Mixed Topics

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.

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

THE DIAGNOSIS: Granuloma Faciale

Histology revealed a dense mixed inflammatory cell infiltrate with conspicuous neutrophils and eosinophils in the upper to mid dermis with a narrow uninvolved grenz zone beneath the epidermis (Figures 1 and 2). These findings along with the clinical presentation (Figure 3) were consistent with a diagnosis of granuloma faciale (GF). Most often seen in middle-aged White men, GF is an uncommon localized inflammatory skin condition that often manifests as a single, well-defined, red-to-brown papule, nodule, or plaque on the face or other sun-exposed areas of the skin. Since numerous other skin diseases manifest similarly to GF, biopsy is necessary for definitive diagnosis.¹ Histopathology of GF classically shows a mixed inflammatory infiltrate with a narrow band of uninvolved dermis separating it from the epidermis (grenz zone). Dilated follicular plugs and vascular changes frequently are appreciated. Despite its name, GF does not include granulomas and is thought to be similar to leukocytoclastic vasculitis.¹ Reports of GF in the literature have shown immunohistochemical staining with the presence of CD4+ lymphocytes that secrete IL-5, a chemotactic agent responsible for attracting eosinophils that contributes to the eosinophilic infiltrate on histology.²

Topical corticosteroids and topical tacrolimus are the first-line treatments for GF. Intralesional corticosteroids also are a treatment option and can be used in combination with cryotherapy.^1,3 Additionally, both topical and oral dapsone have been shown to be effective for GF.¹ Oral dapsone is given at a dose of 50 mg to 150 mg once daily.¹ Clofazimine, typically used as an antileprosy treatment, also has been efficacious in treating GF. Clofazimine has anti-inflammatory and antiproliferative effects on lymphocytes that may attenuate the inflammation underlying GF. It is prescribed at a dose of 300 mg once daily for 3 to 5 months.¹

The differential diagnosis for GF is broad and includes tumid lupus erythematosus, Jessner lymphocytic infiltrate (JLI), cutaneous sarcoidosis, and mycosis fungoides. Tumid lupus erythematosus is a subtype of cutaneous lupus erythematosus that rarely is associated with systemic lupus manifestations. Tumid lupus erythematosus manifests as annular, indurated, erythematous plaques, whereas JLI manifests with erythematous papular to nodular lesions without scale on the upper back or face.⁴ Jessner lymphocytic infiltrate and tumid lupus erythematosus are histopathologically identical, with abundant dermal mucin deposition and a superficial and deep perivascular and periadnexal lymphocytic infiltrate. It is debatable whether JLI is a separate entity or a variant of tumid lupus erythematosus. Sarcoidosis is a granulomatous disease that manifests with a myriad of clinical features. The skin is the second most commonly involved organ.⁵ The most common morphology is numerous small, firm, nonscaly papules, typically on the face. Histology in cutaneous sarcoidosis will show lymphocyte-poor, noncaseating epithelioid cell granulomas with positive reticulin staining, which were not seen in our patient.⁶ Lastly, mycosis fungoides is the most common type of cutaneous T-cell lymphoma. It can manifest as patches, plaques, or tumors. The plaque stage may mimic GF as lesions are infiltrative, annular, and raised, with well-defined margins. Histopathology will show intraepidermal lymphocytes out of proportion with spongiosis.⁷

Dear Friends,

Over the last year, I have been reading more about professional identity and professional branding, all of which have evolved in the setting of social media. However, the root of it remains constant — finding the intersection(s) of what you love. A common problem, especially as a trainee and early-career gastroenterologist, is that you may have many interests: various disease processes, innovation, medical education, leadership development, and much more. Since becoming faculty, I continue to define and refine my professional niche, trying to distinguish my “interests” from “passions.” It is a journey that my mentors advise me not to rush through and I am enjoying every moment of it!

In this issue’s “In Focus,” Dr. Hamza Salim, Dr. Anni Chowdhury, and Dr. Lavanya Viswanathan provide a practical guide for the clinical evaluation of chronic constipation and a systematic approach to treatment.

 

In the first of a two-part series in the “Short Clinical Review” section, Dr. Christopher Velez and Dr. Kara J. Jencks discuss the health inequities among sexual and gender minority (SGM) patients, particularly with disorders of brain-gut interaction (DBGI). They review common SGM terminology, sample verbiage for trauma-informed care, and case presentations to help guide our approach to providing care for SGM patients with DGBI. 

The transition from trainee to early faculty may be difficult for those who are interested in research but struggle with the change from being a part of a research team to running one. In the “Early Career” section, Dr. Lauren Feld and colleagues describes her experience establishing a research lab as an early-career academic, from creating a niche to time management and mentorship.

The Federal Trade Commission’s noncompete ban made big news in April 2024 but there is still a lot of gray area for physicians. Dr. Timothy Craig Allen explains the ruling, what it means to physicians, the status of it today, and what the future may hold. Lastly, for “Private Practice Perspectives” in collaboration with Digestive Health Physicians Alliance, I interview Dr. Vasu Appalaneni on her use of artificial intelligence in private practice.

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Danielle Kiefer ([email protected]), Communications/Managing Editor of TNG.

Until next time, I leave you with a historical fun fact because we would not be where we are now without appreciating where we were: Polyethylene glycol was first used in the 1940s and 1950s to understand the physiology of the intestines, and first published as a compound for colonoscopy bowel preparation in 1981. 

 

Yours truly, 

Judy A. Trieu, MD, MPH

Editor-in-Chief

Assistant Professor of Medicine

Interventional Endoscopy, Division of Gastroenterology

Washington University in St. Louis

Dear Friends,

Over the last year, I have been reading more about professional identity and professional branding, all of which have evolved in the setting of social media. However, the root of it remains constant — finding the intersection(s) of what you love. A common problem, especially as a trainee and early-career gastroenterologist, is that you may have many interests: various disease processes, innovation, medical education, leadership development, and much more. Since becoming faculty, I continue to define and refine my professional niche, trying to distinguish my “interests” from “passions.” It is a journey that my mentors advise me not to rush through and I am enjoying every moment of it!

In this issue’s “In Focus,” Dr. Hamza Salim, Dr. Anni Chowdhury, and Dr. Lavanya Viswanathan provide a practical guide for the clinical evaluation of chronic constipation and a systematic approach to treatment.

 

In the first of a two-part series in the “Short Clinical Review” section, Dr. Christopher Velez and Dr. Kara J. Jencks discuss the health inequities among sexual and gender minority (SGM) patients, particularly with disorders of brain-gut interaction (DBGI). They review common SGM terminology, sample verbiage for trauma-informed care, and case presentations to help guide our approach to providing care for SGM patients with DGBI. 

