually appears between 12 and 36 hours after sun exposure. Although they generally are not pruritic, the eruptions may induce pain. Within 7 to 10 days following development of the rash, hyperpigmentation occurs in the affected area and often persists for months to years.¹⁶ Ingestion of large amounts of celery has been cited to cause generalized phototoxic reactions; however, PPD rarely arises solely after ingestion, unless excessive amounts are consumed with concomitant exposure to psoralen plus UVA or tanning beds.¹⁷ In these cases, patients develop diffuse redness with superficial scaling, pain, and blistering if severe.

Treatment of PPD

Prevention remains the best form of treatment for PPD caused by exposure to celery. Postcontact management includes washing the affected area with soap and water and changing clothes promptly. Topical corticosteroids have mild utility in treatment of PPD.¹⁸ Oral steroid tapers, which reduce acute inflammation, also are an option for treatment. Alternatively, intramuscular triamcinolone acetonide 1 mg/kg mixed with budesonide 0.1 mg/kg is an option and is associated with a reduced risk for adverse effects compared to oral steroids. The resulting hyperpigmentation develops 1 to 2 weeks postepithelialization.¹⁹ Hyperpigmentation often fades slowly over several months in lighter-skinned individuals but may last for years or indefinitely in darker-skinned patients.

Final Thoughts

Dermatologists should be knowledgeable about the various plant culprits that can induce PPD. Understanding the mechanism and pathophysiology can help guide both therapeutic interventions and preventive counseling. Understanding that even readily available vegetables such as celery can induce cutaneous eruptions should put PPD in the differential diagnosis more commonly when unspecified dermatitides are present.

The United States has long been recognized as a global leader in biomedical research and scientific discovery, with federal research and development (R&D) funding serving as the bedrock of national innovation. Substantial federal investment in biomedical research has stemmed from a recognition of its importance in fueling critical discoveries that improve patient care and the health of our communities.

In the United States, academic institutions play a key role in conducting research in the national interest and collaborating with industry, with most of the federal research funding distributed by the National Institutes of Health, National Science Foundation, and other agencies awarded to university-based academic investigators. In a 2014 report, the National Academies of Sciences, Engineering and Medicine identified three pillars of a highly productive research system: a talented and interconnected workforce, adequate and dependable resources, and world-class basic research in all major areas of science. 

 

A series of recent, short-sighted federal policy decisions threaten the future of scientific discovery by eroding these pillars. Decisions to freeze previously awarded federal grant funding, delay grant review panels, fire federal scientists, and propose crippling cuts to indirect cost rates (among others) have sent shock waves through the research community and already have led some prominent research institutions to cut staff and divert resources away from groundbreaking research. While the acute effects of these changes are just beginning to be felt, it is the long-term effects of these decisions on future medical and scientific discovery that will be most devastating to society. If ever there was a time for advocacy to reinforce the critical link between biomedical research and downstream improvements in patient care and public health, it is now. 

In our April issue, we highlight important research advancements in inflammatory bowel disease presented at February’s Congress of the European Crohn’s and Colitis Organisation (ECCO) in Berlin. In this month’s Member Spotlight, Abigail Meyers, MPAS, PA-C, outlines her impactful work as a member of AGA’s newly formed Nurse Practitioner and Physician Assistant Task Force and shares how her personal journey as a patient with inflammatory bowel disease allows her to be a more powerful advocate for important issues impacting other patients with this condition.

Megan A. Adams, MD, JD, MSc

Editor in Chief

The United States has long been recognized as a global leader in biomedical research and scientific discovery, with federal research and development (R&D) funding serving as the bedrock of national innovation. Substantial federal investment in biomedical research has stemmed from a recognition of its importance in fueling critical discoveries that improve patient care and the health of our communities.

In the United States, academic institutions play a key role in conducting research in the national interest and collaborating with industry, with most of the federal research funding distributed by the National Institutes of Health, National Science Foundation, and other agencies awarded to university-based academic investigators. In a 2014 report, the National Academies of Sciences, Engineering and Medicine identified three pillars of a highly productive research system: a talented and interconnected workforce, adequate and dependable resources, and world-class basic research in all major areas of science. 

 

A series of recent, short-sighted federal policy decisions threaten the future of scientific discovery by eroding these pillars. Decisions to freeze previously awarded federal grant funding, delay grant review panels, fire federal scientists, and propose crippling cuts to indirect cost rates (among others) have sent shock waves through the research community and already have led some prominent research institutions to cut staff and divert resources away from groundbreaking research. While the acute effects of these changes are just beginning to be felt, it is the long-term effects of these decisions on future medical and scientific discovery that will be most devastating to society. If ever there was a time for advocacy to reinforce the critical link between biomedical research and downstream improvements in patient care and public health, it is now. 

In our April issue, we highlight important research advancements in inflammatory bowel disease presented at February’s Congress of the European Crohn’s and Colitis Organisation (ECCO) in Berlin. In this month’s Member Spotlight, Abigail Meyers, MPAS, PA-C, outlines her impactful work as a member of AGA’s newly formed Nurse Practitioner and Physician Assistant Task Force and shares how her personal journey as a patient with inflammatory bowel disease allows her to be a more powerful advocate for important issues impacting other patients with this condition.

Megan A. Adams, MD, JD, MSc

Editor in Chief

The United States has long been recognized as a global leader in biomedical research and scientific discovery, with federal research and development (R&D) funding serving as the bedrock of national innovation. Substantial federal investment in biomedical research has stemmed from a recognition of its importance in fueling critical discoveries that improve patient care and the health of our communities.

In the United States, academic institutions play a key role in conducting research in the national interest and collaborating with industry, with most of the federal research funding distributed by the National Institutes of Health, National Science Foundation, and other agencies awarded to university-based academic investigators. In a 2014 report, the National Academies of Sciences, Engineering and Medicine identified three pillars of a highly productive research system: a talented and interconnected workforce, adequate and dependable resources, and world-class basic research in all major areas of science. 