The transition from trainee to early faculty may be difficult for those who are interested in research but struggle with the change from being a part of a research team to running one. In the “Early Career” section, Dr. Lauren Feld and colleagues describes her experience establishing a research lab as an early-career academic, from creating a niche to time management and mentorship.

The Federal Trade Commission’s noncompete ban made big news in April 2024 but there is still a lot of gray area for physicians. Dr. Timothy Craig Allen explains the ruling, what it means to physicians, the status of it today, and what the future may hold. Lastly, for “Private Practice Perspectives” in collaboration with Digestive Health Physicians Alliance, I interview Dr. Vasu Appalaneni on her use of artificial intelligence in private practice.

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Danielle Kiefer ([email protected]), Communications/Managing Editor of TNG.

Until next time, I leave you with a historical fun fact because we would not be where we are now without appreciating where we were: Polyethylene glycol was first used in the 1940s and 1950s to understand the physiology of the intestines, and first published as a compound for colonoscopy bowel preparation in 1981. 

 

Yours truly, 

Judy A. Trieu, MD, MPH

Editor-in-Chief

Assistant Professor of Medicine

Interventional Endoscopy, Division of Gastroenterology

Washington University in St. Louis

Dear Friends,

Over the last year, I have been reading more about professional identity and professional branding, all of which have evolved in the setting of social media. However, the root of it remains constant — finding the intersection(s) of what you love. A common problem, especially as a trainee and early-career gastroenterologist, is that you may have many interests: various disease processes, innovation, medical education, leadership development, and much more. Since becoming faculty, I continue to define and refine my professional niche, trying to distinguish my “interests” from “passions.” It is a journey that my mentors advise me not to rush through and I am enjoying every moment of it!

In this issue’s “In Focus,” Dr. Hamza Salim, Dr. Anni Chowdhury, and Dr. Lavanya Viswanathan provide a practical guide for the clinical evaluation of chronic constipation and a systematic approach to treatment.

 

In the first of a two-part series in the “Short Clinical Review” section, Dr. Christopher Velez and Dr. Kara J. Jencks discuss the health inequities among sexual and gender minority (SGM) patients, particularly with disorders of brain-gut interaction (DBGI). They review common SGM terminology, sample verbiage for trauma-informed care, and case presentations to help guide our approach to providing care for SGM patients with DGBI. 

The transition from trainee to early faculty may be difficult for those who are interested in research but struggle with the change from being a part of a research team to running one. In the “Early Career” section, Dr. Lauren Feld and colleagues describes her experience establishing a research lab as an early-career academic, from creating a niche to time management and mentorship.

The Federal Trade Commission’s noncompete ban made big news in April 2024 but there is still a lot of gray area for physicians. Dr. Timothy Craig Allen explains the ruling, what it means to physicians, the status of it today, and what the future may hold. Lastly, for “Private Practice Perspectives” in collaboration with Digestive Health Physicians Alliance, I interview Dr. Vasu Appalaneni on her use of artificial intelligence in private practice.

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]) or Danielle Kiefer ([email protected]), Communications/Managing Editor of TNG.

Until next time, I leave you with a historical fun fact because we would not be where we are now without appreciating where we were: Polyethylene glycol was first used in the 1940s and 1950s to understand the physiology of the intestines, and first published as a compound for colonoscopy bowel preparation in 1981. 

 

Yours truly, 

Judy A. Trieu, MD, MPH

Editor-in-Chief

Assistant Professor of Medicine

Interventional Endoscopy, Division of Gastroenterology

Washington University in St. Louis

Former Secretary of State Condoleezza Rice once said: “There is no greater challenge and there is no greater honor than to be in public service.” It has been a challenging few months for public servants, including the thousands of federal healthcare and public health workers who care for our veterans, provide critical services to underserved communities, work to fund high-impact biomedical research that improves health outcomes, and otherwise further important public health goals.

From the VA to the Department of Health & Human Services and its operating divisions, including the Centers for Disease Control and Prevention, National Institutes of Health, Centers for Medicare & Medicaid Services, and others, dedicated federal civil servants have had their work ethic, commitment, and productivity questioned in late-night emails from anonymous authors. They have been encouraged indiscriminately to resign and “move from [their] lower-productivity jobs in the public sector to higher-productivity jobs in the private sector,” and been subjected to vague threats of future job loss regardless of role, duration of service, performance, or political persuasion. This includes the roughly 30% of federal employees who are themselves US military veterans.

 

In essence, the message is that their work does not matter, and their service and sacrifice is not valued (which, of course, could not be further from the truth). These actions, along with a plethora of other divisive policies, not only threaten our democratic principles, but also serve to degrade our collective values and norms. We are at a “fork in the road” as a nation. I hope for the greater good that we can work together to uphold the value of public service, of community, of civility — both for the sake of our democracy and to preserve our nation’s health.

In our March issue, we celebrate National Colorectal Cancer Awareness Month with relevant summaries of emerging science, highlights of AGA resources, and a Perspectives column addressing the pros and cons of endoscopic vs. surgical management of large colon polyps. This month’s Member Spotlight features Dr. Pooja Singhal (Oklahoma Gastro Health and Wellness), who describes how she integrates wellness principles into her clinical practice, discusses the evolution of her interest in women’s digestive health, and shares how she serves her community outside of medicine.

Megan A. Adams, MD, JD, MSc

Editor in Chief

Former Secretary of State Condoleezza Rice once said: “There is no greater challenge and there is no greater honor than to be in public service.” It has been a challenging few months for public servants, including the thousands of federal healthcare and public health workers who care for our veterans, provide critical services to underserved communities, work to fund high-impact biomedical research that improves health outcomes, and otherwise further important public health goals.

From the VA to the Department of Health & Human Services and its operating divisions, including the Centers for Disease Control and Prevention, National Institutes of Health, Centers for Medicare & Medicaid Services, and others, dedicated federal civil servants have had their work ethic, commitment, and productivity questioned in late-night emails from anonymous authors. They have been encouraged indiscriminately to resign and “move from [their] lower-productivity jobs in the public sector to higher-productivity jobs in the private sector,” and been subjected to vague threats of future job loss regardless of role, duration of service, performance, or political persuasion. This includes the roughly 30% of federal employees who are themselves US military veterans.

 

In essence, the message is that their work does not matter, and their service and sacrifice is not valued (which, of course, could not be further from the truth). These actions, along with a plethora of other divisive policies, not only threaten our democratic principles, but also serve to degrade our collective values and norms. We are at a “fork in the road” as a nation. I hope for the greater good that we can work together to uphold the value of public service, of community, of civility — both for the sake of our democracy and to preserve our nation’s health.

In our March issue, we celebrate National Colorectal Cancer Awareness Month with relevant summaries of emerging science, highlights of AGA resources, and a Perspectives column addressing the pros and cons of endoscopic vs. surgical management of large colon polyps. This month’s Member Spotlight features Dr. Pooja Singhal (Oklahoma Gastro Health and Wellness), who describes how she integrates wellness principles into her clinical practice, discusses the evolution of her interest in women’s digestive health, and shares how she serves her community outside of medicine.

Megan A. Adams, MD, JD, MSc

Editor in Chief

Former Secretary of State Condoleezza Rice once said: “There is no greater challenge and there is no greater honor than to be in public service.” It has been a challenging few months for public servants, including the thousands of federal healthcare and public health workers who care for our veterans, provide critical services to underserved communities, work to fund high-impact biomedical research that improves health outcomes, and otherwise further important public health goals.

From the VA to the Department of Health & Human Services and its operating divisions, including the Centers for Disease Control and Prevention, National Institutes of Health, Centers for Medicare & Medicaid Services, and others, dedicated federal civil servants have had their work ethic, commitment, and productivity questioned in late-night emails from anonymous authors. They have been encouraged indiscriminately to resign and “move from [their] lower-productivity jobs in the public sector to higher-productivity jobs in the private sector,” and been subjected to vague threats of future job loss regardless of role, duration of service, performance, or political persuasion. This includes the roughly 30% of federal employees who are themselves US military veterans.

 

In essence, the message is that their work does not matter, and their service and sacrifice is not valued (which, of course, could not be further from the truth). These actions, along with a plethora of other divisive policies, not only threaten our democratic principles, but also serve to degrade our collective values and norms. We are at a “fork in the road” as a nation. I hope for the greater good that we can work together to uphold the value of public service, of community, of civility — both for the sake of our democracy and to preserve our nation’s health.

In our March issue, we celebrate National Colorectal Cancer Awareness Month with relevant summaries of emerging science, highlights of AGA resources, and a Perspectives column addressing the pros and cons of endoscopic vs. surgical management of large colon polyps. This month’s Member Spotlight features Dr. Pooja Singhal (Oklahoma Gastro Health and Wellness), who describes how she integrates wellness principles into her clinical practice, discusses the evolution of her interest in women’s digestive health, and shares how she serves her community outside of medicine.

Megan A. Adams, MD, JD, MSc

Editor in Chief

A burst sprinkler pipe and broken steam system caused significant infrastructure failures and wreaked havoc on patient care at Walter Reed National Military Medical Center in January. 

An email sent to Walter Reed staff from the medical center’s director, Navy Capt. Melissa C. Austin, said 60,000 gallons of water, or enough “to fill a 25x50 foot swimming pool” flooded throughout the facility on Jan. 20 before it was contained, damaging 50 rooms and 6 elevators. 

Frozen pipes burst due to extreme cold, and the issues were exacerbated by aging infrastructure and “deferred maintenance due to underfunding,” the Defense Health Agency (DHA), which oversees Walter Reed, said in a public statement. 

The damage was severe enough to impact patient care. The facility had to evacuate the neonatal intensive care unit as well as several clinics. The steam system outages also meant operating rooms had fewer clean surgical tools available and had to send them to regional hospitals for sterilization, staffers told The Washington Post. Health care workers could not “flash sterilize” equipment in emergencies, further risking patient safety.

Rick McNamara, a spokesperson for the Defense Health Network National Capital Region, confirmed other hospitals are “sharing the burden” to sterilize equipment. McNamara said it could take 6 weeks to complete the immediate repairs, which will cost between $1 million and $2 million.

Patient appointments were delayed, and nonemergency procedures were canceled or delayed. Overall, 212 patients were “deferred or rescheduled,” and 56 other patients were sent to other hospitals to receive care.

Defense Secretary Pete Hegseth said on Jan. 31 the problem was “real and unacceptable” in response to a video circulating on social media that showed flooding.

Acknowledging that the water damage “temporarily impacted health care operations,” the Defense Department says DHA and Walter Reed staff were “working diligently around the clock” to find and implement solutions while minimizing disruptions to patient care: “High waters and loss of steam pressure impacted the capacity of services delivered, but the ability to deliver the hospital’s core capabilities of safe, quality care was never compromised,” the agency said.

In response to the flooding, the hospital moved quickly to provide the required urgent care: “We are utilizing all the hospitals and clinics in the National Capital Region Network from Malcom Grow at Joint Base Andrews to Kimbrough Ambulatory Care Center at Fort Meade to the Alexander T. Augusta Military Medical Center at Fort Belvoir,” Capt. Austin said. 

DHA is also funding emergency work orders and contract modifications required to return Walter Reed to full operational capability. It is prioritizing resources for repairs and is collaborating with the Naval Installations Command and Naval Support Activity Bethesda to implement necessary repairs.

“This acute issue is being managed aggressively to ensure patient care continues to be delivered safely,” DHA said

A burst sprinkler pipe and broken steam system caused significant infrastructure failures and wreaked havoc on patient care at Walter Reed National Military Medical Center in January. 

An email sent to Walter Reed staff from the medical center’s director, Navy Capt. Melissa C. Austin, said 60,000 gallons of water, or enough “to fill a 25x50 foot swimming pool” flooded throughout the facility on Jan. 20 before it was contained, damaging 50 rooms and 6 elevators. 

Frozen pipes burst due to extreme cold, and the issues were exacerbated by aging infrastructure and “deferred maintenance due to underfunding,” the Defense Health Agency (DHA), which oversees Walter Reed, said in a public statement. 

The damage was severe enough to impact patient care. The facility had to evacuate the neonatal intensive care unit as well as several clinics. The steam system outages also meant operating rooms had fewer clean surgical tools available and had to send them to regional hospitals for sterilization, staffers told The Washington Post. Health care workers could not “flash sterilize” equipment in emergencies, further risking patient safety.

Rick McNamara, a spokesperson for the Defense Health Network National Capital Region, confirmed other hospitals are “sharing the burden” to sterilize equipment. McNamara said it could take 6 weeks to complete the immediate repairs, which will cost between $1 million and $2 million.

Patient appointments were delayed, and nonemergency procedures were canceled or delayed. Overall, 212 patients were “deferred or rescheduled,” and 56 other patients were sent to other hospitals to receive care.

Defense Secretary Pete Hegseth said on Jan. 31 the problem was “real and unacceptable” in response to a video circulating on social media that showed flooding.