 

A series of recent, short-sighted federal policy decisions threaten the future of scientific discovery by eroding these pillars. Decisions to freeze previously awarded federal grant funding, delay grant review panels, fire federal scientists, and propose crippling cuts to indirect cost rates (among others) have sent shock waves through the research community and already have led some prominent research institutions to cut staff and divert resources away from groundbreaking research. While the acute effects of these changes are just beginning to be felt, it is the long-term effects of these decisions on future medical and scientific discovery that will be most devastating to society. If ever there was a time for advocacy to reinforce the critical link between biomedical research and downstream improvements in patient care and public health, it is now. 

In our April issue, we highlight important research advancements in inflammatory bowel disease presented at February’s Congress of the European Crohn’s and Colitis Organisation (ECCO) in Berlin. In this month’s Member Spotlight, Abigail Meyers, MPAS, PA-C, outlines her impactful work as a member of AGA’s newly formed Nurse Practitioner and Physician Assistant Task Force and shares how her personal journey as a patient with inflammatory bowel disease allows her to be a more powerful advocate for important issues impacting other patients with this condition.

Megan A. Adams, MD, JD, MSc

Editor in Chief

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

The Diagnosis: Leiomyoma

Histopathology revealed a dermal mesenchymal tumor composed of fascicles of bland spindle cells with tapered nuclei, perinuclear vacuoles, eosinophilic cytoplasm, and low cellularity (Figure 1). Immunohistochemical studies of the cells stained strongly positive for smooth muscle actin and desmin, consistent with a smooth muscle neoplasm (Figure 2). Fumarate hydratase (FH) staining revealed loss of expression in tumor cells, consistent with FH deficiency (Figure 3). A diagnosis of cutaneous leiomyoma was made, and although the clinical and histologic findings suggested hereditary leiomyomatosis and renal cell cancer (HLRCC), genetic testing was negative for an FH gene mutation. This negative result indicated that HLRCC was unlikely despite the initial concerns based on the findings. 

Leiomyomas are benign neoplasms that are challenging to diagnose based on the clinical picture alone. Leiomyomas most commonly are found in the genitourinary and gastrointestinal systems, with cutaneous manifestation being the second most common presentation.¹ These benign smooth muscle tumors manifest as tender, firm, flesh-colored, pink or reddish-brown nodules that are subcategorized based on the derivation of the smooth muscle within the tumor.² Angioleiomyomas, the most common type, arise from the tunica media of blood vessels, whereas piloleiomyomas and genital leiomyomas arise from the arrector pili musculature of the hair follicle and the smooth muscle found in the scrotum, labia, or nipple.² Rare cases of cutaneous leiomyosarcomas and angioleiomyosarcomas have been reported in the literature.^3,4 Solitary leiomyomas tend to develop on the lower extremities, whereas multiple lesions frequently manifest on the extensor surfaces of extremities and the trunk. Lesions often are painful, either spontaneously or in association with applied pressure, emotional stress, or exposure to cold temperatures.² 

Although leiomyomas themselves are benign, patients with multiple cutaneous leiomyomas may have an underlying genetic mutation that increases their risk of developing HLRCC, an autosomal-dominant syndrome.⁵ Referral should be considered for individuals with a personal history of or a first-degree relative with cutaneous leiomyomas or renal cell carcinoma (RCC) with histology typical of hereditary leiomyomatosis and RCC, as recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.⁶ In this case, the decision to refer the patient for genetic testing was based on her family history, specifically her paternal uncle having multiple similar lesions, which, while not a first-degree relative, still raised concerns about potential hereditary risks and warranted further evaluation. A germline mutation in the FH gene, which encodes an enzyme that converts fumarate to malate in the Krebs cycle and plays a role in tumor suppression, is the cause of HLRCC.^2,7 When part of this genetic condition, cutaneous leiomyomas tend to occur around 25 years of age (range, 10-50 years).² A diagnosis of HLRCC should be strongly considered if a patient displays multiple cutaneous leiomyomas with at least 1 histologically confirmed lesion or at least 2 of the following: solitary cutaneous leiomyoma with family history of HLRCC, onset of severely symptomatic uterine fibroids before age 40 years, type II papillary or collecting duct renal cell cancer before age 40 years, or a first-degree family member who meets 1 of these criteria.^5,8 

Diagnosis of cutaneous leiomyoma may be accomplished by microscopic examination of a tissue sample; however, further diagnostic workup is warranted due to the strong correlation with HLRCC.² A definitive diagnosis of HLRCC is confirmed with a germline mutation in the FH gene, and genetic screening should be offered to patients before renal cancer surveillance to avoid unwarranted investigations.⁸ Timely clinical diagnosis enables early genetic testing and enhanced outcomes for patients with confirmed HLRCC who may need a multidisciplinary approach of dermatologists, gynecologists, and urologic oncologists.^5,8 

Cutaneous leiomyomas can be excised, and this typically is the gold standard of care for small and localized lesions, although the use of cryosurgery and carbon dioxide lasers has been reported as well.^2,9,10 For more widespread lesions or for patients who are not appropriate candidates for surgery, pharmacologic therapies (α-blockers, calcium channel blockers, nitroglycerin), intralesional corticosteroids, and/or botulinum toxin injections can be utilized.^2,11 

The acronym BLEND AN EGG encompasses the clinical differential diagnosis for painful skin tumors: blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor. Blue rubber bleb nevi are deep blue in color, and angiolipomas sit under the skin and present as subcutaneous swellings. Dermatofibromas and neurofibromas also are included in the differential.¹² Dermatofibromas are firm solitary lesions that have a pathognomonic pinch sign. Neurofibromas are soft and rubbery, have a buttonhole sign, and stain positively for S-100 protein and SOX-10 but negatively for actin and desmin.¹²

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

THE DIAGNOSIS: Tinea Corporis

Due to the scaly and acute nature of the rash, a potassium hydroxide (KOH) preparation was performed, and hyphal elements were floridly present. After further questioning, the patient reported finding a stray kitten a few weeks before the onset of the eruption and shared a picture of it lying on her chest in the area corresponding with the main distribution of the rash (Figure). Based on the patient’s personal history and the positive KOH preparation, a diagnosis of tinea corporis was made. She was immediately started on fluconazole 300 mg once weekly for 4 weeks and naftifine gel 1%, which she used for 6 to 8 weeks with complete resolution of the eruption.