Acknowledging that the water damage “temporarily impacted health care operations,” the Defense Department says DHA and Walter Reed staff were “working diligently around the clock” to find and implement solutions while minimizing disruptions to patient care: “High waters and loss of steam pressure impacted the capacity of services delivered, but the ability to deliver the hospital’s core capabilities of safe, quality care was never compromised,” the agency said.

In response to the flooding, the hospital moved quickly to provide the required urgent care: “We are utilizing all the hospitals and clinics in the National Capital Region Network from Malcom Grow at Joint Base Andrews to Kimbrough Ambulatory Care Center at Fort Meade to the Alexander T. Augusta Military Medical Center at Fort Belvoir,” Capt. Austin said. 

DHA is also funding emergency work orders and contract modifications required to return Walter Reed to full operational capability. It is prioritizing resources for repairs and is collaborating with the Naval Installations Command and Naval Support Activity Bethesda to implement necessary repairs.

“This acute issue is being managed aggressively to ensure patient care continues to be delivered safely,” DHA said

A burst sprinkler pipe and broken steam system caused significant infrastructure failures and wreaked havoc on patient care at Walter Reed National Military Medical Center in January. 

An email sent to Walter Reed staff from the medical center’s director, Navy Capt. Melissa C. Austin, said 60,000 gallons of water, or enough “to fill a 25x50 foot swimming pool” flooded throughout the facility on Jan. 20 before it was contained, damaging 50 rooms and 6 elevators. 

Frozen pipes burst due to extreme cold, and the issues were exacerbated by aging infrastructure and “deferred maintenance due to underfunding,” the Defense Health Agency (DHA), which oversees Walter Reed, said in a public statement. 

The damage was severe enough to impact patient care. The facility had to evacuate the neonatal intensive care unit as well as several clinics. The steam system outages also meant operating rooms had fewer clean surgical tools available and had to send them to regional hospitals for sterilization, staffers told The Washington Post. Health care workers could not “flash sterilize” equipment in emergencies, further risking patient safety.

Rick McNamara, a spokesperson for the Defense Health Network National Capital Region, confirmed other hospitals are “sharing the burden” to sterilize equipment. McNamara said it could take 6 weeks to complete the immediate repairs, which will cost between $1 million and $2 million.

Patient appointments were delayed, and nonemergency procedures were canceled or delayed. Overall, 212 patients were “deferred or rescheduled,” and 56 other patients were sent to other hospitals to receive care.

Defense Secretary Pete Hegseth said on Jan. 31 the problem was “real and unacceptable” in response to a video circulating on social media that showed flooding.

Acknowledging that the water damage “temporarily impacted health care operations,” the Defense Department says DHA and Walter Reed staff were “working diligently around the clock” to find and implement solutions while minimizing disruptions to patient care: “High waters and loss of steam pressure impacted the capacity of services delivered, but the ability to deliver the hospital’s core capabilities of safe, quality care was never compromised,” the agency said.

In response to the flooding, the hospital moved quickly to provide the required urgent care: “We are utilizing all the hospitals and clinics in the National Capital Region Network from Malcom Grow at Joint Base Andrews to Kimbrough Ambulatory Care Center at Fort Meade to the Alexander T. Augusta Military Medical Center at Fort Belvoir,” Capt. Austin said. 

DHA is also funding emergency work orders and contract modifications required to return Walter Reed to full operational capability. It is prioritizing resources for repairs and is collaborating with the Naval Installations Command and Naval Support Activity Bethesda to implement necessary repairs.

“This acute issue is being managed aggressively to ensure patient care continues to be delivered safely,” DHA said

Conducting clinical research as an early career gastroenterologist can take on many forms and has varying definitions of success. This article focuses on key factors to consider and should be supplemented with mentorship tailored to personal interests, goals, and institutional criteria for success. In this article, we will discuss selected high-yield topics that assist in early-career research. We will briefly discuss 1. Defining your niche, 2. Collaboration, 3. Visibility, 4. Time management, 5. Funding, 6. Receiving mentorship, and 7. Providing mentorship. We will conclude with discussing several authors’ experience in the research lab of the first author (FELD Lab – Fostering Equity in Liver and Digestive disease).

Defining Your Niche

Defining your niche is an essential component of an early career, as when academicians must transition from a trainee, who is supporting the research of an established mentor, to defining their own subspeciality area of investigation. Early-career academics should build on their prior work, but should also explore their own passions and skill set to define what will be unique about their research program and contributions to the field. Of course, positioning oneself at the intersection of two or more seemingly unrelated fields opens much opportunity for large impact but comes at a cost of identifying mentorship and justifying the niche to funders.

Collaboration

Fostering a collaborative environment is essential for early-career physician-researchers. One effective approach is to establish collaboration circles with other early career academics. Expanding research endeavors beyond a single institution to a multi-center framework enriches both scope and impact. This collaborative approach not only amplifies the depth of research but also facilitates peer mentorship and sponsorship. Participation in such networks can significantly enhance scholarly output and broaden professional reach during this critical phase of academic progression. Furthermore, prioritizing the promotion of colleagues within these networks is crucial. Proactive sponsorship opportunities, such as inviting peers to present at institutional seminars, strengthen both individual and collective academic visibility.

Collaboration is also essential to foster between trainees involved in early-career investigators’ work. An interconnected lab environment ensures that trainees remain informed about concurrent projects, thereby fostering a culture of shared knowledge and optimized productivity. Encouraging trainees to spearhead research aligned with their interests, under mentor guidance, nurtures independent inquiry and leadership. By establishing explicit roles, responsibilities, and authorship agreements at the outset of collaborative projects, early career mentors can avoid future conflicts and preserve a collaborative culture within the lab. This structured approach cultivates a supportive ecosystem, advancing both individual and collective research achievements.

 

Visibility

Establishing visibility and developing name recognition are crucial components of career advancement for early-career academic physicians. By clearly defining their areas of expertise, faculty can position themselves as leaders within their discipline. Active participation in professional societies, both at the local and national level, engagement with interest groups, and frequent contributions to educational events can be effective strategies for gaining recognition. Leveraging social media platforms can be helpful in enhancing visibility by facilitating connections and promoting research to a broader audience.

Moreover, research visibility plays a vital role in academic promotion. A strong publication record, reflected by an increasing h-index, demonstrates the impact and relevance of one’s research. Self-citation, when appropriate, can reinforce the continuity and progression of scholarly contributions. While publishing in high-impact journals is desirable, adaptability in resubmitting to other journals following rejections ensures that research remains visible and accessible. It also clearly establishes by whom the work was first done, before someone else investigates the line of inquiry. Through a combination of strategic engagement and publication efforts, early-career physicians can effectively build their professional reputation and advance their academic careers.