Tinea corporis is a dermatophyte infection that typically affects exposed areas of the skin such as the chest, arms, and legs. Spread via human-to-human contact, Trichophyton rubrum is the most common cause worldwide. The second most common is Trichophyton mentagrophytes, which is spread through animal-to-human contact.^1,2

Symptoms of tinea corporis usually appear 1 to 3 weeks after exposure and manifest as itchy scaly papules that spread outward, forming annular, circinate, and petaloid erythematous plaques with central clearing. The condition most commonly is diagnosed through the examination of scale from the affected area using a KOH preparation, which will reveal hyphae when positive.^2-4 Cultures are the gold standard for identifying dermatophyte species,⁵ but results can take several weeks. Biopsy also can confirm the diagnosis by showing the presence of hyphae in the stratum corneum, which can be highlighted using periodic acid–Schiff or silver stains.³

Topical antifungals are the first-line treatment for cutaneous dermatophyte infections.^3-5 The most effective topical therapies are allylamines and azoles, which work by inhibiting the growth of the fungus. Allylamines are more effective than azoles due to their fungicidal properties and ability to penetrate the skin more effectively.^6,7 Topical medications should be applied at least 2 cm beyond the infected area for 2 to 4 weeks or until the infection has cleared.³ Systemic antifungals may be necessary in more complicated cases.

It is important to consider a broad differential and take into consideration the distribution of the plaques, the patient’s history, and other clinical features when differentiating tinea corporis from other conditions. Erythema annulare centrifugum more often presents as nonpruritic annular plaques with a trailing scale instead of a leading scale seen in tinea corporis. Biopsy exhibits a dense, perivascular, lymphocytic infiltrate in superficial vessels, resembling a coat sleeve.^3,8 Pemphigus foliaceous can manifest with painful crusted scaly plaques and vesicles in a seborrheic distribution. Biopsy reveals subcorneal acantholytic vesicles and can be confirmed on direct immunofluorescence.^3,8 Subacute cutaneous lupus erythematosus presents with annular plaques that often are symmetric and most prominent in sun-exposed areas, sparing the face.^3,9,10 It can be associated with other autoimmune conditions as well as medications such as thiazides, terbinafine, and calcium channel blockers. Additionally, 76% to 90% of patients are Ro/SSA antibody positive.³ Biopsy often demonstrates follicular plugging, perivascular and periadnexal lymphocytic infiltrates, and mucin.^3,10 Lastly, pityriasis rosea typically begins with a herald patch, followed by a widespread rash that often appears in a Christmas tree distribution.³

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Prosthetic joint infection (PJI) occurs in about 1% to 2% of joint replacements. ¹ Risk factors include immunosuppression, diabetes, chronic illnesses, and prolonged operative time.² Bacterial infections constitute most of these infections, while fungal pathogens account for about 1%. Candida (C.) species, predominantly C. albicans, are responsible for most PJIs.^1,3 In contrast, C. glabrata is a rare cause of fungal PJI, with only 18 PJI cases currently reported in the literature.⁴ C. glabrata PJI occurs more frequently among immunosuppressed patients and is associated with a higher treatment failure rate despite antifungal therapy.⁵ Treatment of fungal PJI is often complicated, involving multiple surgical debridements, prolonged antifungal therapy, and in some cases, prosthesis removal.⁶ However, given the rarity of C. glabrata as a PJI pathogen, no standardized treatment guidelines exist, leading to potential delays in diagnosis and tailored treatment.^7,8

CASE PRESENTATION

A male Vietnam veteran aged 75 years presented to the emergency department in July 2023 with a fluid collection over his left hip surgical incision site. The patient had a complex medical history that included chronic kidney disease, well-controlled type 2 diabetes, hypertension, and osteoarthritis. His history was further complicated by nonalcoholic steatohepatitis with hepatocellular carcinoma that was treated with transarterial radioembolization and yttrium-90. The patient had undergone a left total hip arthroplasty in 1996 and subsequent open reduction and internal fixation about 9 months prior to his presentation. The patient reported the fluid had been present for about 6 weeks, while he received outpatient monitoring by the orthopedic surgery service. He sought emergency care after noting a moderate amount of purulent discharge on his clothing originating from his hip. In the week prior to admission, the patient observed progressive erythema, warmth, and tenderness over the incision site. Despite these symptoms, the patient remained ambulatory and able to walk long distances with the use of an assistive device.

Upon presentation, the patient was afebrile and normotensive. Laboratory testing revealed an elevated erythrocyte sedimentation rate of 77 mm/h (reference range, 0-20 mm/h) and a C-reactive protein of 9.8 mg/L (reference range, 0-2.5 mg/L), suggesting an underlying infectious process. A physical examination revealed a well-healed incision over the left hip with a poorly defined area of fluctuance and evidence of wound dehiscence. The left lower extremity was swollen with 2+ pitting edema, but tenderness was localized to the incision site. Magnetic resonance imaging of the left hip revealed a multiloculated fluid collection abutting the left greater trochanter with extension to the skin surface and inferior extension along the entire length of the surgical fixation hardware (Figure).

Upon admission, orthopedic surgery performed a bedside aspiration of the fluid collection. Samples were sent for analysis, including cell count and bacterial and fungal cultures. Initial blood cultures were sterile. Due to concerns for a bacterial infection, the patient was started on empiric intravenous (IV) ceftriaxone 2 g/day and IV vancomycin 1250 mg/day. Synovial fluid analysis revealed an elevated white blood cell count of 45,000/ìL, but bacterial cultures were negative. Five days after admission, the fungal culture from the left hip wound was notable for presence of C. glabrata, prompting an infectious diseases (ID) consultation. IV micafungin 100 mg/day was initiated as empiric antifungal therapy.