 

Time Management

Time management is essential for any research, and particularly in early career when efficiency in clinical care duties is still being gained. Securing protected time for research is essential to develop a niche, build connections (both institutionally and beyond their institutions), and demonstrate productivity that can be utilized to support future grant efforts.

Similarly, using protected time efficiently is required. Without organization and planning, research time can be spent with scattered meetings and responding to various tasks that do not directly support your research. It is helpful to be introspective about the time of the day you are most productive in your research efforts and blocking off that time to focus on research tasks and minimizing distractions. Blocking monthly time for larger scale thinking and planning is also important. Weekly lab and individual one-on-one meetings also support time management for trainees and lab members, to ensure efficiency and progress. Additionally, robust clinical support is essential to ensure that research time remains protected and patient care moves forward. When negotiating for positions, and in regular meetings thereafter, it is important to advocate for sufficient clinical staffing such that non-physician tasks can be appropriately delegated to another member of the care team. 

 

Funding

Securing adequate funding poses a significant challenge for all early-career physician-scientists, particularly because of the discrepancy between National Institutes of Health salary caps and the higher average salaries in academic gastroenterology. This financial gap can deter physicians from pursuing research-intensive careers altogether and can derail early investigators who do not obtain funding rapidly. To overcome this, early-career investigators may need to adopt flexible strategies, such as accepting a lower salary that aligns with grant funding limits or funneling incentive or bonus pay to research accounts. Alternatively, they can advocate for institutional support to bridge the salary gap, ensuring their research efforts remain financially viable.

Institutions committed to fostering research excellence may offer supplemental funding or bridge programs to retain talented physician-scientists, thereby mitigating the financial strain and encouraging long-term engagement in research. Regular meetings to review salary and support sources, including philanthropy, foundation grants, and other streams, should be undertaken with leadership to align the researcher’s timeline and available funding. If career development funding appears untenable, consideration of multi–principal investigator R01s or equivalent with senior established investigators can be a promising path. 

 

Receiving Mentorship

Effective mentorship for early-career physician-scientists should be approached through a team-based model that leverages both internal and external mentors. Internal mentors, familiar with the specific culture, expectations, and advancement pathways of the institution, can provide invaluable guidance on navigating institutional metrics for success, such as promotion criteria, grant acquisition, and clinical-research balance. External mentors, on the other hand, bring a broader perspective by offering innovative career development strategies and solutions derived from experiences at their home institutions. This multimodal mentorship model ensures a well-rounded approach to professional growth.

All national gastroenterology societies, including the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy, and American Association for the Study of Liver Disease, offer structured early-career mentorship programs designed to connect emerging researchers with experienced leaders in the field (see below). These programs typically require a formal application process and are highly regarded for their exceptional quality and impact. Participation in such initiatives can significantly enhance career development by expanding networks, fostering interdisciplinary collaboration, and providing tailored guidance that complements institutional support. Integrating both internal and external mentorship opportunities ensures a robust and dynamic foundation for long-term success in academic medicine.

• AGA Career Compass (https://gastro.org/fellows-and-early-career/mentoring/)
• ACG Early Career Leadership Program (https://gi.org/acg-institute/early-career-leadership-program/)
• AGA-AASLD Academic Skills Workshop (https://gastro.org/news/applications-now-being-accepted-for-the-2024-aga-aasld-academic-skills-workshop/)
• AASLD Women’s Initiative Committee Leadership Program (https://www.aasld.org/promoting-leadership-potential-women-hepatology)
• Scrubs n Heels Mentorship Matrix (https://scrubsandheels.com/matrix/)

Providing Mentorship

The trainee authors on this manuscript describe in this section what has been helpful for them as mentees in the FELD research lab.

Student doctor Nguyen describes her experience as a lab member and things she finds most helpful as a medical student in the lab:

• Upon joining the team, a one-to-one meeting to discuss trainee’s personal and professional goals, and availability, was crucial to building the mentor-mentee relationship. Establishing this meaningful mentorship early on clarified expectations on both sides, built trust, and increased motivation. As a trainee, it is essential for me to see how my work aligns with a long-term goal and to receive ample guidance throughout the process.
• One of the most impactful experiences has been joining informal lunch sessions where trainees discussed data collection protocols and exchanged insights. In doing so, Dr. Feld has cultivated a lab culture that encourages curiosity, constructive feedback, and collaborative learning.
• To increase productivity, our team of trainees created a useful group message thread where we coordinated more sessions to collaborate. This coordination formed stronger relationships between team members and fostered a sense of shared purpose.

Dr. Cooper, a third year internal medicine resident, describes her experience as both a research mentee and a mentor to the junior trainees: “As a resident pursuing a career in academic gastroenterology and hepatology, I have found three key elements to be most helpful: intentional mentorship, structured meetings, and leadership development.”

• Intentional mentorship: Prior to joining the lab, I met with Dr. Feld to discuss my research experience and my goals. She took the time to understand these within the context of my training timeline and tailored project opportunities that aligned with my interests and were both feasible and impactful for my next steps. This intentional approach not only fostered a productive research experience but also established a mentor-mentee relationship built on genuine care for my growth and development.
• Regular meetings: Frequent lab meetings promote accountability, teamwork, and shared problem-solving skills. The open exchange of ideas fosters collaboration and joint problem solving to elevate the quality of our research. They are also an opportunity to observe key decision-making points during the research process and have been a great way to learn more about solid methodology.
• Supervised leadership: I have had ample time to lead discussions and coordinate projects among the junior trainees. These monitored leadership experiences promote project management skills, mentorship, and team dynamic awareness while maintaining the safety net of senior guidance. This model helped me transition from a trainee supporting others’ research to a more independent role, contributing to multi-disciplinary projects while mentoring junior members.

Conclusion

In conclusion, many exciting opportunities and notable barriers exist to establishing a clinical research laboratory in the early career. Individual and institutional investment and support are vital to the success of junior physicians seeking a career in clinical research. While excellence in each of the areas outlined may evolve, some aspects will come easier than others and with time, persistence, and a bit of luck, the research world will be a better place because of your contributions!

Dr. Feld is assistant professor of gastroenterology and hepatology and physician executive of Diversity, Equity, Inclusion and Belonging for the department of medicine at the University of Massachusetts (UMass) Chan Medical School, Worcester. Ms. Nguyen is a medical student at UMass Chan Medical School. Dr. Cooper is a resident physician at UMass Chan Medical School. Dr. Rabinowitz is an attending physician in the Inflammatory Bowel Disease Center at Beth Israel Deaconess Medical Center, Boston, Mass. Dr. Uchida is codirector of the Multidisciplinary Eosinophilic Gastrointestinal Disease Clinic at the University of Utah School of Medicine, Salt Lake City.