ID and orthopedic surgery teams determined that a combined medical and surgical approach would be best suited for infection control. They proposed 2 main approaches: complete hardware replacement with washout, which carried a higher morbidity risk but a better chance of infection resolution, or partial hardware replacement with washout, which was associated with a lower morbidity risk but a higher risk of infection persistence and recurrence. This decision was particularly challenging for the patient, who prioritized maintaining his functional status, including his ability to continue dancing for pleasure. The patient opted for a more conservative approach, electing to proceed with antifungal therapy and debridement while retaining the prosthetic joint.

After 11 days of hospitalization, the patient was discharged with a peripherally inserted central catheter for long-term antifungal infusions of micafungin 150 mg/day at home. Fungal sensitivity test results several days after discharge confirmed susceptibility to micafungin.

About 2 weeks after discharge, the patient underwent debridement and implant retention (DAIR). Wound cultures were positive for C. glabrata, Enterococcus faecalis, Staphylococcus epidermidis, and Corynebacterium tuberculostearicum. Based on susceptibilities, he completed a 2-month course of IV micafungin 150 mg daily and daptomycin 750 mg daily, followed by an oral suppressive regimen consisting of doxycycline 100 mg twice daily, amoxicillin-clavulanate 2 g twice daily, and fluconazole initially 800 mg daily adjusted to 400 mg daily. The patient continued wound management with twice-daily dressing changes.

Nine months after DAIR, the patient remained on suppressive antifungal and antibacterial therapy. He continued to experience serous drainage from the wound, which greatly affected his quality of life. After discussion with his family and the orthopedic surgery team, he agreed to proceed with a 2-staged revision arthroplasty involving prosthetic explant and antibiotic spacer placement. However, the surgery was postponed due to findings of anemia (hemoglobin, 8.9 g/dL) and thrombocytopenia (platelet count, 73 x 10³/λL). At the time of this report, the patient was being monitored closely with his multidisciplinary care team for the planned orthopedic procedure.

DISCUSSION

PJI is the most common cause of primary hip arthroplasty failure; however, fungal species only make up about 1% of PJIs.^3,9-11 Patients are typically immunocompromised, undergoing antineoplastic therapies for malignancy, or have other comorbid conditions such as diabetes.^12,13 C. glabrata presents a unique diagnostic and therapeutic challenge as it is not only rare but also notorious for its resistance to common antifungal agents. C. glabrata is known to develop multidrug resistance through the rapid accumulation of genomic mutations.¹⁴ Its propensity towards forming protective biofilm also arms it with intrinsic resistance to agents like fluconazole.¹⁵ Furthermore, based on a review of the available reports in the literature, C. glabrata PJIs are often insidious and present with symptoms closely mimicking those of bacterial PJIs, as it did in the patient in this case.¹⁶

Synovial fluid analysis, fungal cultures, and sensitivity testing are paramount for ensuring proper diagnosis for fungal PJI. The patient in this case was empirically treated with micafungin based on recommendations from the ID team. When the sensitivities results were reviewed, the same antifungal therapy was continued. Echinocandins have a favorable toxicity profile in long-term use, as well as efficacy against biofilm-producing organisms like C. glabrata.^17,18

While there are a few cases citing DAIR as a feasible surgical strategy for treating fungal PJI, more recent studies have reported greater success with a 2-staged revision arthroplasty involving some combination of debridement, placement of antibiotic-loaded bone cement spacers, and partial or total exchange of the infected prosthetic joint.^4,19-23 In this case, complete hardware replacement would have offered the patient the most favorable outlook for eliminating this fungal infection. However, given the patient’s advanced age, significant underlying comorbidities, and functional status, medical management with antifungal therapy and DAIR was favored.

Based on the discussion from the 6-month follow-up visit, the patient was experiencing progressive and persistent wound drainage and frequent dressing changes, highlighting the limitations of medical management for PJI in the setting of retained prosthesis. If the patient ultimately proceeds with a more invasive surgical intervention, another important consideration will be the likelihood of fungal PJI recurrence. At present, fungal PJI recurrence rates following antifungal and surgical treatment have been reported to range between 0% to 50%, which is too imprecise to be considered clinically useful.^22-24

Given the ambiguity surrounding management guidelines and limited treatment options, it is crucial to emphasize the timeline of this patient’s clinical presentation and subsequent course of treatment. Upon presentation to the ED in late July, fungal PJI was considered less likely. Initial blood cultures from presentation were negative, which is common with PJIs. It was not until 5 days later that the left hip wound culture showed moderate growth of C. glabrata. Identifying a PJI is clinically challenging due to the lack of standardized diagnostic criteria. However, timely identification and diagnosis of fungal PJI with appropriate antifungal therapy, in patients with limited curative options due to comorbidities, can significantly improve quality of life and overall outcomes.²⁵ Routine fungal and mycobacterial cultures are not currently recommended in PJI guidelines, but this case illustrates it is imperative in immunocompromised hosts.²⁶

This case and the current paucity of similar cases in the literature stress the importance of clinicians publishing their experience in the management of fungal PJI. We strongly recommend that clinicians approach each suspected PJI with careful consideration of the patient’s unique risk factors, comorbidities, and goals of care, when deciding on a curative vs suppressive approach to therapy.

CONCLUSIONS

This case report highlights the importance of considering fungal pathogens for PJIs, especially in high-risk patients, the value of obtaining fungal cultures, the necessity of a multidisciplinary approach, the role of antifungal susceptibility testing, and consideration for the feasibility of a surgical intervention. It underscores the challenges in diagnosis and treatment of C. glabrata-associated PJI, emphasizing the importance of clinician experience-sharing in developing evidence-based management strategies. As the understanding of fungal PJI evolves, continued research and clinical data collection remain crucial for improving patient outcomes in the management of these complex cases.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunologic phenomenon characterized by a systemic inflammatory response syndrome—like clinical picture with additional features, including hepatosplenomegaly, hyperferritinemia, and increased natural killer cell activity. Clinical manifestations of HLH often are nonspecific, making HLH diagnosis challenging. High persistent fever is a key feature of HLH; patients also may report gastrointestinal distress, lethargy, and/or widespread rash.¹

Hemophagocytic lymphohistiocytosis is believed to stem from inherited defects in several genes, such as perforin (PRF1), as well as immune dysregulation due to infections, rheumatologic diseases, hematologic malignancies, or drug reactions.² The primary mechanism of HLH is hypothesized to be driven by aberrant immune activation, interferon gamma released from CD8+ T cells, and uncontrolled phagocytosis by activated macrophages. The cytokine cascade results in tissue injury and multiorgan dysfunction.^3,4

Although HLH historically has been categorized as primary (familial) or secondary (acquired), the most recent guidelines suggest the etiology is not always binary.^3,5 That said, the concept of secondary causes is useful in understanding risk factors for developing HLH. Both forms of the disease are thought to be elicited by a trigger (eg, infection), even when inherited genetic mutations exist.⁶ The primary form commonly affects the pediatric population,^4,6-8 whereas the secondary form is more common in adults.⁷

Several sets of diagnostic criteria for HLH have been developed, the most well-known being the HLH-2004 criteria.^1,3 The HLH-2009 modified criteria were developed after further evidence provided a refined sense of how the HLH-2004 criteria should be stratified.⁹ Finally, Fardet et al¹⁰ presented the HScore as an estimation of likelihood of diagnosis of HLH. These sets of HLH criteria include clinical and laboratory features that demonstrate inflammation, natrual killer cell activity, hemophagocytosis, end-organ damage, and cell lineage effects. The HScore differs from the other sets of HLH criteria in that it is designed to estimate an individual patient’s risk of having reactive hemophagocytic syndrome, which likely is equivalent to secondary HLH, although the authors do not use this exact terminology.¹⁰

While these criteria provide a framework for diagnosing HLH, they may fail to distinguish between HLH disease and HLH disease mimics, a concept described by the North American Consortium for Histiocytosis that may impact the success of immunosuppressive treatment.³ Individuals with HLH syndrome meet the aforementioned diagnostic criteria; HLH syndrome is further divided into HLH disease and HLH disease mimics (Figure 1). The “disease” label describes the traditional concept of HLH, driven by aberrant immune overactivation, in which patients benefit from immunosuppression. In contrast, HLH mimics include a subset of patients who meet the HLH criteria but are unlikely to benefit from immunosuppression because the primary mechanism driving their condition is not owed to immune overactivation, as is the case with HLH disease. Examples of HLH mimics include certain infections, such as Epstein-Barr virus (EBV), that may demonstrate clinical findings consistent with HLH but would not benefit from immunosuppression. Ironically, infections (including EBV) also are known triggers of HLH disease, making this concept difficult to understand and adopt. In this study, we refer to HLH disease simply as HLH.

Although cutaneous manifestations of HLH are not included in the diagnostic criteria, skin findings are common and may coincide with the severity and progression of the disease.¹¹ Despite the fact that HLH can manifest with rash,¹ comprehensive reviews of reported cutaneous findings in adult HLH are lacking. Thus, the goal of this study was to provide an organized characterization of reported cutaneous findings in adults with HLH and context for how the dermatologic examination may support the diagnosis or uncover the underlying etiology of this condition.

Methods

A search of PubMed articles indexed for MEDLINE using the phrase (cutaneous OR dermatologic OR skin) findings) AND hemophagocytic lymphohistiocytosis performed on September 20, 2023, yielded 423 results (Figure 2). Filters to exclude non–English language publications and pediatric populations were applied, resulting in 161 articles. Other exclusion criteria included the absence of a description of dermatologic findings. Seventy-five articles remained after screening titles and abstracts, and full-text review yielded 55 articles that were deemed appropriate for inclusion in the study. Subsequent reference searches and use of the online resource Litmaps revealed 45 additional publications that underwent full-text screening; of these articles, 5 were included in the final review.

Results

Sixty studies were included in this systematic review.^5,7,11-68 The reported prevalence of skin findings among patients with HLH from the included retrospective studies ranged from 15% to 85%.^12-15 Several literature reviews reported similarly varied prevalence among adult patients with HLH.^7,16 Fardet et al¹⁴ categorized cutaneous manifestations of HLH into 3 types: direct manifestations of HLH not explained by systemic features (eg, generalized maculopapular eruption), indirect manifestations of HLH that are explained by systemic features of the disease (eg, purpura due to HLH-induced coagulopathy), and findings specific to the underlying etiology of HLH (eg, malar rash seen in systemic lupus erythematosus [SLE]–associated HLH). This categorization served as the outline for the results below, providing an organized review of cutaneous findings and context for how they may support the diagnosis or uncover the underlying etiology of HLH.

Category I: Direct Manifestations of HLH

Several articles reported cutaneous findings that seemed to be the direct result of HLH and not attributed to an underlying trigger or sequalae of HLH.^11,14,16-31 The most common descriptions were a generalized, morbilliform, or nonspecific eruption that encompasses large areas of the skin, commonly the trunk and extremities, sometimes extending to the face and scalp.^{14,16-23,25,31,32} There were variations in secondary features such as pruritus and tenderness; some studies also described violaceous discoloration in addition to erythema.^16,23

Other skin findings thought to be a direct result of HLH were described in detail by Zerah and DeWitt¹¹ in their retrospective study, including pyoderma gangrenosum, panniculitis, Stevens-Johnson syndrome, atypical targetoid lesions, and bullous eruptions. The authors also analyzed dermatopathologic data that ultimately revealed that pathologic analysis was largely inconsistent and nondescript.¹¹ There was a single case report of purpura fulminans arising alongside signs and symptoms of HLH,²⁶ and several case reports described Sweet syndrome developing around the same time as HLH.^27-29 Lastly, Collins et al³⁰ described a case of HLH manifesting with violaceous ulcerating papules and nodules scattered across the legs, abdomen, and arms. Biopsy of this patient’s lesions showed a diffuse dermal infiltrate of histiocytes and hemophagocytosis.