Conducting clinical research as an early career gastroenterologist can take on many forms and has varying definitions of success. This article focuses on key factors to consider and should be supplemented with mentorship tailored to personal interests, goals, and institutional criteria for success. In this article, we will discuss selected high-yield topics that assist in early-career research. We will briefly discuss 1. Defining your niche, 2. Collaboration, 3. Visibility, 4. Time management, 5. Funding, 6. Receiving mentorship, and 7. Providing mentorship. We will conclude with discussing several authors’ experience in the research lab of the first author (FELD Lab – Fostering Equity in Liver and Digestive disease).

Defining Your Niche

Defining your niche is an essential component of an early career, as when academicians must transition from a trainee, who is supporting the research of an established mentor, to defining their own subspeciality area of investigation. Early-career academics should build on their prior work, but should also explore their own passions and skill set to define what will be unique about their research program and contributions to the field. Of course, positioning oneself at the intersection of two or more seemingly unrelated fields opens much opportunity for large impact but comes at a cost of identifying mentorship and justifying the niche to funders.

Collaboration

Fostering a collaborative environment is essential for early-career physician-researchers. One effective approach is to establish collaboration circles with other early career academics. Expanding research endeavors beyond a single institution to a multi-center framework enriches both scope and impact. This collaborative approach not only amplifies the depth of research but also facilitates peer mentorship and sponsorship. Participation in such networks can significantly enhance scholarly output and broaden professional reach during this critical phase of academic progression. Furthermore, prioritizing the promotion of colleagues within these networks is crucial. Proactive sponsorship opportunities, such as inviting peers to present at institutional seminars, strengthen both individual and collective academic visibility.

Collaboration is also essential to foster between trainees involved in early-career investigators’ work. An interconnected lab environment ensures that trainees remain informed about concurrent projects, thereby fostering a culture of shared knowledge and optimized productivity. Encouraging trainees to spearhead research aligned with their interests, under mentor guidance, nurtures independent inquiry and leadership. By establishing explicit roles, responsibilities, and authorship agreements at the outset of collaborative projects, early career mentors can avoid future conflicts and preserve a collaborative culture within the lab. This structured approach cultivates a supportive ecosystem, advancing both individual and collective research achievements.

 

Visibility

Establishing visibility and developing name recognition are crucial components of career advancement for early-career academic physicians. By clearly defining their areas of expertise, faculty can position themselves as leaders within their discipline. Active participation in professional societies, both at the local and national level, engagement with interest groups, and frequent contributions to educational events can be effective strategies for gaining recognition. Leveraging social media platforms can be helpful in enhancing visibility by facilitating connections and promoting research to a broader audience.

Moreover, research visibility plays a vital role in academic promotion. A strong publication record, reflected by an increasing h-index, demonstrates the impact and relevance of one’s research. Self-citation, when appropriate, can reinforce the continuity and progression of scholarly contributions. While publishing in high-impact journals is desirable, adaptability in resubmitting to other journals following rejections ensures that research remains visible and accessible. It also clearly establishes by whom the work was first done, before someone else investigates the line of inquiry. Through a combination of strategic engagement and publication efforts, early-career physicians can effectively build their professional reputation and advance their academic careers.

 

Time Management

Time management is essential for any research, and particularly in early career when efficiency in clinical care duties is still being gained. Securing protected time for research is essential to develop a niche, build connections (both institutionally and beyond their institutions), and demonstrate productivity that can be utilized to support future grant efforts.

Similarly, using protected time efficiently is required. Without organization and planning, research time can be spent with scattered meetings and responding to various tasks that do not directly support your research. It is helpful to be introspective about the time of the day you are most productive in your research efforts and blocking off that time to focus on research tasks and minimizing distractions. Blocking monthly time for larger scale thinking and planning is also important. Weekly lab and individual one-on-one meetings also support time management for trainees and lab members, to ensure efficiency and progress. Additionally, robust clinical support is essential to ensure that research time remains protected and patient care moves forward. When negotiating for positions, and in regular meetings thereafter, it is important to advocate for sufficient clinical staffing such that non-physician tasks can be appropriately delegated to another member of the care team. 

 

Funding

Securing adequate funding poses a significant challenge for all early-career physician-scientists, particularly because of the discrepancy between National Institutes of Health salary caps and the higher average salaries in academic gastroenterology. This financial gap can deter physicians from pursuing research-intensive careers altogether and can derail early investigators who do not obtain funding rapidly. To overcome this, early-career investigators may need to adopt flexible strategies, such as accepting a lower salary that aligns with grant funding limits or funneling incentive or bonus pay to research accounts. Alternatively, they can advocate for institutional support to bridge the salary gap, ensuring their research efforts remain financially viable.

Institutions committed to fostering research excellence may offer supplemental funding or bridge programs to retain talented physician-scientists, thereby mitigating the financial strain and encouraging long-term engagement in research. Regular meetings to review salary and support sources, including philanthropy, foundation grants, and other streams, should be undertaken with leadership to align the researcher’s timeline and available funding. If career development funding appears untenable, consideration of multi–principal investigator R01s or equivalent with senior established investigators can be a promising path. 

 

Receiving Mentorship

Effective mentorship for early-career physician-scientists should be approached through a team-based model that leverages both internal and external mentors. Internal mentors, familiar with the specific culture, expectations, and advancement pathways of the institution, can provide invaluable guidance on navigating institutional metrics for success, such as promotion criteria, grant acquisition, and clinical-research balance. External mentors, on the other hand, bring a broader perspective by offering innovative career development strategies and solutions derived from experiences at their home institutions. This multimodal mentorship model ensures a well-rounded approach to professional growth.

All national gastroenterology societies, including the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy, and American Association for the Study of Liver Disease, offer structured early-career mentorship programs designed to connect emerging researchers with experienced leaders in the field (see below). These programs typically require a formal application process and are highly regarded for their exceptional quality and impact. Participation in such initiatives can significantly enhance career development by expanding networks, fostering interdisciplinary collaboration, and providing tailored guidance that complements institutional support. Integrating both internal and external mentorship opportunities ensures a robust and dynamic foundation for long-term success in academic medicine.

• AGA Career Compass (https://gastro.org/fellows-and-early-career/mentoring/)
• ACG Early Career Leadership Program (https://gi.org/acg-institute/early-career-leadership-program/)
• AGA-AASLD Academic Skills Workshop (https://gastro.org/news/applications-now-being-accepted-for-the-2024-aga-aasld-academic-skills-workshop/)
• AASLD Women’s Initiative Committee Leadership Program (https://www.aasld.org/promoting-leadership-potential-women-hepatology)
• Scrubs n Heels Mentorship Matrix (https://scrubsandheels.com/matrix/)

Providing Mentorship

The trainee authors on this manuscript describe in this section what has been helpful for them as mentees in the FELD research lab.