Category II: Secondary Complications and Sequelae of HLH

This was the smallest group among the 3 categories, comprising a few case reports and retrospective cohort studies primarily reporting jaundice/icterus and hemorrhagic lesions such as purpura, petechiae, and scleral hemorrhage.^{11,21,23,33-35} Several literature reviews described these conditions as nonspecific findings in HLH.^16,20 The cause of jaundice in HLH likely can be attributed to its characteristic hepatic dysfunction, whereas hemorrhagic lesions likely are the result of both hepatic and bone marrow dysfunction resulting in coagulopathy.

Category III: Manifestations of Underlying Etiology or Triggers of HLH

Infectious—Infection is known to be one of the most common triggers of HLH, with several retrospective studies reporting infectious triggers in approximately 20% of cases.^13,15 Although many pathogens have been implicated, only a few of these infection-induced HLH reports described cutaneous findings, which included a case of varicella zoster virus, Escherichia coli necrotizing fasciitis, leprosy, EBV reactivation, parvovirus B19, and both focal and disseminated herpes simplex virus 2.^36-42 Most of these patients presented with classic findings of each disease. The case of varicella zoster virus exhibited pruritic erythematous papules on the face, trunk, and limbs.³⁶ The necrotizing fasciitis case presented with tender erythematous swelling of the lower extremity.³⁷ The patient with leprosy exhibited leonine facies and numerous erythematous nodules, plaques, and superficial ulcerating plaques over the trunk and limbs with palmoplantar involvement,³⁹ and both cases of herpes simplex virus 2 reported small bullae either diffusely over the face, trunk, and extremities or over the genitalia.^38,40 Interestingly, the cases of parvovirus B19 and EBV reactivation both exhibited polyarteritis nodosa and occurred in patients with underlying autoimmune conditions, raising the question of whether these cases of HLH had a single trigger or were the result of the overall immunologic dysregulation induced by both infection and autoimmunity.^41,42

Rheumatologic—Several articles reported dermatologic findings associated with macrophage activation syndrome, a term that often is used to describe HLH associated with autoimmune conditions. Cases of HLH in adult-onset Still disease, dermatomyositis, polyarteritis nodosa, and SLE described skin findings characteristic of the underlying rheumatologic disease, sometimes with acutely worse dermatologic findings at the time of HLH presentation.^35,41-48 With regard to SLE, the acute manifestation of classic findings of the disease with HLH has sometimes been described as acute lupus hemophagocytic syndrome (HPS).⁴⁸ Lambotte at al⁴⁸ described common findings of acute lupus hemophagocytic syndrome in their retrospective study as malar rash, weight loss, polyarthralgia, and nephritis in addition to classic HLH findings including fever, lymphadenopathy, and hepatosplenomegaly. Many other rheumatologic conditions have been associated with HLH, including rheumatoid arthritis, mixed connective tissue disease, systemic sclerosis, and Sjögren disease. All these conditions can have dermatologic manifestations; however, no descriptions of dermatologic findings in cases of HLH associated with these diseases were found.¹³

Malignancy—Several cases of malignancy-induced HLH described cutaneous findings, the majority being cutaneous lymphomas, namely subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Other less commonly reported malignancies in this group included Kaposi sarcoma, intravascular lymphoma, Sézary syndrome, mycosis fungoides, cutaneous diffuse large B-cell lymphoma, and several subtypes of primary cutaneous T-cell lymphoma.^2,32,49-60 The most common description of SPTCL included multiple scattered plaques and subcutaneous nodules, some associated with tenderness, induration, drainage, or hemorrhagic features.^{32,50,52,55,57,60} Cases of mycosis fungoides and Sézary syndrome presented with variations in size and distribution of erythroderma with associated lymphadenopathy.² A unique case of HLH developing in a patient with intravascular lymphoma described an eruption of multiple telangiectasias and petechial hemorrhages on the trunk,⁵⁸ while one case associated with primary cutaneous anaplastic large cell lymphoma presented with a rapidly enlarging tumor with central ulceration and eschar.⁵⁹

Drug Induced—Interestingly, most of the drug-induced cases of HLH identified in our search were secondary to biologic therapies used in the treatment of metastatic melanoma, specifically the immune checkpoint inhibitors (ICIs), which have been reported to have an association with HLH in prior literature reviews.^61-65 Choi et al⁶⁶ described an interesting case of ICI-induced HLH presenting with a concurrent severe lichenoid drug eruption that progressed from a pruritic truncal rash to mucocutaneous bullae, erosions, and desquamation resembling a Stevens-Johnson syndrome–type picture. This patient had treatment-refractory, HIV-negative Kaposi sarcoma, where the underlying immunologic dysregulation may explain the more severe cutaneous presentation not observed in other reported cases of ICI-induced HLH.

Yang et al’s⁶⁷ review of 23 cases with concurrent diagnoses of HLH and DIHS found that 61% (14/23) of cases were diagnosed initially as DIHS before failing treatment and receiving a diagnosis of HLH several weeks later. Additionally, the authors found that several cases met criteria for one diagnosis while clinically presenting strongly for the other.⁶⁷ This overlap in clinical presentation also was demonstrated in Zerah and DeWitt’s11 retrospective study regarding cutaneous findings in HLH, in which several of the morbilliform eruptions thought to be contributed to HLH ultimately were decided to be drug reactions.

Comment

Regarding direct (or primary) cutaneous findings in HLH (category I), there seem to be 2 groups of features associated with the onset of HLH that are not related to its characteristic hepatic dysfunction (category II) nor its underlying triggers (category III): a nonspecific, generalized, erythematous eruption; and dermatologic conditions separate from HLH itself (eg, Sweet syndrome, pyoderma gangrenosum). Whether the latter group truly is a direct manifestation of HLH is difficult to discern with the evidence available. Nevertheless, we can conclude that there is some type of association between these dermatologic diseases and HLH, and this association can serve as both a diagnostic tool for clinicians and a point of interest for further clinical research.

The relatively low number of articles identified through our systematic review that specifically reported secondary findings, such as jaundice or coagulopathy-associated hemorrhagic lesions, may lead one to believe that these are not common findings in HLH; however, it is possible that these are not regularly reported in the literature simply because these findings are nonspecific and can be considered expected results of the characteristic organ dysfunction in HLH.