Student doctor Nguyen describes her experience as a lab member and things she finds most helpful as a medical student in the lab:

• Upon joining the team, a one-to-one meeting to discuss trainee’s personal and professional goals, and availability, was crucial to building the mentor-mentee relationship. Establishing this meaningful mentorship early on clarified expectations on both sides, built trust, and increased motivation. As a trainee, it is essential for me to see how my work aligns with a long-term goal and to receive ample guidance throughout the process.
• One of the most impactful experiences has been joining informal lunch sessions where trainees discussed data collection protocols and exchanged insights. In doing so, Dr. Feld has cultivated a lab culture that encourages curiosity, constructive feedback, and collaborative learning.
• To increase productivity, our team of trainees created a useful group message thread where we coordinated more sessions to collaborate. This coordination formed stronger relationships between team members and fostered a sense of shared purpose.

Dr. Cooper, a third year internal medicine resident, describes her experience as both a research mentee and a mentor to the junior trainees: “As a resident pursuing a career in academic gastroenterology and hepatology, I have found three key elements to be most helpful: intentional mentorship, structured meetings, and leadership development.”

• Intentional mentorship: Prior to joining the lab, I met with Dr. Feld to discuss my research experience and my goals. She took the time to understand these within the context of my training timeline and tailored project opportunities that aligned with my interests and were both feasible and impactful for my next steps. This intentional approach not only fostered a productive research experience but also established a mentor-mentee relationship built on genuine care for my growth and development.
• Regular meetings: Frequent lab meetings promote accountability, teamwork, and shared problem-solving skills. The open exchange of ideas fosters collaboration and joint problem solving to elevate the quality of our research. They are also an opportunity to observe key decision-making points during the research process and have been a great way to learn more about solid methodology.
• Supervised leadership: I have had ample time to lead discussions and coordinate projects among the junior trainees. These monitored leadership experiences promote project management skills, mentorship, and team dynamic awareness while maintaining the safety net of senior guidance. This model helped me transition from a trainee supporting others’ research to a more independent role, contributing to multi-disciplinary projects while mentoring junior members.

Conclusion

In conclusion, many exciting opportunities and notable barriers exist to establishing a clinical research laboratory in the early career. Individual and institutional investment and support are vital to the success of junior physicians seeking a career in clinical research. While excellence in each of the areas outlined may evolve, some aspects will come easier than others and with time, persistence, and a bit of luck, the research world will be a better place because of your contributions!

Dr. Feld is assistant professor of gastroenterology and hepatology and physician executive of Diversity, Equity, Inclusion and Belonging for the department of medicine at the University of Massachusetts (UMass) Chan Medical School, Worcester. Ms. Nguyen is a medical student at UMass Chan Medical School. Dr. Cooper is a resident physician at UMass Chan Medical School. Dr. Rabinowitz is an attending physician in the Inflammatory Bowel Disease Center at Beth Israel Deaconess Medical Center, Boston, Mass. Dr. Uchida is codirector of the Multidisciplinary Eosinophilic Gastrointestinal Disease Clinic at the University of Utah School of Medicine, Salt Lake City.

Conducting clinical research as an early career gastroenterologist can take on many forms and has varying definitions of success. This article focuses on key factors to consider and should be supplemented with mentorship tailored to personal interests, goals, and institutional criteria for success. In this article, we will discuss selected high-yield topics that assist in early-career research. We will briefly discuss 1. Defining your niche, 2. Collaboration, 3. Visibility, 4. Time management, 5. Funding, 6. Receiving mentorship, and 7. Providing mentorship. We will conclude with discussing several authors’ experience in the research lab of the first author (FELD Lab – Fostering Equity in Liver and Digestive disease).

Defining Your Niche

Defining your niche is an essential component of an early career, as when academicians must transition from a trainee, who is supporting the research of an established mentor, to defining their own subspeciality area of investigation. Early-career academics should build on their prior work, but should also explore their own passions and skill set to define what will be unique about their research program and contributions to the field. Of course, positioning oneself at the intersection of two or more seemingly unrelated fields opens much opportunity for large impact but comes at a cost of identifying mentorship and justifying the niche to funders.

Collaboration

Fostering a collaborative environment is essential for early-career physician-researchers. One effective approach is to establish collaboration circles with other early career academics. Expanding research endeavors beyond a single institution to a multi-center framework enriches both scope and impact. This collaborative approach not only amplifies the depth of research but also facilitates peer mentorship and sponsorship. Participation in such networks can significantly enhance scholarly output and broaden professional reach during this critical phase of academic progression. Furthermore, prioritizing the promotion of colleagues within these networks is crucial. Proactive sponsorship opportunities, such as inviting peers to present at institutional seminars, strengthen both individual and collective academic visibility.

Collaboration is also essential to foster between trainees involved in early-career investigators’ work. An interconnected lab environment ensures that trainees remain informed about concurrent projects, thereby fostering a culture of shared knowledge and optimized productivity. Encouraging trainees to spearhead research aligned with their interests, under mentor guidance, nurtures independent inquiry and leadership. By establishing explicit roles, responsibilities, and authorship agreements at the outset of collaborative projects, early career mentors can avoid future conflicts and preserve a collaborative culture within the lab. This structured approach cultivates a supportive ecosystem, advancing both individual and collective research achievements.

 

Visibility

Establishing visibility and developing name recognition are crucial components of career advancement for early-career academic physicians. By clearly defining their areas of expertise, faculty can position themselves as leaders within their discipline. Active participation in professional societies, both at the local and national level, engagement with interest groups, and frequent contributions to educational events can be effective strategies for gaining recognition. Leveraging social media platforms can be helpful in enhancing visibility by facilitating connections and promoting research to a broader audience.

Moreover, research visibility plays a vital role in academic promotion. A strong publication record, reflected by an increasing h-index, demonstrates the impact and relevance of one’s research. Self-citation, when appropriate, can reinforce the continuity and progression of scholarly contributions. While publishing in high-impact journals is desirable, adaptability in resubmitting to other journals following rejections ensures that research remains visible and accessible. It also clearly establishes by whom the work was first done, before someone else investigates the line of inquiry. Through a combination of strategic engagement and publication efforts, early-career physicians can effectively build their professional reputation and advance their academic careers.