As suspected, the skin findings in category III were the most broad given the variety of underlying etiologies that have been associated with HLH. Like the other 2 categories, these skin findings generally are nonspecific to HLH; however, the ones in category III are specific to underlying etiology of HLH and may aid in identifying and treating the underlying cause of a patient’s HLH when indicated.

Most of the rheumatologic diseases seem to have been known at the time of HLH development and diagnosis, which may highlight the importance of considering a diagnosis of HLH early on in patients with known autoimmune disease and systemic signs of illness or acutely worsening signs and symptoms of their underlying autoimmune disease.

Interestingly, several cases of malignancy-associated HLH reported signs and symptoms of HLH at initial presentation of the malignant disease.^32,50,59 This situation seems to be somewhat common, as Go and Wester’s⁶⁸ systematic analysis of 156 patients with SPTCL found HLH was the presenting feature in 37% of patients included in their study. This may call attention to the importance of considering cutaneous lymphomas as the cause of skin lesions in patients with signs and symptoms of HLH, where it may be easy to assume that skin findings are a result of their systemic disease.

In highlighting cases of HLH related to medication use, we found it pertinent to include and discuss the complex relationship between drug-induced hypersensitivity syndrome (DIHS [formerly known as drug rash with eosinophilia and systemic symptoms [DRESS] syndrome) and HLH. The results of this study suggest that DIHS may have considerable clinical overlap with HLH¹¹ and may even lead to development of HLH,⁶⁷ creating difficulty in distinguishing between these conditions where there may be similar findings, such as cutaneous eruptions, fever, and hepatic or other internal organ involvement. We agree with Yang et al⁶⁷ that there can be large overlap in symptomology between these two conditions and that more investigation is necessary to explore the relationship between them.

Conclusion

Diagnosis of HLH in adults continues to be challenging, with several diagnostic tools but no true gold standard. In addition to the nonspecific symptomology, there is a myriad of cutaneous findings that can be present in adults with HLH (eTable), all of which are also nonspecific. Even so, awareness of which dermatologic findings have been associated with HLH may provide a cue to consider HLH in the systemically ill patient with a notable dermatologic examination. Furthermore, there are several avenues for further investigation that can be drawn, including further dermatologic analysis among nonspecific eruptions attributed to HLH, clinical and pathologic differentiation between DIHS/DRESS and HLH, and correlation between severity of skin manifestations and severity of HLH disease.

Limitations of this study included a lack of clarity in diagnosis of HLH in patients described in the included articles, as some reports use variable terminology (HLH vs hemophagocytic syndrome vs macrophage activation syndrome, etc), and it is impossible to know if all authors used the same diagnostic criteria—or any validated diagnostic criteria—unless specifically stated. Additionally, including case reports in our study limited the amount and quality of information described in each report. Despite its limitations, this systematic review outlines the cutaneous manifestations associated with HLH. These data will promote clinical awareness of this complex condition and allow for consideration of HLH in patients meeting criteria for HLH syndrome. More studies ultimately are needed to differentiate HLH from its mimics.

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.

Idiopathic postprandial syndrome (IPP), initially termed reactive hypoglycemia, presents with hypoglycemic-like symptoms in the absence of biochemical hypoglycemia and remains a diagnosis of exclusion. Its pathophysiology is poorly understood. The diagnosis requires thorough evaluation of cardiac, metabolic, neurologic, and gastrointestinal causes, as well as Whipple triad criteria. Dietary modifications, including reduced carbohydrate intake, increased protein and fiber, and frequent small meals, remain the cornerstone of IPP management. Continuous glucose monitoring (CGM) may be a useful adjunct in correlating symptoms with glucose trends, but its role is still evolving.

In the evaluation of patients with symptoms suggestive of hypoglycemia (Figure 1), patients should first be assessed for Whipple triad: symptoms consistent with hypoglycemia, blood glucose level < 55 mg/dL, and reversal of symptoms with glucose.¹ Patients who meet Whipple triad criteria should be investigated to identify further etiologies of hypoglycemia. They may include insulinoma, medication-induced (insulin, sulfonylurea, meglitinide, or β blocker use), postbariatric surgery complications, noninsulinoma pancreatogenous hypoglycemia syndrome, ackee fruit consumption, or familial conditions.² The presence of hypoglycemic symptoms in the postprandial or fasting state can provide valuable insights into underlying etiology. 

Patients who do not meet Whipple triad criteria, but exhibit postprandial symptoms consistent with hypoglycemia, as in this case, present a diagnostic dilemma. IPP is defined as hypoglycemic symptoms occuring after carbohydrate ingestion without biochemical hypoglycemia. Initially termed reactive hypoglycemia, it was renamed in 1981to reflect the absence of low blood glucose levels.³

The understanding of this diagnosis has not significantly progressed since the 1980s. Its prevalence, incidence, risk factors, and societal burden remain unclear. IPP is a challenging diagnosis due to nonspecific symptoms that overlap with a myriad of conditions. These symptoms may include adrenergic symptoms such as diaphoresis, tremulousness, palpitations, anxiety, and hunger. Potentially severe neuroglycopenic symptoms, including weakness, dizziness, behavior changes, confusion, and coma, are not typically observed.⁴ Given that objective criteria are not well established, IPP remains a diagnosis of exclusion. It is imperative to rule out alternative etiologies, particularly cardiac, gastrointestinal, and neurologic causes.

CASE PRESENTATION

A male aged 41 years presented to primary care for evaluation of acute on chronic symptomatic postprandial episodes. He reported a history of symptomatic sinus bradycardia in the setting of sick sinus syndrome following dual-chamber pacemaker placement, posttraumatic stress disorder, and gastroesophageal reflux disease. He was a retired Navy sailor without any known occupational exposures who worked in the real estate industry. The patient reported feeling lightheaded, tremulous, and anxious most afternoons after lunch for several years. He also reported that meals heavy in carbohydrates exacerbated his symptoms, whereas skipping meals or lying down alleviated his symptoms. The patient also reported concomitant arm numbness, shortness of breath, palpitations, and nausea during these episodes. Review of systems was otherwise negative, including no weight changes, fever, chills, night sweats, chest pain, or syncope.

The patient’s medications included ferrous sulfate 325 mg once every other day, bupropion 200 mg once daily, metoprolol succinate 25 mg once daily, and as-needed lorazepam 1 mg once daily. The patient reported no current substance use but reported previous tobacco use 3 years prior (maximum 1 pack/week) and alcohol use 5 years prior (750 ml/day for 15 years). The patient did not exercise and typically ate oatmeal for breakfast, a sandwich or salad for lunch, and taquitos or salad for dinner, with snacks throughout the day. Notable family history included a maternal grandmother with colon cancer. The patient’s vital signs included a 36.8 °C temperature, heart rate 87 beats/min, 118/71 mm Hg blood pressure, oxygen saturation 98% on room air, 125.2 kg weight, and 38.5 body mass index. There were no orthostatic vital sign changes. A physical examination demonstrated obesity with an unremarkable cardiopulmonary and volume examination. 

Additional testing included Gallium-68 dototate positron emission tomography/computed tomography, brain magnetic resonance imaging, echocardiogram, electromyogram, exercise tolerance test, Holter monitoring, invasive cardiopulmonary exercise testing, pacemaker interrogation, pulmonary function testing, stress echocardiogram, tilt table test, and venogram computed tomography of the chest, but the results were unremarkable (Appendix). His afternoon nonfasting glucose level was 138 mg/dL with a concurrent hemoglobin A_1c of 5.2%. The patient had a fasting C-peptide level of 3.7 ng/mL (reference range 0.5-2.0 ng/mL), fasting insulin level 19.1 mIU/L (reference range < 25 mIU/L), and a fasting glucose level of 93 mg/dL (reference range 70-99 mg/dL). The patient’s urine 5-HIAA, plasma metanephrines, urine metanephrines, insulin-like growth factor 1, prolactin, corticotropin, fasting cortisol, and thyrotropin yielded results within reference ranges (Table). The veteran was prescribed a CGM, which demonstrated normal glucose levels (≥ 55 mg/dL) during symptomatic episodes (Figure 2).

The patient was diagnosed with IPP given normoglycemia, exclusion of alternative diagnoses, and symptomatic improvement with dietary changes. He was referred to a nutritionist for a high-protein, high-fiber, and low-carbohydrate diet.

DISCUSSION

Seemingly simple diagnostic tools can lead to diagnostic pitfalls. Home glucose monitoring with the use of a standard glucometer during an episode is the typical first step in identifying hypoglycemia, as it is both pragmatic and accurate, with a mean absolute relative difference (MARD) of about 10% in hypoglycemic ranges.⁵ While the advent of CGM provides real-time data and can reveal clinically relevant fluctuations, it reveals mild hypoglycemia (54 to 70 mg/dL) of no clinical significance in a large proportion of individuals.

Additionally, CGM is less accurate than glucometers with a MARD of about 20% in hypoglycemia ranges.⁶ CGM technology, however, is rapidly evolving and undergoing further investigation for hypoglycemia detection. Therefore, CGM may be considered in select patients as prospective study results are established; the newest CGMs have MARDs very similar to fingerstick blood glucose data.^7,8 In the patient described in this case, CGM helped corroborate the diagnosis, given that symptomatic episodes correlated with lower glucose levels. Provocative testing with oral glucose tolerance testing can frequently result in false positive hypoglycemic readings and is not recommended.⁹ Supervised mixed meal testing can also be used, which entails monitoring after consuming a mixed macronutrient meal. The test concludes after hypoglycemic symptoms develop or 5 hours elapse, whichever occurs first.¹

The pathophysiology of IPP is poorly understood. Proposed mechanisms include increased insulin sensitivity, increased adrenergic sensitivity, impaired glucagon regulation, emotional distress, insulin resistance, and increased glucagon-like peptide-1 production.^10-13 Research suggests this may occur as pancreatic β cells fail in early type 2 diabetes mellitus, with diminished first-phase insulin release leading to an initial exuberant rise in blood glucose, an overshooting of the second phase of insulin secretion, and the feeling of the postprandial blood glucose falling, even though the final glucose level achieved is not truly low.¹³ There are contradictory studies in the literature demonstrating no association between insulin resistance and hypoglycemic symptoms.¹⁴ In 2022, Kosuda and colleagues looked at homeostatic model assessment for insulin resistance in patients with postprandial syndrome. They found that the patients were slightly insulin resistant but had normal or exaggerated insulin secretory capacity compared to an oral glucose load, whereas glucagon levels were robustly suppressed by a glucose load. The observed hormonal responses may result in the glycemic patterns and symptoms observed; further study is warranted to elucidate the mechanism.¹⁵

Dietary modification is the cornerstone treatment for postprandial syndrome, including reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals. There is also evidence that a Mediterranean diet may be beneficial for managing hypoglycemic symptoms.¹⁶ Furthermore, α-glucosidase inhibitors, whose mechanism of action delays the digestion of carbohydrates, have demonstrated promise. This medication class has demonstrated significance in raising postprandial glucose levels and alleviating hypoglycemic symptoms in patients with true postprandial hypoglycemia.¹⁷

CONCLUSIONS

IPP is a benign diagnosis encompassing hypoglycemic symptoms without biochemical hypoglycemia. It is not a true hypoglycemic disorder. IPP is challenging to diagnose, given that it is an interpretation of exclusion, supported by symptom improvement with dietary changes (ie, reduced carbohydrate intake, increased protein and fiber intake, and more frequent and smaller meals). Supervised mixed meal testing or CGM can be used to assist with diagnosis. Even though CGM is undergoing further study in this patient population, it corroborated the diagnosis in the patient described in this case.

For hypoglycemic symptoms, physicians should first assess for evidence of Whipple triad to evaluate for true biochemical hypoglycemia. For true hypoglycemia (< 55 mg/dL), physicians may conduct an examination in conjunction with an endocrinologist. For normoglycemia (≥ 55 mg/dL), physicians should first exclude alternative etiologies (including cardiac and neurologic), and subsequently consider IPP.