 

Time Management

Time management is essential for any research, and particularly in early career when efficiency in clinical care duties is still being gained. Securing protected time for research is essential to develop a niche, build connections (both institutionally and beyond their institutions), and demonstrate productivity that can be utilized to support future grant efforts.

Similarly, using protected time efficiently is required. Without organization and planning, research time can be spent with scattered meetings and responding to various tasks that do not directly support your research. It is helpful to be introspective about the time of the day you are most productive in your research efforts and blocking off that time to focus on research tasks and minimizing distractions. Blocking monthly time for larger scale thinking and planning is also important. Weekly lab and individual one-on-one meetings also support time management for trainees and lab members, to ensure efficiency and progress. Additionally, robust clinical support is essential to ensure that research time remains protected and patient care moves forward. When negotiating for positions, and in regular meetings thereafter, it is important to advocate for sufficient clinical staffing such that non-physician tasks can be appropriately delegated to another member of the care team. 

 

Funding

Securing adequate funding poses a significant challenge for all early-career physician-scientists, particularly because of the discrepancy between National Institutes of Health salary caps and the higher average salaries in academic gastroenterology. This financial gap can deter physicians from pursuing research-intensive careers altogether and can derail early investigators who do not obtain funding rapidly. To overcome this, early-career investigators may need to adopt flexible strategies, such as accepting a lower salary that aligns with grant funding limits or funneling incentive or bonus pay to research accounts. Alternatively, they can advocate for institutional support to bridge the salary gap, ensuring their research efforts remain financially viable.

Institutions committed to fostering research excellence may offer supplemental funding or bridge programs to retain talented physician-scientists, thereby mitigating the financial strain and encouraging long-term engagement in research. Regular meetings to review salary and support sources, including philanthropy, foundation grants, and other streams, should be undertaken with leadership to align the researcher’s timeline and available funding. If career development funding appears untenable, consideration of multi–principal investigator R01s or equivalent with senior established investigators can be a promising path. 

 

Receiving Mentorship

Effective mentorship for early-career physician-scientists should be approached through a team-based model that leverages both internal and external mentors. Internal mentors, familiar with the specific culture, expectations, and advancement pathways of the institution, can provide invaluable guidance on navigating institutional metrics for success, such as promotion criteria, grant acquisition, and clinical-research balance. External mentors, on the other hand, bring a broader perspective by offering innovative career development strategies and solutions derived from experiences at their home institutions. This multimodal mentorship model ensures a well-rounded approach to professional growth.

All national gastroenterology societies, including the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy, and American Association for the Study of Liver Disease, offer structured early-career mentorship programs designed to connect emerging researchers with experienced leaders in the field (see below). These programs typically require a formal application process and are highly regarded for their exceptional quality and impact. Participation in such initiatives can significantly enhance career development by expanding networks, fostering interdisciplinary collaboration, and providing tailored guidance that complements institutional support. Integrating both internal and external mentorship opportunities ensures a robust and dynamic foundation for long-term success in academic medicine.

• AGA Career Compass (https://gastro.org/fellows-and-early-career/mentoring/)
• ACG Early Career Leadership Program (https://gi.org/acg-institute/early-career-leadership-program/)
• AGA-AASLD Academic Skills Workshop (https://gastro.org/news/applications-now-being-accepted-for-the-2024-aga-aasld-academic-skills-workshop/)
• AASLD Women’s Initiative Committee Leadership Program (https://www.aasld.org/promoting-leadership-potential-women-hepatology)
• Scrubs n Heels Mentorship Matrix (https://scrubsandheels.com/matrix/)

Providing Mentorship

The trainee authors on this manuscript describe in this section what has been helpful for them as mentees in the FELD research lab.

Student doctor Nguyen describes her experience as a lab member and things she finds most helpful as a medical student in the lab:

• Upon joining the team, a one-to-one meeting to discuss trainee’s personal and professional goals, and availability, was crucial to building the mentor-mentee relationship. Establishing this meaningful mentorship early on clarified expectations on both sides, built trust, and increased motivation. As a trainee, it is essential for me to see how my work aligns with a long-term goal and to receive ample guidance throughout the process.
• One of the most impactful experiences has been joining informal lunch sessions where trainees discussed data collection protocols and exchanged insights. In doing so, Dr. Feld has cultivated a lab culture that encourages curiosity, constructive feedback, and collaborative learning.
• To increase productivity, our team of trainees created a useful group message thread where we coordinated more sessions to collaborate. This coordination formed stronger relationships between team members and fostered a sense of shared purpose.

Dr. Cooper, a third year internal medicine resident, describes her experience as both a research mentee and a mentor to the junior trainees: “As a resident pursuing a career in academic gastroenterology and hepatology, I have found three key elements to be most helpful: intentional mentorship, structured meetings, and leadership development.”

• Intentional mentorship: Prior to joining the lab, I met with Dr. Feld to discuss my research experience and my goals. She took the time to understand these within the context of my training timeline and tailored project opportunities that aligned with my interests and were both feasible and impactful for my next steps. This intentional approach not only fostered a productive research experience but also established a mentor-mentee relationship built on genuine care for my growth and development.
• Regular meetings: Frequent lab meetings promote accountability, teamwork, and shared problem-solving skills. The open exchange of ideas fosters collaboration and joint problem solving to elevate the quality of our research. They are also an opportunity to observe key decision-making points during the research process and have been a great way to learn more about solid methodology.
• Supervised leadership: I have had ample time to lead discussions and coordinate projects among the junior trainees. These monitored leadership experiences promote project management skills, mentorship, and team dynamic awareness while maintaining the safety net of senior guidance. This model helped me transition from a trainee supporting others’ research to a more independent role, contributing to multi-disciplinary projects while mentoring junior members.

Conclusion

In conclusion, many exciting opportunities and notable barriers exist to establishing a clinical research laboratory in the early career. Individual and institutional investment and support are vital to the success of junior physicians seeking a career in clinical research. While excellence in each of the areas outlined may evolve, some aspects will come easier than others and with time, persistence, and a bit of luck, the research world will be a better place because of your contributions!

Dr. Feld is assistant professor of gastroenterology and hepatology and physician executive of Diversity, Equity, Inclusion and Belonging for the department of medicine at the University of Massachusetts (UMass) Chan Medical School, Worcester. Ms. Nguyen is a medical student at UMass Chan Medical School. Dr. Cooper is a resident physician at UMass Chan Medical School. Dr. Rabinowitz is an attending physician in the Inflammatory Bowel Disease Center at Beth Israel Deaconess Medical Center, Boston, Mass. Dr. Uchida is codirector of the Multidisciplinary Eosinophilic Gastrointestinal Disease Clinic at the University of Utah School of Medicine, Salt Lake City.